BAX mutations are associated with an adverse prognosis in Lynch syndrome-associated colorectal cancer

Abstract

Lynch syndrome-associated colorectal cancer (CRC) is associated with a favorable prognosis compared to sporadic CRC, yet prognostic factors for Lynch syndrome-associated CRC are poorly investigated. We analyzed 70 colorectal neoplasms with high levels of microsatellite instability from 65 patients for frameshift mutations in the coding regions in the TGFBR2, ACVR2, BAX, MSH3, MSH6, AIM2, SEC63L genes as well as for P53 overexpression and loss of SMAD4 expression. In order to minimize selection bias, we restricted the evaluation of the prognostic value to 45 patients in whom MSI testing was initiated within 6 months after tumor diagnosis. TGFBR2, ACVR2, BAX, MSH3, MSH6, AIM2, and SEC63 frameshift mutations were detected in 55%, 87%, 52%, 23%, 30%, 25%, and 26%, respectively. Overexpression of P53 was detected in 64%, whereas loss or reduction of SMAD4 expression was observed in 7% and 33% respectively. MSH6 mutations occurred more frequently in MSH2 or MSH6 mutation carriers than in MLH1 mutation carriers (57% vs.11%, p=0.04). In addition SEC63L mutations were observed more frequently in right-sided CRC as compared to left-sided CRC (40% vs. 9%, p=0.02). No further correlations with sex, age at diagnosis, inclusion criteria (Amsterdam vs. Bethesda), mutation status, location or stage of the CRC, and resection status were observed. The median follow-up of the 45 patients evaluated for prognosis was 37 months with a total of 1839 person months. Seven patients died during the follow-up period: 5 due to CRC, 1 due to pancreatic cancer, 1 due to myocardial infarction. In univariate analysis BAX mutations, T stage (T3/4), positive nodal status (N+), metastatic disease (M1), resection status (non-R0), and UICC stage were significantly associated with an adverse overall (OS) and disease-specific survival (DSS). A strong negative trend was observed for TGFBR2 mutations.