Duodenal Adenomas in Patients With Multiple Colorectal Adenomas Without Germline APC or MUTYH Mutations.
Kallenberg Frank G J,Latchford Andrew,Lips Nikki C,Aalfs Cora M,Bastiaansen Barbara A J,Clark Susan K,Dekker Evelien
Diseases of the colon and rectum
BACKGROUND:Patients with genetic adenomatous polyposis syndromes have an increased risk for duodenal cancer, and clear surveillance recommendations exist for this group. However, limited data are available on the duodenal phenotype of patients with multiple colorectal adenomas (10-99) without a germline APC or MUTYH mutation. OBJECTIVE:We aimed to assess the frequency, extent, and progression of duodenal adenomas in patients with multiple colorectal adenomas without a germline APC or MUTYH mutation. DESIGN:This was an historical cohort study. SETTINGS:This study was undertaken at 2 polyposis registries: the Academic Medical Center in the Netherlands, and St. Mark's Hospital in the United Kingdom. PATIENTS:We collected data on all patients with 10 to 99 colorectal adenomas and absent APC and MUTYH mutations, who underwent ≥1 esophagogastroduodenoscopy. MAIN OUTCOME MEASURES:The frequency, extent, and progression of duodenal adenomas were measured. Demographic and endoscopic data were collected, described, and compared between patients with and without duodenal adenomas. RESULTS:Eighty-three patients were identified, of which 8 (9.6%) had duodenal adenomas, detected at a median of 58 years (range, 45-75 y). Duodenal adenomas were detected in 6 of 8 patients at first esophagogastroduodenoscopy. At diagnosis, all 8 patients had Spigelman stage I or II disease. Two of 5 patients with duodenal adenomas who underwent follow-up esophagogastroduodenoscopies increased to stage III disease. The other 3 remained stable. No one developed duodenal cancer. No differences in demographic and endoscopic data were found between patients with and without duodenal adenomas. LIMITATIONS:This study was limited by its retrospective design, selection bias, and small sample size. CONCLUSIONS:Duodenal adenomas are found in a minority of patients with multiple colorectal adenomas without a germline APC or MUTYH mutation, at an average age of 58 years, and, at diagnosis, disease severity is mild. These results are a first step in unraveling the duodenal phenotype of these patients, which is needed to provide appropriate upper GI screening and surveillance recommendations. See Video Abstract at http://links.lww.com/DCR/A357.
Meta-analysis of postoperative adjuvant therapy for small bowel adenocarcinoma.
Ye Xiaojian,Zhang Guoqiang,Chen Haibin,Li Yong
OBJECTIVE:The role of adjuvant therapy in small bowel adenocarcinoma (SBA), a rare malignancy with a poor prognosis, is controversial. The purpose of this article is to investigate the impact of adjuvant therapy on the survival of patients with SBA in a meta-analysis. METHODS:We performed a comprehensive search of PubMed, EMBASE and the Cochrane Library database between 2010 and 2017. Hazard ratios (HR) with 95% confidence intervals (95%CI) were used to assess the effect of adjuvant chemotherapy and/or radiation treatment after curative surgery in patients with SBA. Moreover, impact of age, sex, stage, differentiation, lymph node involvement, and margin status was also evaluated. RESULTS:We included 15 studies to evaluate the effect of adjuvant therapy on the survival of patients with SBA. The pooled HR of overall survival (OS) involving 5986 patients showed that adjuvant therapy did not have a statistically significant effect on the survival of patients with SBA (pooled HR = 0.89, 95% CI = 0.73-1.09, p = 0.25). Further, 607 patients with duodenal adenocarcinoma (DA) had similar results (pooled HR = 0.96, 95% CI = 0.75-1.23, p = 0.77). Similarly, adjuvant treatment vs. non-adjuvant treatment in terms of disease-free survival (DFS) or relapse-free survival (RFS) showed the same results (pooled HR = 0.89, 95% CI = 0.64-1.23, p = 0.48). However, we found that adjuvant therapy resulted in favorable postoperative survival in Europe according to the subgroup analysis (pooled HR = 0.63, 95% CI = 0.5-0.8, p = 0.0002). In addition, the pooled HR shows that stage, differentiation, lymph node involvement, and margin status were related to the OS of patients with SBA. CONCLUSION:Patients with SBA who received adjuvant therapy after surgery did not receive a significant survival benefit. Adjuvant therapy may be more useful in advanced cancer or metastatic patients.
DNA mismatch repair deficiency but not ARID1A loss is associated with prognosis in small intestinal adenocarcinoma.
González Iván,Goyal Bella,Xia Michelle D,Pai Reetesh K,Ma Changqing
Small intestinal adenocarcinoma is an uncommon neoplasm with poor prognosis. It is clinically approached similarly to colorectal carcinoma (CRC). The prognostic value of DNA mismatch repair protein deficiency (dMMR) in CRC is well established, but its role in small intestinal adenocarcinoma remains inconclusive. Recently, loss of expression of ARID1A, a tumor suppressor gene product, by immunohistochemistry (IHC) was linked to dMMR and poor outcome in small intestinal adenocarcinoma, suggesting that it may be an emerging prognostic biomarker. We hypothesized that dMMR and/or ARID1A loss may be associated with clinical outcome in small intestinal adenocarcinoma. We examined dMMR and ARID1A loss by IHC in 120 surgically resected, nonampullary small intestinal adenocarcinomas collected from 2 tertiary centers. ARID1A loss was detected in 6 (7%) of 92 ARID1A-stained adenocarcinomas, whereas 21 (18%) of 120 adenocarcinomas demonstrated dMMR. ARID1A loss was not associated with survival or dMMR. dMMR adenocarcinomas had no distant metastasis, whereas 22 (22%) of 99 MMR-proficient adenocarcinomas had (P = .01). dMMR was an independent, positive predictor of disease-free survival (P = .035, hazard ratio: 0.2). Compared with dMMR CRC, dMMR small intestinal adenocarcinomas more frequently demonstrated loss of MSH2 and MSH6 and less often showed loss of MLH1 and PMS2 (both P < .001). In summary, ARID1A loss by IHC is uncommon in small intestinal adenocarcinomas. dMMR small intestinal adenocarcinomas are nonmetastatic tumors, frequently demonstrate loss of MSH2 and MSH6, and have superior disease-free survival. Our results suggest that all small intestinal adenocarcinomas should be tested for MMR protein deficiency.
Small Bowel Adenocarcinoma: Is There a Difference in Survival for Crohn's Versus Sporadic Cases?
Fields Adam C,Hu Frances Y,Lu Pamela,Irani Jennifer,Bleday Ronald,Goldberg Joel E,Melnitchouk Nelya
Journal of Crohn's & colitis
BACKGROUND AND AIMS:It is well known that Crohn's disease is a risk factor for the development of small bowel adenocarcinoma. However, the association between Crohn's disease-associated small bowel adenocarcinoma and survival is less understood. The goal of this study was to determine the impact of Crohn's disease on survival in small bowel adenocarcinoma. METHODS:Patients with small bowel adenocarcinoma, either associated with Crohn's disease or diagnosed sporadic, were identified in the National Cancer Database from 2004-2016. The primary outcome was overall survival. RESULTS:Of 2668 patients, 493 had Crohn's disease-associated small bowel adenocarcinoma and 2175 had sporadic small bowel adenocarcinoma. Crohn's disease patients were more likely to present at a younger age [62 vs 65, p < 0.001], have tumours located in the ileum [62.7% vs 25.0%, p < 0.001], and have poorly differentiated tumours [47.0% vs 31.7%, p < 0.001] compared with sporadic small bowel adenocarcinoma. Factors associated with significantly decreased survival included older age (hazard ratio [HR]: 1.02, 95% confidence interval [CI]: 1.02-1.03, p < 0.00)], higher Charlson score [HR: 1.39, 95% CI: 1.13-1.72, p = 0.002], higher tumour grade [HR: 1.09, 95% CI: 1.04-1.14, p < 0.001], positive surgical margins [HR: 1.60, 95% CI: 1.39-1.84, p < 0.001], and higher stage of disease [HR: 1.90, 3.75, 8.13, 95% CI: 1.37-2.64, 2.68-5.24, 5.77-11.47, for II, III, IV, respectively, compared with I, all p < 0.001]. Receipt of chemotherapy was associated with significantly improved survival [HR: 0.61, 95% CI: 0.53-0.70, p < 0.001]. Crohn's disease [HR: 1.01, 95% CI: 0.99-1.02, p = 0.39], was not significantly associated with survival. CONCLUSION:Compared with sporadic patients, Crohn's disease patients have similar overall survival, and Crohn's disease is not an independent risk factor for mortality.
Clinical Outcomes of Small Bowel Adenocarcinoma.
Akce Mehmet,Jiang Renjian,Zakka Katerina,Wu Christina,Alese Olatunji B,Shaib Walid L,Behera Madhusmita,El-Rayes Bassel F
Clinical colorectal cancer
BACKGROUND:Small bowel adenocarcinomas (SBAs) are rare tumors. Management of SBA is extrapolated from colorectal cancer treatments. Recent evidence suggests that the biology and molecular features of SBA differ from colorectal cancer. The aim of this study was to evaluate the management and outcome of SBA patients. PATIENTS AND METHODS: The National Cancer Data Base (NCDB) was queried for patients with SBA between 2004 and 2013 using ICD-O-3 histology code 8140/3 and topography codes C17.0, C17.1, C17.2, C17.8, and C17.9. Univariate and multivariate survival analyses were conducted to analyze the association between SBA location and overall survival (OS) stratified by stage. Treatment outcomes of surgery, radiation, and systemic therapy were compared. RESULTS:A total of 7954 SBA patients were identified; duodenum (D) 4607 (57.9%), jejunum (J) 1241 (15.6%), ileum (I) 857 (10.8%), and unspecified 1249 (15.7%). A total of 53.6% patients were male, and 76.6% white. Median age was 66 years. D mostly presented as stage IV disease (37.6%), J as stage II (34.5%) and IV disease (33.8%), and I as stage II (32.2%) and III (30.3%) disease (P < .001). Grade distribution was similar among D, J, and I; the majority were moderately differentiated (40.8%-55.0%), followed by poorly differentiated (30.9%-35.8%) and well differentiated (6.0%-12.4%) (P < .001). D underwent surgery (50.2%) less often than J (90.8%) and I (94.5%) (P < .001). Adjuvant radiation was provided in 8.5% of D, 2.6% of J, and 2.1% of I (P < .001). Adjuvant chemotherapy was provided in 21.9% of D, 50.2% of J, and 42.0% of I (P < .001). The rate of adjuvant chemotherapy was the highest in patients with stage III SBA, and was as follows: D (43.4%), J (65.4%), and I (63.6%) (P < .001). In univariate and multivariate analyses of all patients, adjuvant chemotherapy was associated with improved OS in stage II-III SBA patients. J had the best 5-year OS rate (42.0%; 95% confidence interval, 38.8-45.1, P < .001), and D had the worst (23.0%; 95% confidence interval, 21.6-24.2, P < .001). In multivariate analysis stratified by stage, chemotherapy was associated with improved OS in patients with stage II-IV SBA. CONCLUSION:Most SBA patients present with stage IV disease. D underwent surgery less often than J and I. Stage II and III D received adjuvant chemotherapy less often compared to stage II and III J and I. Adjuvant chemotherapy was associated with improved OS in patients with stage II-III disease. J had the best 5-year OS rate, and D had the worst.
Heat Shock Protein 90 Alpha, Lass B Member 1: a Key Regulative Gene of Monitoring Duodenal Tumor for Obesity Induced by High-Fat Diet.
Zheng Li,Bai Jie,Zhang Jin-Ling,Meng Xia,Hao Yan-Na
BACKGROUND:Effective methods of preventing and treating duodenal carcinoma, especially cancer induced by obesity (resulting from a high-fat diet) remains a longstanding challenge in medicine. METHODS:With regard to the objective, key genes were explored in the evolutional process in a group of normal, obese (high-fat diet), and duodenal tumor mice. Here, 23 genes were selected by the bioinformatics method. In order to correct the result, verification experiments were performed twice through online analysis. RESULTS:Finally, heat shock protein 90 alpha class B member 1, enriched in inflammation, tumors and steroid hormones-related pathways, was the statistically different gene in the evolutional process. CONCLUSIONS:This work provided a new perspective to understand the evolutional process in a group of normal, obese (high-fat diet), and duodenal tumor mice and a potential target gene for monitoring duodenal tumors for normal individuals especially for obesity induced by high-fat diet.
Prognostic Factors and Survival Time in Patients with Small Bowel Tumors: A Retrospective Observational Study.
Taghipour Zahir Shokouh,Heidarymeybodi Zahra,AleSaeidi Sogol
International journal of surgical oncology
This study examines survival time in patients with small bowel tumors and determines its contributing factors. In this retrospective analytical study, the medical records of 106 patients with small bowel cancer (from 2006 to 2011) were investigated. The patients' data were extracted, including age, gender, clinical presentation, location of tumor, histological type, grade of tumor, site of metastasis, and type of treatment. The Kaplan-Meier test was used to estimate the overall survival time and the Log-rank test to compare the survival curves. The Cox regression was also used to evaluate the effect of the confounding variables on survival time. This study was conducted on 106 patients with a median age of 60 years (Min: 7, Max: 87). The tumor types included adenocarcinoma (n=78, 73.6%), MALToma (n=22, 20.8%), neuroendocrine tumors (n=4, 3.8%), and sarcoma (n=2. 1.8%). Grade 3 adenocarcinomas had a significantly lower survival time (HR: 1.48, 95% CI: 0.46-2.86; P=.001). Combined therapy (chemotherapy and surgery) vs. single-therapy (only surgery) had no significant effects on the survival of the patients with MALToma (5 vs. 3 months, 95% CI: 1.89-5.26; P=.06). There were no significant differences between the survival time in adenocarcinoma and MALToma (12 vs. 20 months, 95% CI: 6.24-24.76; P=.49). Tumor grade was the only independent prognostic factor that affected survival in adenocarcinoma. The patients diagnosed with MALToma in the study also had a poor prognosis, and the type of treatment had no significant effect on their survival.
Small Bowel Adenocarcinoma Frequently Exhibits Lynch Syndrome-associated Mismatch Repair Protein Deficiency But Does Not Harbor Sporadic MLH1 Deficiency.
Xia Michelle,Singhi Aatur D,Dudley Beth,Brand Randall,Nikiforova Marina,Pai Reetesh K
Applied immunohistochemistry & molecular morphology : AIMM
Universal screening for Lynch syndrome has been advocated for colorectal carcinoma but its utility in small bowel adenocarcinoma has not been reported. We analyzed a consecutive series of 71 small bowel adenocarcinomas identified over an 8-year period for DNA mismatch repair (MMR) protein expression to (1) compare the clinicopathologic features of small bowel adenocarcinoma stratified into MMR-deficient (MMRD) and MMR-proficient (MMRP) groups and (2) examine the patterns of MMR protein expression in small bowel adenocarcinoma compared with colorectal carcinoma. Six of 71 (8.5%) small bowel adenocarcinomas and 149 of 1291 (11.5%) colorectal carcinomas demonstrated MMRD. The 6 MMRD small bowel adenocarcinomas had the following expression pattern: 3 with concurrent loss of MSH2 and MSH6, 1 with isolated loss of MSH6, and 2 with concurrent loss of MLH1 and PMS2 in patients with a family history suggestive of genetic cancer susceptibility. Histopathology suggestive of MMR protein deficiency as proposed by the revised Bethesda guidelines was commonly seen in both MMRP (63%) and MMRD (67%) small bowel adenocarcinomas (P>0.05). MMRD small bowel adenocarcinoma more frequently demonstrated abnormalities of MSH2 and/or MSH6 (4/6, 67%) compared with MMRD colorectal carcinoma (23/149, 15%) (P=0.01). None of the MMRD small bowel adenocarcinomas harbored the BRAF V600E mutation, whereas 60% of MMRD colorectal carcinomas were positive for BRAF V600E with concurrent loss of MLH1 and PMS2 expression. Small bowel adenocarcinoma more frequently harbored Lynch syndrome-associated MMRD compared with colorectal carcinoma, providing support for screening of small bowel adenocarcinoma to identify patients at risk for Lynch syndrome. In contrast to colorectal carcinoma, sporadic MLH1 deficiency is not seen in small bowel adenocarcinoma. Clinicopathologic and histologic features do not distinguish between MMRP and MMRD small bowel adenocarcinoma indicating that universal screening in small bowel adenocarcinoma is necessary to detect patients at risk for Lynch syndrome.
Microsatellite instability in colorectal cancer: from molecular oncogenic mechanisms to clinical implications.
Zaanan Aziz,Meunier Katy,Sangar Fatiha,Fléjou Jean-François,Praz Françoise
Cellular oncology (Dordrecht)
BACKGROUND:Microsatellite instability (MSI) constitutes an important oncogenic molecular pathway in colorectal cancer (CRC), representing approximately 15% of all colorectal malignant tumours. In roughly one third of the cases, the underlying DNA mismatch repair (MMR) defect is inherited through the transmission of a mutation in one of the genes involved in MMR, predominantly MSH2 and MLH1, or less frequently, MSH6 or PMS2. In the overwhelming number of sporadic cases, MSI results from epigenetic MLH1 silencing through hypermethylation of its promoter. MMR deficiency promotes colorectal oncogenesis through the accumulation of numerous mutations in crucial target genes harbouring mononucleotide repeats, notably in those involved in the control of cell proliferation and differentiation, as well as DNA damage signalling and repair. DESIGN:In this review, we describe the molecular aspects of the MMR system and the biological consequences of its defect on the oncogenic process, and we discuss the various experimental systems used to evaluate the efficacy of cytotoxic drugs on MSI colorectal cells lines. There is increasing evidence showing that MSI CRCs differ from all CRCs in terms of prognosis and response to the treatment. We report the clinical studies that have evaluated the prognostic and predictive value of MSI status on clinical outcome in patients treated with various chemotherapy regimens used in the adjuvant setting or for advanced CRCs. CONCLUSION:In view of this, the opportunity of a systematic MSI phenotyping in the clinical management of patients with CRC is further discussed.
Immunophenotype and molecular characterisation of adenocarcinoma of the small intestine.
Overman M J,Pozadzides J,Kopetz S,Wen S,Abbruzzese J L,Wolff R A,Wang H
British journal of cancer
BACKGROUND:Despite having a dramatically larger surface area than the large intestine, the small intestine is an infrequent site for the development of adenocarcinoma. To better understand the molecular abnormalities in small bowel adenocarcinoma (SBA), we characterised a number of candidate oncogenic pathways and the immunophenotype of this rare cancer. METHODS:Tissue microarrays were constructed from tumour samples from 54 patients with all stages of the disease. Immunohistochemistry and microsatellite instability (MSI) testing were conducted. RESULTS:The profile of cytokeratin 20 and 7 coexpression was variable, but expression of caudal type homeobox transcription factor 2 (CDX2) was present in 70% of cases. In this young population (median age 54 years), loss of mismatch repair (MMR) proteins occurred in 35% of patients, with confirmed MSI in 100% of tested cases. Expression of vascular endothelial growth factor-A (VEGF-A) and epidermal growth factor receptor (EGFR) was common, occurring in 96 and 71% of patients, respectively. Only one case showed HER2 expression and none showed loss of phosphatase and tensin homologue mutated on chromosome 10 (PTEN). CONCLUSIONS:These results suggest that alterations in DNA MMR pathways are common in SBAs, similar to what is observed in large bowel adenocarcinomas. Furthermore, the high percentage of tumours expressing both EGFR and VEGF suggests that patients with this rare cancer may benefit from therapeutic strategies targeting EGFR and VEGF receptor (VEGFR).
Microsatellite instability and expression of MLH1 and MSH2 in carcinomas of the small intestine.
Planck Maria,Ericson Kajsa,Piotrowska Zofia,Halvarsson Britta,Rambech Eva,Nilbert Mef
BACKGROUND:Carcinomas of the small intestine are rare, but the risk is greatly increased in patients with hereditary nonpolyposis colorectal cancer (HNPCC) due to an inherited mismatch repair (MMR) gene mutation, most commonly affecting the genes MLH1 or MSH2. Defective MMR is characterized by microsatellite instability (MSI) and loss of MMR protein expression in the tumor tissue. However, a subset of several sporadic tumor types, including about 15% of colon cancers, also evolve through defective MMR. METHODS:The authors have assessed the frequency of MSI and analyzed the immunohistochemical expression of MLH1 and MSH2 in a population-based series of 89 adenocarcinomas of the small intestine. To study the contribution of MSI and defective MMR protein expression in young patients, 43 cancers of the small intestine from patients below age 60 years (including 24 tumors from the population-based series and an additional 19 tumors from young individuals) were also analyzed. RESULTS:MSI was detected in 16/89 tumors (18%) in the population-based series, and immunohistochemistry revealed loss of expression for MLH1 in 7/16 MSI tumors and in 2/73 MSS tumors, whereas all tumors showed normal expression for MSH2. Among the young patients, the authors identified MSI in 10/43 tumors (23%), and 6 of these 10 MSI tumors showed immunohistochemical loss of MMR protein expression, which affected MLH1 in 3 cases and MSH2 in 3 cases. CONCLUSIONS:The frequency of MSI (18%) in adenocarcinomas of the small intestine equals that of colon cancer. However, silencing of MLH1 seems to explain the MSI status in only about half of the MSI tumors. Among patients with cancer of the small intestine before age 60 years, MSI is found in 23% of the cases, with MLH1 and MSH2 being affected at equal frequencies, indicating that HNPCC may underly a subset of such cases.
Comprehensive molecular pathology analysis of small bowel adenocarcinoma reveals novel targets with potential for clinical utility.
Alvi Muhammad A,McArt Darragh G,Kelly Paul,Fuchs Marc-Aurel,Alderdice Matthew,McCabe Clare M,Bingham Victoria,McGready Claire,Tripathi Shailesh,Emmert-Streib Frank,Loughrey Maurice B,McQuaid Stephen,Maxwell Perry,Hamilton Peter W,Turkington Richard,James Jacqueline A,Wilson Richard H,Salto-Tellez Manuel
Small bowel accounts for only 0.5% of cancer cases in the US but incidence rates have been rising at 2.4% per year over the past decade. One-third of these are adenocarcinomas but little is known about their molecular pathology and no molecular markers are available for clinical use. Using a retrospective 28 patient matched normal-tumor cohort, next-generation sequencing, gene expression arrays and CpG methylation arrays were used for molecular profiling. Next-generation sequencing identified novel mutations in IDH1, CDH1, KIT, FGFR2, FLT3, NPM1, PTEN, MET, AKT1, RET, NOTCH1 and ERBB4. Array data revealed 17% of CpGs and 5% of RNA transcripts assayed to be differentially methylated and expressed respectively (p < 0.01). Merging gene expression and DNA methylation data revealed CHN2 as consistently hypermethylated and downregulated in this disease (Spearman -0.71, p < 0.001). Mutations in TP53 which were found in more than half of the cohort (15/28) and Kazald1 hypomethylation were both were indicative of poor survival (p = 0.03, HR = 3.2 and p = 0.01, HR = 4.9 respectively). By integrating high-throughput mutational, gene expression and DNA methylation data, this study reveals for the first time the distinct molecular profile of small bowel adenocarcinoma and highlights potential clinically exploitable markers.
Methylation of MGMT Is Associated with Poor Prognosis in Patients with Stage III Duodenal Adenocarcinoma.
Fu Tao,Sharmab Anup,Xie Fei,Liu Yanliang,Li Kai,Wan Weiwei,Baylin Stephen B,Wolfgang Christopher L,Ahuja Nita
BACKGROUND:O6-methylguanine-DNA methyltransferase (MGMT) methylation status has not been extensively investigated in duodenal adenocarcinoma (DA). The aim of this study was to evaluate the MGMT methylation status and examine its possible prognostic value in patients with stage III DA. METHODS:Demographics, tumor characteristics and survival were available for 64 patients with stage III DA. MGMT methylation was detected by using MethyLight. A Cox proportional hazard model was built to predict survival, adjusted for clinicopathological characteristics and tumor molecular features, including the CpG island methylator phenotype (CIMP), microsatellite instability (MSI), and KRAS mutations. RESULTS:MGMT methylation was detected in 17 of 64 (26.6%) patients, and was not correlated with sex, age, tumor differentiation, CIMP, MSI, or KRAS mutations. MGMT methylation was the only one factor associated with both overall survival (OS) and disease-free survival (DFS) on both univariate and multivariate analyses. In patients treated with surgery alone, MGMT-methylated group had worse OS and DFS when compared with MGMT-unmethylated group. However, in patients treated with chemotherapy/radiotherapy, outcomes became comparable between the two groups. CONCLUSIONS:Our results demonstrate MGMT methylation is a reliable and independent prognostic factor in DAs. Methylation of MGMT is associated with poor prognosis in patients with stage III DAs.
Overexpression of p53 protein and point mutation of K-ras genes in primary carcinoma of the small intestine.
Nishiyama Ken-ichi,Yao Takashi,Yonemasu Hirotoshi,Yamaguchi Koji,Tanaka Masao,Tsuneyoshi Masazumi
Primary carcinoma of the small intestine is rare and represent about 0.5% of all gastrointestinal malignancies. The aim of this study was to examine the biological characteristics of primary carcinoma of the small intestine by immunohistochemical and nested polymerase chain reaction methods. Thirty-five primary carcinomas (12 in the duodenum and 23 in the jejunum or ileum) from 35 patients were studied clinicopathologically and examined for overexpression of p53 protein. In 22 of these 35 cases, point mutation at codon 12 of the K-ras gene was detected by the nested polymerase chain reaction and restriction fragment length polymorphism method. All the duodenal carcinomas were well-differentiated type and the rate of these carcinomas was significantly higher than that of jejunal or ileal carcinomas (100% vs. 65%). Fourteen cases showed overexpression of p53 (40%), and p53 tended to be expressed more frequently in poorly-differentiated type (71%) compared to well-differentiated type (30%). Only 2 out of 22 carcinoma cases showed K-ras gene mutation, and both were duodenal carcinomas. These findings suggest that p53 plays a major role in the progression of carcinoma of the small intestine, whereas the role of K-ras mutation is much less significant.
Genetics and epigenetics of small bowel adenocarcinoma: the interactions of CIN, MSI, and CIMP.
Warth Arne,Kloor Matthias,Schirmacher Peter,Bläker Hendrik
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc
Characterization of tumor genetics and epigenetics allows to stratify a tumor entity according to molecular pathways and may shed light on the interactions of different types of DNA alterations during tumorigenesis. Small intestinal adenocarcinoma is rare, and to date the interrelation of genomic instability and epigenetics has not been investigated in this tumor type. We therefore analyzed 37 primary small bowel carcinomas with known microsatellite instability and KRAS status for chromosomal instability using comparative genomic hybridization, for the presence of aberrant methylation (CpG island methylation phenotype) by methylation-specific polymerase chain reaction, and for BRAF mutations. Chromosomal instability was detected in 22 of 37 (59%) tumors (3 of 9 microsatellite instable, and 19 of 28 microsatellite stable carcinomas). Nine carcinomas (24%) were microsatellite and chromosomally stable. High-level DNA methylation was found in 16% of chromosomal instable tumors and in 44% of both microsatellite instable and microsatellite and chromosomally stable carcinomas. KRAS was mutated in 55, 0, and 10% of chromosomal instable, microsatellite instable, and microsatellite and chromosomally stable tumors, respectively whereas the frequencies of BRAF mutations were 6% for chromosomal instable and 22% for both microsatellite instable and microsatellite and chromosomally stable carcinomas. In conclusion, in this study we show that chromosomal instable carcinomas of the small intestine are distinguished from microsatellite instable and microsatellite and chromosomally stable tumors by a high frequency of KRAS mutations, low frequencies of CpG island methylation phenotype, and BRAF mutations. In microsatellite instable and microsatellite and chromosomally stable cancers, CpG island methylation phenotype and BRAF/KRAS mutations are similarly distributed, indicating common mechanisms of tumor initiation or progression in their molecular pathogenesis.
CpG island methylator phenotype-positive tumors in the absence of MLH1 methylation constitute a distinct subset of duodenal adenocarcinomas and are associated with poor prognosis.
Fu Tao,Pappou Emmanouil P,Guzzetta Angela A,Jeschke Jana,Kwak Ruby,Dave Pujan,Hooker Craig M,Morgan Richard,Baylin Stephen B,Iacobuzio-Donahue Christine A,Wolfgang Christopher L,Ahuja Nita
Clinical cancer research : an official journal of the American Association for Cancer Research
PURPOSE:Little information is available on genetic and epigenetic changes in duodenal adenocarcinomas. The purpose was to identify possible subsets of duodenal adenocarcinomas based on microsatellite instability (MSI), DNA methylation, mutations in the KRAS and BRAF genes, clinicopathologic features, and prognosis. EXPERIMENTAL DESIGN:Demographics, tumor characteristics, and survival were available for 99 duodenal adenocarcinoma patients. Testing for KRAS and BRAF mutations, MSI, MLH1 methylation, and CpG island methylator phenotype (CIMP) status was conducted. A Cox proportional hazard model was built to predict survival. RESULTS:CIMP(+) was detected in 27 of 99 (27.3%) duodenal adenocarcinomas and was associated with MSI (P = 0.011) and MLH1 methylation (P < 0.001), but not with KRAS mutations (P = 0.114), as compared with CIMP(-) tumors. No BRAF V600E mutation was detected. Among the CIMP(+) tumors, 15 (55.6%) were CIMP(+)/MLH1-unmethylated (MLH1-U). Kaplan-Meier analysis showed that tumors classified by CIMP, CIMP/MLH1 methylation status, or CIMP/MSI status could predict overall survival (OS; P = 0.047, 0.002, and 0.002, respectively), whereas CIMP/MLH1 methylation status could also predict time-to-recurrence (TTR; P = 0.016). In multivariate analysis, CIMP/MLH1 methylation status showed a significant prognostic value in both OS (P < 0.001) and TTR (P = 0.023). Patients with CIMP(+)/MLH1-U tumors had the worst OS and TTR. CONCLUSIONS:Our results showed existence of CIMP in duodenal adenocarcinomas. The combination of CIMP(+)/MLH1-U seems to be independently associated with poor prognosis in patients with duodenal adenocarcinomas. This study also suggests that BRAF mutations are not involved in duodenal tumorigenesis, MSI, or CIMP development.
Small bowel adenocarcinoma phenotyping, a clinicobiological prognostic study.
Aparicio T,Svrcek M,Zaanan A,Beohou E,Laforest A,Afchain P,Mitry Emmanuel,Taieb J,Di Fiore F,Gornet J-M,Thirot-Bidault A,Sobhani I,Malka D,Lecomte T,Locher C,Bonnetain F,Laurent-Puig P
British journal of cancer
BACKGROUND:Small bowel adenocarcinoma (SBA) is a rare tumour with a poor prognosis. Molecular biology data on SBA carcinogenesis are lacking. METHODS:Expression of HER2, β-catenin, p53 and mismatch repair (MMR) protein was assessed by immunohistochemistry. KRAS, V600E BRAF mutations and microsatellite instability were investigated. RESULTS:We obtained samples from 63 SBA patients (tumour stages: I-II: 30%; III: 35%; IV: 32%; locally advanced: 3%). HER2 overexpression (3+) was observed in 2 out of 62 patients, overexpression of p53 in 26 out of 62, abnormal expression of β-catenin in 12 out of 61, KRAS mutation in 21 out of 49, BRAF V600E mutation in 1 out of 40 patients, MMR deficiency (dMMR) in 14 out of 61 and was consistent with Lynch syndrome in 9 out of 14 patients. All of the dMMR tumours were in the duodenum or jejunum and only one was stage IV. Median overall survival (OS) was 36.6 months (95% CI, 26.9-72.2). For all patients, in univariate analysis, stages I-II (P<0.001), WHO PS 0-1 (P=0.01) and dMMR phenotype (P=0.02) were significantly associated with longer OS. In multivariate analysis, disease stage (P=0.01) and WHO PS 0-1 (P=0.001) independently predicted longer OS. For stage IV patients, median OS was 20.5 months (95% CI: 14.6; 36.6 months). In multivariate analysis, WHO PS 0-1 (P=0.0001) and mutated KRAS status (P=0.02) independently predicted longer OS. CONCLUSION:This large study suggests that molecular alterations in SBA are closer to those in colorectal cancer (CRC) than those in gastric cancer, with low levels of HER 2 overexpression and high frequencies of KRAS mutations. The seemingly higher frequency of dMMR than in CRC may be explained by the higher frequency of Lynch syndrome in SBA patients. A dMMR phenotype was significantly associated with a non-metastatic tumour (P=0.02). A trend for a good prognosis and a duodenum or jejunum primary site was associated with dMMR.
Immunohistochemical analysis of adenocarcinoma of the small intestine: a tissue microarray study.
Svrcek M,Jourdan F,Sebbagh N,Couvelard A,Chatelain D,Mourra N,Olschwang S,Wendum D,Fléjou J-F
Journal of clinical pathology
BACKGROUND:Primary adenocarcinomas of the small intestine are rare, and the genetic mechanisms involved in their carcinogenesis remain unclear. AIM:To examine the expression of candidate proteins in small intestinal adenocarcinomas by immunohistochemistry performed on tissue microarrays (TMAs). METHODS:Twenty seven primary sporadic small intestinal adenocarcinomas were analysed. The TMA technique was validated by comparing immunohistochemical labelling of hMLH1 and hMSH2 on TMAs and the tissue sections they derived from. The expression of Smad4, hMSH6, beta catenin, and p53 was investigated and results compared with those obtained in 14 malignant ampullary tumours. RESULTS:TMA technology with threefold redundancy adequately represented the immunohistochemical pattern of small intestinal adenocarcinomas. Loss of hMLH1 expression, but not hMSH2 or hMSH6, was seen in two of 27 small intestinal adenocarcinomas. All ampullary tumours showed nuclear staining for hMSH2 and hMSH6. One case showed lack of immunostaining for hMLH1. Smad4 expression was absent in five small intestinal adenocarcinomas and two ampullary tumours. Overexpression of p53 was detected in the nuclei of 14 of the 27 small intestinal adenocarcinomas, and five of the 14 ampullary tumours. Nuclear or cytoplasmic expression of beta catenin was present in all specimens. CONCLUSION:Inactivation of the SMAD4/DPC4 gene seems to be involved in small intestinal adenocarcinoma tumorigenesis. Overexpression of p53 and abnormal expression of beta catenin are two common events, unlike the loss of expression of the DNA mismatch repair proteins (hMLH1, hMSH2, and hMSH6). The carcinogenetic process appears to be similar in small intestinal adenocarcinomas and malignant ampullary tumours.
Genetic alterations in sporadic and Crohn's-associated adenocarcinomas of the small intestine.
Rashid A,Hamilton S R
BACKGROUND & AIMS:Small intestinal carcinomas are rare but occur with increased incidence in Crohn's disease. The aim of this study was to elucidate the genetic alterations. METHODS:Mutations and deletions involved in colorectal carcinoma were studied in sporadic and Crohn's-associated intestinal carcinomas and precursors. RESULTS:c-K-ras mutations were present in all four sporadic carcinomas with contiguous adenomas, in only 18% without adenomas (P = 0.01), in 43% of Crohn's-associated carcinomas, and in 14% of dysplasias. Overexpression of p53 gene product and/or 17p allelic loss were present in 47% of sporadic carcinomas and 33% of contiguous adenomas and in 71% of Crohn's-associated carcinomas and 43% of dysplasias. In contrast, allelic losses of 5q (adenomatous polyposis coli [APC] gene region) and 18q (deleted in colorectal cancer [DCC] gene region) were rare. DNA replication errors (RERs) were present in 13% of sporadic carcinomas and in the carcinoma and dysplasias of 1 patient with Crohn's disease (14%), but mutations in the transforming growth factor beta type II receptor (TGFbeta RII) gene were absent. CONCLUSIONS:Accumulation of ras and p53 alterations occurs during the adenoma/dysplasia-carcinoma sequence in small intestinal carcinogenesis, but a ras-independent pathway may also exist. The infrequent loss of the APC and DCC regions and the absence of TGFbeta RII gene mutation in RER-positive neoplasms contrast with colorectal carcinogenesis.
The DCC gene: structural analysis and mutations in colorectal carcinomas.
Cho K R,Oliner J D,Simons J W,Hedrick L,Fearon E R,Preisinger A C,Hedge P,Silverman G A,Vogelstein B
DCC is a candidate tumor-suppressor gene encoding a protein with sequence similarity to cell adhesion molecules such as N-CAM. A set of overlapping YAC clones that contains the entire DCC coding region was isolated. Studies of this YAC contig showed that the DCC gene spans approximately 1.4 Mb. For elucidation of exon-intron structure, lambda phage clones containing all known coding sequences were isolated from a genomic library. These clones were used to demonstrate the existence of 29 DCC exons, and the sequences of the exon-intron boundaries were determined for each. Twenty-three polymorphic markers from chromosome 18 were then studied in a panel of primary colorectal tumors that had lost some, but not all, of chromosome 18. In most of these tumors, the region that was lost included DCC. Finally, Southern blot and PCR-based approaches were used to search for subtle mutations in several DCC exons. One tumor that had a point mutation in exon 28 was found, resulting in a proline to histidine substitution. A second tumor with a point mutation in intron 13 was also found. The regional map and genomic structure of DCC should provide the means to more extensively study DCC gene alterations and protein function in normal and neoplastic cells.
Smad4-mediated signaling inhibits intestinal neoplasia by inhibiting expression of β-catenin.
Freeman Tanner J,Smith J Joshua,Chen Xi,Washington M Kay,Roland Joseph T,Means Anna L,Eschrich Steven A,Yeatman Timothy J,Deane Natasha G,Beauchamp R Daniel
BACKGROUND & AIMS:Mutational inactivation of adenomatous polyposis coli (APC) is an early event in colorectal cancer (CRC) progression that affects the stability and increases the activity of β-catenin, a mediator of Wnt signaling. Progression of CRC also involves inactivation of signaling via transforming growth factor β and bone morphogenetic protein (BMP), which are tumor suppressors. However, the interactions between these pathways are not clear. We investigated the effects of loss of the transcription factor Smad4 on levels of β-catenin messenger RNA (mRNA) and Wnt signaling. METHODS:We used microarray analysis to associate levels of Smad4 and β-catenin mRNA in colorectal tumor samples from 250 patients. We performed oligonucleotide-mediated knockdown of Smad4 in human embryonic kidney (HEK293T) and in HCT116 colon cancer cells and transgenically expressed Smad4 in SW480 colon cancer cells. We analyzed adenomas from (APC(Δ1638/+)) and (APC(Δ1638/+)) × (K19Cre(ERT2)Smad4(lox/lox)) mice by using laser capture microdissection. RESULTS:In human CRC samples, reduced levels of Smad4 correlated with increased levels of β-catenin mRNA. In Smad4-depleted cell lines, levels of β-catenin mRNA and Wnt signaling increased. Inhibition of BMP or depletion of Smad4 in HEK293T cells increased binding of RNA polymerase II to the β-catenin gene. Expression of Smad4 in SW480 cells reduced Wnt signaling and levels of β-catenin mRNA. In mice with heterozygous disruption of Apc(APC(Δ1638/+)), Smad4-deficient intestinal adenomas had increased levels of β-catenin mRNA and expression of Wnt target genes compared with adenomas from APC(Δ1638/+) mice that expressed Smad4. CONCLUSIONS:Transcription of β-catenin is inhibited by BMP signaling to Smad4. These findings provide important information about the interaction among transforming growth factor β, BMP, and Wnt signaling pathways in progression of CRC.
Bevacizumab combined with capecitabine and oxaliplatin in patients with advanced adenocarcinoma of the small bowel or ampulla of vater: A single-center, open-label, phase 2 study.
Gulhati Pat,Raghav Kanwal,Shroff Rachna T,Varadhachary Gauri R,Kopetz Scott,Javle Milind,Qiao Wei,Wang Huamin,Morris Jeffrey,Wolff Robert A,Overman Michael J
BACKGROUND:Capecitabine with oxaliplatin (CAPOX) has previously demonstrated clinical activity in patients with small bowel adenocarcinoma (SBA) and ampullary adenocarcinoma (AAC). Herein, the authors conducted a phase 2 trial to evaluate the benefit of adding bevacizumab to CAPOX. METHODS:In this phase 2, single-arm, single-center, open-label study, patients aged ≥18 years with untreated, advanced SBA or AAC were recruited. Patients received capecitabine at a dose of 750 mg/m orally twice daily on days 1 to 14, oxaliplatin at a dose of 130 mg/m intravenously on day 1, and bevacizumab at a dose of 7.5 mg/kg intravenously on day 1 of a 21-day cycle. The primary endpoint was progression-free survival (PFS) at 6 months. Secondary objectives included response rate, overall PFS, overall survival, and toxicity. RESULTS:Between August 2011 and November 2014, a total of 30 patients were enrolled into the study (male/female ratio of 13/17; median age of 63 years [range, 33-78 years]; and 7 patients with an Eastern Cooperative Oncology Group performance status [ECOG PS] of 0, 20 patients with an ECOG PS of 1, and 3 patients with an ECOG PS of 2). Of the 30 patients, 23 (77%) had SBA (18 of duodenal origin and 5 of jejunal/ileal origin) and 7 patients (23%) had AAC (5 of pancreaticobiliary subtype, 1 of mixed subtype, and 1 of intestinal subtype). The most common grade 3 toxicities observed were fatigue and hypertension (7 patients each [23%]), neutropenia (6 patients [20%]), and diarrhea (3 patients [10%]) (toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). The probability of PFS at 6 months was 68% (95% confidence interval [95% CI], 52% to 88%). The response rate was 48.3%, with 1 complete response and 13 partial responses; 10 patients achieved stable disease. At a median follow-up of 25.9 months, the median PFS was 8.7 months (95% CI, 4.9-10.5 months) and the median overall survival was 12.9 months (95% CI, 9.2-19.7 months). CONCLUSIONS:The results of the current study indicate that CAPOX with bevacizumab is an active and well-tolerated regimen for patients with SBA and AAC. These findings support the need for further investigation into the clinical benefit of targeting angiogenesis in patients with SBA and AAC. Cancer 2017;123:1011-17. © 2016 American Cancer Society.
Advanced small bowel adenocarcinoma: Molecular characteristics and therapeutic perspectives.
Zaaimi Yosra,Aparicio Thomas,Laurent-Puig Pierre,Taieb Julien,Zaanan Aziz
Clinics and research in hepatology and gastroenterology
Small bowel cancer represents less than 5% of all gastrointestinal cancers, while small bowel adenocarcinoma (SBA) accounts for about one third of all cancers of the small bowel. Although SBA frequently appears sporadically, some diseases are risk factors, such as Crohn's disease and some genetic predispositions to cancer. Progress in the identification of molecular alterations suggests some similarities in carcinogenesis between SBA and colorectal cancer. Evidence levels for the treatment and prognosis of these tumors are insufficient because of the scarcity of this disease and the absence of randomized trials. Chemotherapy based on fluoropyrimidine plus a platinum salt appears to be the most effective treatment regimen in non-randomized prospective trials for advanced SBA. Targeted therapy, against the angiogenic pathway or the epidermal growth factor receptor (EGFR) pathway, for example, is not yet established, but seems promising given the over-expression of vascular epithelial growth factor (VEGF)-A or EGFR observed in SBA. Phase I and II studies are currently evaluating the safety and efficacy of these targeted therapies in SBA treatment. The low incidence of SBA should promote the development of international collaborations to improve our knowledge of the biological mechanisms underlying these tumors and to set up therapeutic trials.
Combined loss of E-cadherin and aberrant β-catenin protein expression correlates with a poor prognosis for small intestinal adenocarcinomas.
Lee Hee Jin,Lee Ok-Jun,Jang Kee-Taek,Bae Young Kyung,Chung Joon-Yong,Eom Dae Woon,Kim Joon Mee,Yu Eunsil,Hong Seung-Mo
American journal of clinical pathology
Small intestinal adenocarcinomas (SIACs) are rare, and their molecular pathogenesis is largely unknown. To define the roles of E-cadherin and β-catenin, we performed immunohistochemistry for E-cadherin and β-catenin in 194 surgically resected SIACs with tissue microarrays and compared the data with clinicopathologic factors, including survival rates of patients with SIAC. Loss of E-cadherin expression and aberrant β-catenin expression were observed in 41.8% (81/194 cases) and 40.7% (79/194 cases) of SIACs, respectively. Combined loss of E-cadherin and aberrant β-catenin expression was observed in 24.2% (47/194 cases) of SIACs, and this feature was most frequently observed in mucinous adenocarcinomas and signet ring cell carcinomas (P < .001), poorly differentiated and undifferentiated carcinomas (P < .001), and tumors with advanced pT classification (P = .03). Survival times for patients with SIAC with both loss of E-cadherin and aberrant β-catenin expression (median, 13.9 months) were significantly shorter than those for patients without aberrant expression of both proteins (49.9 months), as determined by univariate (P < .001) and multivariate (P = .01) analyses. In conclusion, loss of E-cadherin and aberrant β-catenin expression correlate with poorly differentiated tumors, advanced T classification, and decreased patient survival time; therefore, it could be a prognostic factor in patients with SIAC.
Mutational activation of the RAS-RAF-MAPK and the Wnt pathway in small intestinal adenocarcinomas.
Bläker H,Helmchen B,Bönisch A,Aulmann S,Penzel R,Otto H F,Rieker R J
Scandinavian journal of gastroenterology
BACKGROUND:Adenocarcinomas of the small and the large intestine share risk factors and morphological features but both tumor types seem to follow different genetic pathways. The aim of this study on small intestinal carcinomas was to analyze alternative mechanisms of activation of pathways that are typically affected in colorectal cancer. METHODS:Twenty-one sporadic carcinomas were investigated for mutations in KRAS, BRAF, the beta-catenin gene CTNNB1, and the mutational cluster region of APC. Immunohistochemical analysis was performed with a monoclonal antibody for beta-catenin, the transcriptionally active downstream component of wnt signaling. RESULTS:Oncogene mutations were found in 13 (62%) small intestinal adenocarcinomas. Twelve tumors displayed a KRAS mutation, and a novel BRAF mutation at codon 603/604 was seen in one carcinoma without KRAS mutation. One tumor harbored a CTNNB1 mutation consisting of an insertion of 247 nucleotides deriving from chromosome 9. APC mutations were identified in 2 tumors. Immunohistochemistry demonstrated nuclear accumulation of beta-catenin in 5 carcinomas. These carcinomas included the tumor with a CTNNB1 mutation but not those with APC mutations. CONCLUSIONS:Our data show frequent activation of the RAS-RAF-MAPK pathway through mutations of either KRAS or, infrequently, BRAF. Activation of the wnt pathway through accumulation of beta-catenin may have a role in a subset of small intestinal adenocarcinomas but in contrast to colorectal carcinoma, accumulation of beta-catenin is generally not caused by inactivating APC or activating CTNNB1 mutations.
Immunohistochemical investigation of tumorigenic pathways in small intestinal adenocarcinoma: a comparison with colorectal adenocarcinoma.
Zhang Megan Q,Chen Zong-Ming E,Wang Hanlin L
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc
Small intestinal adenocarcinoma is an uncommon neoplasm morphologically similar to or indistinguishable from colorectal adenocarcinoma. Although much has been learned about genetic pathways critical to colorectal tumorigenesis, little is known about molecular alterations involved in the development of small intestinal adenocarcinoma. In this study, we immunohistochemically compared non-ampullary small intestinal adenocarcinomas with sporadic colorectal adenocarcinomas for the expression of several proteins known to serve pivotal roles in colorectal tumorigenesis. These included adenomatous polyposis coli and beta-catenin involved in the Wnt signaling pathway, and DNA mismatch repair enzymes hMLH1, hMSH2 and hMSH6 involved in the microsatellite instability pathway. The expression of two important tumor suppressors, p53 and RB, was also examined. The results show that complete loss of adenomatous polyposis coli immunoreactivity, presumably resulting from its gene mutations, was observed in eight of 26 (31%) small intestinal adenocarcinomas and 36 of 51 (71%) colorectal adenocarcinomas (P = 0.0008). Nuclear localization of beta-catenin, an indirect evidence of deregulated Wnt signaling pathway, was observed in 5 (19%) small intestinal adenocarcinomas and 36 (71%) colorectal adenocarcinomas (P<0.0001). Total lack of nuclear staining for one or more of the DNA mismatch repair enzymes occurred in a similar low frequency in both small intestinal and colorectal adenocarcinomas, seen in two of 25 (8%) and 10 of 47 (21%) cases, respectively (P = 0.1958). The frequencies of aberrant p53 and RB expression were also similar between small intestinal and colorectal adenocarcinomas. These observations indicate that defects in the Wnt and microsatellite instability pathways occur in over 90% of colorectal adenocarcinomas, but in only 40% of small intestinal adenocarcinomas. Small intestinal tumorigenesis appears to follow a distinct, yet unidentified, molecular pathway(s) from its colorectal counterpart despite their morphologic similarity.
Different APC genotypes in proximal and distal sporadic colorectal cancers suggest distinct WNT/β-catenin signalling thresholds for tumourigenesis.
Christie M,Jorissen R N,Mouradov D,Sakthianandeswaren A,Li S,Day F,Tsui C,Lipton L,Desai J,Jones I T,McLaughlin S,Ward R L,Hawkins N J,Ruszkiewicz A R,Moore J,Burgess A W,Busam D,Zhao Q,Strausberg R L,Simpson A J,Tomlinson I P M,Gibbs P,Sieber O M
Biallelic protein-truncating mutations in the adenomatous polyposis coli (APC) gene are prevalent in sporadic colorectal cancer (CRC). Mutations may not be fully inactivating, instead producing WNT/β-catenin signalling levels 'just-right' for tumourigenesis. However, the spectrum of optimal APC genotypes accounting for both hits, and the influence of clinicopathological features on genotype selection remain undefined. We analysed 630 sporadic CRCs for APC mutations and loss of heterozygosity (LOH) using sequencing and single-nucleotide polymorphism microarrays, respectively. Truncating APC mutations and/or LOH were detected in 75% of CRCs. Most truncating mutations occurred within a mutation cluster region (MCR; codons 1282-1581) leaving 1-3 intact 20 amino-acid repeats (20AARs) and abolishing all Ser-Ala-Met-Pro (SAMP) repeats. Cancers commonly had one MCR mutation plus either LOH or another mutation 5' to the MCR. LOH was associated with mutations leaving 1 intact 20AAR. MCR mutations leaving 1 vs 2-3 intact 20AARs were associated with 5' mutations disrupting or leaving intact the armadillo-repeat domain, respectively. Cancers with three hits had an over-representation of mutations upstream of codon 184, in the alternatively spliced region of exon 9, and 3' to the MCR. Microsatellite unstable cancers showed hyper-mutation at MCR mono- and di-nucleotide repeats, leaving 2-3 intact 20AARs. Proximal and distal cancers exhibited different preferred APC genotypes, leaving a total of 2 or 3 and 0 to 2 intact 20AARs, respectively. In conclusion, APC genotypes in sporadic CRCs demonstrate 'fine-tuned' interdependence of hits by type and location, consistent with selection for particular residual levels of WNT/β-catenin signalling, with different 'optimal' thresholds for proximal and distal cancers.
An insight into the genetic pathway of adenocarcinoma of the small intestine.
Wheeler J M D,Warren B F,Mortensen N J McC,Kim H C,Biddolph S C,Elia G,Beck N E,Williams G T,Shepherd N A,Bateman A C,Bodmer W F
BACKGROUND:Although the adenoma to carcinoma pathway in colorectal cancer is well described, the mechanisms of carcinogenesis in the small intestine remain unclear. AIMS:The aim of this study was to investigate candidate genes in the genetic pathway of adenocarcinoma of the small intestine. SUBJECTS AND METHODS:A total of 21 non-familial, non-ampullary adenocarcinomas of the small intestine were analysed. DNA was extracted from formalin fixed paraffin wax embedded tissue using standard techniques. The replication error (RER) status was determined by amplification of BAT26. The mutation cluster region (MCR) of the adenomatous polyposis coli (APC) gene was screened using polymerase chain reaction single strand conformational polymorphism and direct sequencing. Immunohistochemistry was performed on formalin fixed paraffin wax embedded tissue using monoclonal antibodies for hMLH1, hMSH2, beta-catenin, E-cadherin, and p53. RESULTS:Fourteen male and seven female patients with a median age of 64 years (range 21-85) presented with adenocarcinoma of the duodenum (10), jejunum (7), and ileum (4). One cancer (5%) was found to be RER+, and all tumours stained positive for hMLH1 and hMSH2. No mutations were detected in the MCR of the APC gene. beta-Catenin showed increased nuclear expression with loss of membranous staining in 10 cancers (48%). Absent or decreased membrane expression of E-cadherin was found in eight cancers (38%). Strong staining of p53 was found in the nucleus of five cancers (24%). CONCLUSION:We did not detect mutations in the MCR of the APC gene, and this suggests that adenocarcinoma of the small intestine may follow a different genetic pathway to colorectal cancer. Abnormal expression of E-cadherin and beta-catenin was common and reflects an early alternative to APC in this pathway in which mutations may be found in adenocarcinoma of the small intestine.
Loss of SMAD4 function in small intestinal adenocarcinomas: comparison of genetic and immunohistochemical findings.
Bläker Hendrik,Aulmann Sebastian,Helmchen Birgit,Otto Herwart F,Rieker Ralf J,Penzel Roland
Pathology, research and practice
Despite morphological similarities between adenocarcinomas of the small and the large intestine, recent evidence suggests that both tumor types follow different genetic pathways. In particular, inactivation of the APC tumor suppressor gene, a characteristic alteration of colorectal carcinomas, does not seem to play a significant role in sporadic small intestinal tumorigenesis. We could recently show that inactivating mutations of the SMAD4 gene frequently occur in small intestinal adenocarcinomas. To further elucidate the role of SMAD4 dysfunction for tumor development in the small intestine, we immunohistochemically analyzed 20 sporadic, non-ampullary carcinomas for the expression of the SMAD4 protein. We further determined homozygous SMAD4 gene deletions by real time PCR and compared SMAD4 immunohistochemical data with SMAD4 genetic data. Immunohistochemistry was negative for the tumor cells in two (10%) cases and strongly reduced in four (20%). Negative immunohistochemical staining corresponded with homozygous gene deletions. A regular or only slightly reduced staining pattern was noted in 14 carcinomas, including four tumors with previously identified SMAD4 missense and frame shift mutations. In conclusion, our data suggest a significant role of impaired SMAD4 function in the pathogenesis of small intestinal adenocarcinomas. Furthermore, our results show that SMAD4 immunohistochemistry may serve as a surrogate for analysis of homozygous gene deletions. However, the method fails to identify SMAD4 inactivation due to missense mutations.
Occupational risk factors for small bowel carcinoid tumor: a European population-based case-control study.
Kaerlev Linda,Teglbjaerg Peter Stubbe,Sabroe Svend,Kolstad Henrik A,Ahrens Wolfgang,Eriksson Mikael,Guénel Pascal,Hardell Lennart,Cyr Diane,Ballard Terri,Zambon Paola,Morales Suárez-Varela María M,Stang Andreas,Olsen Jorn
Journal of occupational and environmental medicine
Small bowel carcinoid tumor (SBC) is a rare disease of unknown etiology but with an age-, sex-, and place-specific occurrence that may indicate an occupational origin. A European multicenter population-based case-control study was conducted from 1995 through 1997. Incident SBC cases between 35 and 69 years of age (n = 101) were identified, together with 3335 controls sampled from the catchment area of the cases. Histological review performed by a reference pathologist left 99 cases for study; 84 cases and 2070 population controls were interviewed. The industries most closely associated (a twofold or more odds ratio [OR]) with SBC, taking into account a 10-year time lag after exposure were, among women, employment in wholesale industry of food and beverages (OR, 8.2; 95% confidence interval [CI], 1.9 to 34.9]) and among men, manufacture of motor vehicle bodies (OR, 5.2; 95% CI, 1.2 to 22.4), footwear (OR, 3.9; 95% CI, 0.9 to 16.1), and metal structures (OR, 3.3; 95% CI, 1.0 to 10.4). The identified high-risk occupations with an OR above 2 were shoemakers, structural metal preparers, construction painters and other construction workers, bookkeepers, machine fitters, and welders (men). The OR for regular occupational use of organic solvents for at least half a year was 2.0 (95% CI, 1.0 to 4.2). Exposure to rust-preventive paint containing lead was suggested as another potential occupational exposure (OR, 9.1; 95% CI, 0.8 to 107). This explorative study suggests an association between certain occupational exposures and SBC, but some of these associations could be attributable to chance. All findings should be regarded as tentative.
Cancer incidence among Australian nuclear industry workers.
Habib Rima R,Abdallah Samer M,Law Matthew,Kaldor John
Journal of occupational health
To assess whether workers at Lucas Heights Science and Technology Centre (LHSTC) had different levels of cancer incidence from the New South Wales (NSW) population in Australia. A retrospective cohort study was undertaken at LHSTC. Data on 7,076 workers employed between 1957-98 were abstracted from personnel, dosimetry, and medical files. An inception cohort was defined which included 4,523 workers in employment between 1972-96 to examine cancer incidence. Cancer registrations in the inception cohort were identified to 1996 through electronic linkage of records with the NSW and the Australian national registers of cancer incidence. All-cancer incidence in workers at LHSTC was 15% below the NSW rates [SIR=0.85; 95% CI=(0.75, 0.95)]. Of 37 specific cancers and groups of cancers examined, statistically significant excesses relative to NSW rates were observed only for pleural cancer incidence [SIR=17.71; 95%=(7.96, 39.43)], and for incidence of cancer of the small intestine [SIR=4.34; 95% CI=(1.40, 13.46)]. This study gives little evidence of an increased risk of cancers associated with radiation exposure in a cohort of nuclear workers in Australia. The observed increase in the risk of cancer of the pleura was probably due to unmeasured exposures, given the lack of an established association with radiation exposure, and the strong link to asbestos exposure. Findings for cancers of the small intestine were based on small numbers and were likely to be due to chance.
Prognosis of small bowel adenocarcinoma in Crohn's disease compares favourably with de novo small bowel adenocarcinoma.
Wieghard N,Mongoue-Tchokote S,Young J I,Sheppard B C,Tsikitis V L
Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland
AIM:Limited data exist on Crohn's disease (CD)-associated small bowel adenocarcinoma (SBA). A large-scale retrospective cohort study was conducted comparing the clinical features and outcome of CD-associated SBA and de novo SBA. METHOD:Data for patients with small bowel adenocarcinoma were gathered from the 1992-2010 United States Surveillance, Epidemiology and End Results cancer registry-Medicare linked database. We identified 2123 patients, of whom 179 had CD-associated and 1944 de novo SBA. The main outcome measures were overall survival (OS) and cancer-specific survival (CSS). RESULTS:CD-associated SBA was most commonly located in the ileum (62% vs 31%, P < 0.0001). CD patients were diagnosed at an earlier stage (I/II), compared with de novo SBA (55% vs 32%, P < 0.0001), and were more likely to undergo surgery (81% vs 72%, P = 0.0016). Chemotherapy use was similar (25% vs 21%, P = 0.1886). Patients with CD-associated SBA had better 5-year OS (43% vs 34%, P = 0.0121) but a similar CSS (65% vs 64%, P = 0.77). There was no difference in the OS between the cohorts when stratified by stage. On multivariate analysis, CD was not significantly related to OS [hazard ratio (HR) 0.97, 95% CI: 0.79-1.20, P = 0.7889]. Surgery and the extent of lymphadenectomy improved OS for all SBA patients (HR 0.73, 95% CI: 0.60-0.88, P = 0.001), whereas chemotherapy did not (HR 1.13, 95% CI: 0.99-1.28, P = 0.0665). CONCLUSION:Patients with CD-associated SBA present at an earlier stage than patients with de novo SBA, they receive more surgery but similar rates of chemotherapy, and have similar OS and CSS. The presence of CD does not worsen survival after treatment of SBA.
Prospective study of dietary fiber, whole grain foods, and small intestinal cancer.
Schatzkin Arthur,Park Yikyung,Leitzmann Michael F,Hollenbeck Albert R,Cross Amanda J
BACKGROUND & AIMS:Although a number of epidemiologic studies have found dietary fiber and whole grains to be inversely associated with colorectal cancer incidence, studies of dietary and other risk factors for small intestinal cancer have been sparse and all of a case-control design. We conducted a prospective cohort study to determine the relationship between intake of dietary fiber/whole grains and the incidence of small intestinal cancer. METHODS:We analyzed dietary data collected in 1995 and 1996 from 293,703 men and 198,618 women in the National Institutes of Health-AARP Diet and Health Study. We used multivariate Cox proportional hazards models to estimate relative risk (RR) and 2-sided 95% confidence intervals (CIs) for quintiles of dietary fiber and whole grain intake. RESULTS:Through 2003, 165 individuals developed small intestinal cancers. Dietary fiber/whole grain intake was generally associated with a lower risk of small intestinal cancer. The multivariate RRs (95% CIs; 5th vs 1st intake quintile) were 0.79 (0.43-1.44; P trend, .41) for total dietary fiber, 0.51 (0.29-0.89; P trend, .01) for fiber from grains, and 0.59 (0.33-1.05; P trend, .06) for whole grain foods. CONCLUSIONS:Intake of fiber from grains and whole-grain foods was inversely associated with small intestinal cancer incidence; the RR values were consistent with those from the same dietary factors for large bowel cancer in this cohort. In conjunction with the anatomic and physiologic commonalities of the large and small bowel, as well as the mutually increased risks for second cancer for both organs, grain fiber and whole grain foods seem to protect against lower gastrointestinal cancers.
A large prospective study of risk factors for adenocarcinomas and malignant carcinoid tumors of the small intestine.
Cross Amanda J,Hollenbeck Albert R,Park Yikyung
Cancer causes & control : CCC
PURPOSE:Small intestinal cancer is increasing in the U.S.A, yet little is known about its etiology. Our aim was to prospectively evaluate risk factors for this malignancy by the two main histologic subtypes (adenocarcinomas and carcinoids). METHODS:Hazard ratios and 95% confidence intervals (CI) were estimated for all incident small intestinal cancers (n = 237), adenocarcinomas (n = 84), and malignant carcinoids (n = 124), by demographic and lifestyle factors among 498,376 men and women. RESULTS:Age was the only risk factor for adenocarcinomas (HR for ≥ 65 vs. 50-55 years = 3.12, 95% CI 1.33, 7.31). Age (HR for ≥ 65 vs. 50-55 years = 3.31, 95% CI 1.51, 7.28), male sex (HR = 1.44, 95% CI 1.01, 2.05), body mass index (BMI, HR for ≥ 35 vs. 18.5-< 25 kg/m2 = 1.95, 95% CI 1.06, 3.58), and current menopausal hormone therapy use (HR = 1.94, 95% CI 1.07, 3.50) were positively associated with malignant carcinoids. A family history of any cancer or colorectal cancer (HR = 1.42, 95% CI 0.99, 2.03; 1.61, 0.97, 2.65, respectively), or a personal history of colorectal polyps (HR = 1.51, 95% CI 0.92, 2.46) produced elevated, but not statistically significant, risks for malignant carcinoids. Race, education, diabetes, smoking, physical activity, and alcohol intake were not associated with either histologic subtype. CONCLUSIONS:Risk factors differed according to cancer subtype; only age was associated with adenocarcinomas, whereas age, male sex, BMI, and menopausal hormone therapy use were positively associated with malignant carcinoids.
Body mass, tobacco smoking, alcohol drinking and risk of cancer of the small intestine--a pooled analysis of over 500,000 subjects in the Asia Cohort Consortium.
Boffetta P,Hazelton W D,Chen Y,Sinha R,Inoue M,Gao Y T,Koh W P,Shu X O,Grant E J,Tsuji I,Nishino Y,You S L,Yoo K Y,Yuan J M,Kim J,Tsugane S,Yang G,Wang R,Xiang Y B,Ozasa K,Nagai M,Kakizaki M,Chen C J,Park S K,Shin A,Ahsan H,Qu C X,Lee J E,Thornquist M,Rolland B,Feng Z,Zheng W,Potter J D
Annals of oncology : official journal of the European Society for Medical Oncology
BACKGROUND:The evidence for a role of tobacco smoking, alcohol drinking, and body mass index (BMI) in the etiology of small intestine cancer is based mainly on case-control studies from Europe and United States. SUBJECTS AND METHODS:We harmonized the data across 12 cohort studies from mainland China, Japan, Korea, Singapore, and Taiwan, comprising over 500,000 subjects followed for an average of 10.6 years. We calculated hazard ratios (HRs) for BMI and (only among men) tobacco smoking and alcohol drinking. RESULTS:A total of 134 incident cases were observed (49 adenocarcinoma, 11 carcinoid, 46 other histologic types, and 28 of unknown histology). There was a statistically non-significant trend toward increased HR in subjects with high BMI [HR for BMI>27.5 kg/m2, compared with 22.6-25.0, 1.50; 95% confidence interval (CI) 0.76-2.96]. No association was suggested for tobacco smoking; men drinking>400 g of ethanol per week had an HR of 1.57 (95% CI 0.66-3.70), compared with abstainers. CONCLUSIONS:Our study supports the hypothesis that elevated BMI may be a risk factor for small intestine cancer. An etiologic role of alcohol drinking was suggested. Our results reinforce the existing evidence that the epidemiology of small intestine cancer resembles that of colorectal cancer.
A prospective study of meat and fat intake in relation to small intestinal cancer.
Cross Amanda J,Leitzmann Michael F,Subar Amy F,Thompson Frances E,Hollenbeck Albert R,Schatzkin Arthur
Diets high in red and processed meats are associated with carcinogenesis of the large intestine, but no prospective study has examined meat and fat intake in relation to cancer of the small intestine. We prospectively investigated meat and fat intakes, estimated from a food frequency questionnaire, in relation to small intestinal cancer among half a million men and women enrolled in the NIH-AARP Diet and Health Study. We used Cox proportional hazards regression to estimate hazard ratios (HR) and 95% confidence intervals (95% CI). During up to 8 years of follow-up, 60 adenocarcinomas and 80 carcinoid tumors of the small intestine were diagnosed. Despite slightly elevated HRs for red meat, there were no clear associations for red or processed meat intake and either adenocarcinoma or carcinoid tumors of the small intestine. In contrast, we noted a markedly elevated risk for carcinoid tumors of the small intestine with saturated fat intake in both the categorical (highest versus lowest tertile: HR, 3.18; 95% CI, 1.62-6.25) and continuous data (HR, 3.72; 95% CI, 1.79-7.74 for each 10-g increase in intake per 1,000 kcal). Our findings suggest that the positive associations for meat intake reported in previous case-control studies may partly be explained by saturated fat intake.
A population-based comparison of adenocarcinoma of the large and small intestine: insights into a rare disease.
Overman Michael J,Hu Chung-Yuan,Kopetz Scott,Abbruzzese James L,Wolff Robert A,Chang George J
Annals of surgical oncology
BACKGROUND:Because of its rarity, adenocarcinoma of the small intestine is frequently compared to adenocarcinoma of the colon, although the validity of this comparison is not known. METHODS:Patients with small and large bowel adenocarcinoma (SBA and LBA) diagnosed between 1988 and 2007 were identified from the Surveillance, Epidemiology, and End Results registry. Age-standardized incidence and mortality rates were determined. Cancer-specific survival (CSS) stratified by stage and by number of assessed lymph nodes was calculated. RESULTS:A total of 4518 and 261,521 patients with SBA and LBA, respectively, were identified. In comparison to LBA, patients with SBA were younger and presented with disease of higher stage and histologic grade. The age-standardized incidence rates decreased for LBA (-1.24% per year) but increased for SBA (+1.47% per year). Although age-standardized mortality rates decreased for both LBA and SBA, the decreases were more pronounced for LBA. Five-year CSS was worse for resected SBA compared with resected LBA, although this difference diminished when comparing cases having eight or more lymph nodes assessed. The relative reduction in CSS when selecting eight or more lymph nodes was much greater for duodenal as opposed to jejunal/ileal subsite of the small bowel. With nodal selection the absolute difference in CSS between LBA and SBA for stages I, II, and III was 13, 15.9, and 18.5%, respectively. CONCLUSIONS:Adequate nodal assessment is much less common in SBA than LBA; and it appears that SBA, in particular duodenal adenocarcinoma, is understaged. Even after corrections to minimize the effect of stage migration and inadequate lymph node evaluation, SBA demonstrated distinctly worse CSS than LBA.