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.
Highlights
Small bowel adenocarcinoma (SBA) is a rare tumour of poor prognosis [1]
Our study on a large number of patients with SBA revealed different tumour mutation profiles according to predisposing diseases (Crohn’s disease or Lynch syndrome compared to tumour without predisposing disease) or an mismatch repair (MMR) status
Our results are concordant with the genomic alteration profile reported in three previous studies that reported a mutation rate for KRAS from 43.4% to 53.6%, TP53 from 41% to 58.4%, PIK3CA from 9% to 18.4%, APC from 13.2% to 26.8%, SMAD4 from 9.6% to 17.4% and ERBB2 from 8.4% to 14% [7,8,10]
Summary
Small bowel adenocarcinoma (SBA) is a rare tumour of poor prognosis [1]. it is the first aetiology of small bowel cancer in France [2] and second aetiology in the USA [3]. A large genomic analysis mainly on stage IV tumours has reported a distinct profile of SBA compared to gastric or colon adenocarcinoma [7]. The NADEGE cohort has enrolled prospectively consecutive patients with all stages of SBA during a four-year period in France. The BIONADEGE study is an ancillary study of the NADEGE cohort aimed to assess the genomic profile according to a predisposing disease for SBA, to SBA localisation or stage and assess the prognostic value of these genomic alterations. Immunostaining of MLH1, MSH2, MSH6 and PMS2 in tumour cells was evaluated as positive or negative as assessed in TMA. Tumours were considered negative when there was a complete absence of nuclear staining of neoplastic cells in the presence of an internal positive control assessed in a whole slide. As the analyses were exploratory, p values were not adjusted for multiple testing
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