Panel gene profiling of small bowel adenocarcinoma: Results from theNADEGEprospective cohort

Abstract

Small bowel adenocarcinoma (SBA) is a rare tumour. Large genomic analyses with prognostic assessments are lacking. The NADEGE cohort has enrolled 347 patients with all stage SBA from 2009 to 2012. Next‐generation sequencing investigates the presence of 740 hotspot somatic mutations in a panel of 46 genes involved in carcinogenesis. The mismatch repair (MMR) status was assessed by immunochemistry. We have collected 196 tumour samples and 125 had conclusive results for mutation analysis. The number of mutations was 0 in 9.6% of tumours, only 1 in 32.0%, 2 in 26.4% and ≥3 in 32.0%. Overall, at least one genomic alteration was observed in 90.4% of tumour. The most frequent genomic alteration was in KRAS (44.0%), TP53 (38.4%), PIK3CA (20.0%), APC (18.4%), SMAD4 (14.4%) and ERBB2 (7.2%) genes. KRAS mutations were more frequent in synchronous metastatic tumours than in localised tumours (72.7% vs 38.2%, P = .003). There was no significant difference in the mutation rates according to primary location for the most frequently altered gene. ATM, FGFR3 and FGFR1 gene alterations were associated with Lynch syndrome and IDH1 mutations with Crohn disease. dMMR tumours were associated with younger age, localised tumours, less KRAS but more SMARCB1 mutations. No genomic alteration was associated with overall survival. There is a trend for better survival in patient with dMMR tumours. In conclusion, there is a different genomic alteration profile in SBA according to predisposing diseases. No association between genomic alterations and prognoses was observed except for a trend of better prognoses associated with dMMR.

Small Bowel Epithelial Precursor Lesions: A Focus on Molecular Alterations

“…CrD-related dysplasia characteristically shows p53 overexpression at a high rate (47–59%), in keeping with the frequent detection of TP53 mutations in CrD-associated small bowel adenocarcinomas [ 8 , 11 , 113 , 117 ]. These findings indicate a key role of TP53 gene in the initial steps of small bowel carcinogenesis of CrD patients.…”

“…Alterations in mutational cluster regions seem to be more common in intestinal-type NADAs (86%) in comparison with intestinal-type intramucosal adenocarcinomas (33%) [ 16 ]. In addition, APC alterations have been found to be rarer in advanced duodenal carcinomas [ 8 , 9 , 10 , 11 , 19 , 20 ], suggesting that most NADAs have a low potential for malignant progression to duodenal adenocarcinomas and that the adenoma-carcinoma sequence may play a small role in the development of invasive duodenal adenocarcinomas.…”

“…ERBB2 mutations occur in less than 5% of NADAs, while the combined prevalence of mutations or copy number gains in any members of ERBB receptor family may reach 34% [ 16 ]. ERBB2 mutations and/or amplifications have been detected in up to 23% of small bowel adenocarcinomas and they are associated with duodenal location and microsatellite instability [ 8 , 9 , 10 , 11 , 20 , 22 ]. Interestingly ERBB2 inhibitors have been found to display anti-cancer activity in small bowel adenocarcinomas, both in vitro and in vivo [ 10 ].…”

“…TP53 abnormalities are infrequent among intestinal-type NADAs [ 15 ]. In particular, TP53 mutations have been identified in only 5% of NADAs by Ota et al [ 16 ], while recent studies indicate that TP53 (38–58%), KRAS (27–54%), and APC (11–27%) are the most frequently mutated genes in small bowel adenocarcinomas [ 9 , 10 , 11 , 20 ], suggesting that this molecular alteration is a late event in tumorigenesis.…”

“…The identification of such precursor lesions may have clinical implications, requiring specific endoscopic surveillance programs on the bases of their malignant potential [ 5 ] or screening of remaining organs and family members, when they are associated with hereditary tumor syndromes, such as familial adenomatous polyposis 1 (FAP), MUTYH -associated polyposis (MAP) or multiple endocrine neoplasia 1 syndrome (MEN1). While the molecular landscape of malignant small bowel neoplasms has been extensively studied in recent years [ 6 , 7 , 8 , 9 , 10 , 11 ], the genetic and epigenetic alterations of small bowel precursor lesions are less known. The aim of this review is to provide a global view of the molecular aspects of precursor epithelial lesions of the small intestine.…”