Open AccessClinicopathological characterization of SMAD4-mutated intestinal adenocarcinomas: A case-control study
Author(s) -
Xiaoyan Liao,
Yansheng Hao,
Xiaofei Zhang,
Stephen Ward,
Jane Houldsworth,
Alexandros Polydorides,
Noam Harpaz
Publication year - 2019
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0212142
Subject(s) - kras , adenocarcinoma , colorectal cancer , cancer research , biology , mutation , mucin , gene , cancer , pathology , medicine , genetics
The SMAD4 tumor suppressor gene product inhibits transforming growth factor-β-mediated signaling and is mutated in ~10% of colorectal carcinomas. The prognostic significance of SMAD4 mutations has been controversial. We studied the pathological and clinical characteristics of SMAD4 -mutated intestinal adenocarcinomas using a retrospective case-control study design. Cases and controls were identified among 443 primary adenocarcinomas that had undergone next generation DNA sequencing (NGS) with the Ion AmpliSeq Cancer Hotspot Panel v2, which evaluates 50 cancer-related genes. Twenty-eight SMAD4 -mutated ( SMAD4 m) patients were matched 1:2 with 56 consecutive SMAD4 wild-type ( SMAD4 wt) control patients from the same analysis stream. Compared with the SMAD4 wt controls, the SMAD4 m tumors were of higher stage ( P = 0.026) and were more likely to feature mucinous differentiation ( P = 0.0000), to occur in the setting of Crohn’s disease ( P = 0.0041), and to harbor concurrent RAS mutations ( P = 0.0178). Tumor mucin content was significantly correlated with mutations involving the MH2 domain of the SMAD4 protein ( P = 0.0338). Correspondence between mutation sites and morphology was demonstrated directly in a mixed adenocarcinoma and neuroendocrine tumor where SMAD4 mutations involving different protein domains were found in histologically disparate tumor regions despite both containing identical KRAS and TP53 mutations.