Abstract
BackgroundCarcinomas of the small bowel are rare tumors usually with dismal prognosis. Most recently, some potentially treatable molecular alterations were described. We emphasize the growing evidence of individualized treatment options in small bowel carcinoma.MethodsWe performed a DNA- based multi-gene panel using ultra-deep sequencing analysis (including 14 genes with up to 452 amplicons in total; KRAS, NRAS, HRAS, BRAF, DDR2, ERBB2, KEAP1, NFE2L2, PIK3CA, PTEN, RHOA, BRCA1, BRCA2 and TP53) as well as an RNA-based gene fusion panel including ALK, BRAF, FGFR1, FGFR2, FGFR3, MET, NRG1, NTRK1, NTRK2, NTRK3, RET and ROS1 on eleven formalin fixed and paraffin embedded small bowel carcinomas. Additionally, mismatch-repair-deficiency was analyzed by checking the microsatellite status using the five different mononucleotide markers BAT25, BAT26, NR-21, NR-22 and NR-27 and loss of mismatch repair proteins using four different markers (MLH1, MSH6, MSH2, PMS2).ResultsIn five out of eleven small bowel carcinomas we found potentially treatable genetic alterations. Three patients demonstrated pathogenic (class 5) BRCA1 or BRCA2 mutations – one germline-related in a mixed neuroendocrine-non neuroendocrine neoplasm (MiNEN). Two additional patients revealed an activating ERBB2 mutation or PIK3CA mutation.Furthermore two tumors were highly microsatellite-instable (MSI-high), in one case associated to Lynch-syndrome. We did not find any gene fusions.ConclusionOur results underscore, in particular, the relevance of potentially treatable molecular alterations (like ERBB2, BRCA and MSI) in small bowel carcinomas. Further studies are needed to proof the efficacy of these targeted therapies in small bowel carcinomas.
Highlights
Carcinomas of the small bowel are rare tumors usually with dismal prognosis
Parallel sequencing All tumors were analyzed for a panel of 14 different genes including RAS (K, N, H-RAS), DDR2, BRAF, ERBB2, KEAP1, PIK3CA, NFE2L2, PTEN, TP53, RHOA, Breast cancer gene 1 (BRCA1) and BRCA2 resulting in a total of 452 amplicons
In about half of our cohort we found potentially treatable genomic alterations in the genes BRCA, ERBB2 and PIK3CA as well as microsatellite instability
Summary
Carcinomas of the small bowel are rare tumors usually with dismal prognosis. Some potentially treatable molecular alterations were described. We emphasize the growing evidence of individualized treatment options in small bowel carcinoma. Small intestinal carcinomas account for about 3% of all gastro-intestinal tract tumors [1]. Recent epidemiological data were reported from a Netherland registry showing a 0.7 / 100,000 incidence [2]. Small bowel carcinoma has an annual incidence of about 6 cases per million and is much rarer than colo-rectal carcinomas, which have an incidence of about 420 cases per million inhabitants in the same period (1995–2002) [3,4,5]. The most common tumor location is the duodenum, followed by jejunum and ileum. The mean age at occurrence is in their middle to late sixties [6]
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