Novel recurrently mutated genes and a prognostic mutation signature in colorectal cancer

Abstract

BackgroundCharacterisation of colorectal cancer (CRC) genomes by next-generation sequencing has led to the discovery of novel recurrently mutated genes. Nevertheless, genomic data has not yet been used for CRC prognostication.ObjectiveTo identify recurrent somatic mutations with prognostic significance in patients with CRC.MethodExome sequencing was performed to identify somatic mutations in tumour tissues of 22 patients with CRC, followed by validation of 187 recurrent and pathway-related genes using targeted capture sequencing in additional 160 cases.ResultsSeven significantly mutated genes, including four reported (APC, TP53, KRAS and SMAD4) and three novel recurrently mutated genes (CDH10, FAT4 and DOCK2), exhibited high mutation prevalence (6–14% for novel cancer genes) and higher-than-expected number of non-silent mutations in our CRC cohort. For prognostication, a five-gene-signature (CDH10, COL6A3, SMAD4, TMEM132D, VCAN) was devised, in which mutation(s) in one or more of these genes was significantly associated with better overall survival independent of tumor-node-metastasis (TNM) staging. The median survival time was 80.4 months in the mutant group versus 42.4 months in the wild type group (p=0.0051). The prognostic significance of this signature was successfully verified using the data set from the Cancer Genome Atlas study.ConclusionsThe application of next-generation sequencing has led to the identification of three novel significantly mutated genes in CRC and a mutation signature that predicts survival outcomes for stratifying patients with CRC independent of TNM staging.

Fat4 suppression induces Yap translocation accounting for the promoted proliferation and migration of gastric cancer cells

“…[1][2][3][4][5][6][7] However reports recognizing it as a tumor suppressor in human cancers are limited. Fat4 gene mutations and decreased expression were observed in esophageal, hepatocellular, colorectal cancer and gastric cancer, 11,12,15,18 however the signaling cascades and regulatory mechanisms lying downstream of Fat4 remain unclear. In the present study, we first investigated the functional role of Fat4 by observing the effects of Fat4 silencing on proliferation and migration and evaluating expression of various components of the Hippo signaling cascade, including p-LATS1, LATS1, pYap and Yap.…”

“…Although previous studies [11][12][13][14][15][16][17][18] demonstrate that Fat4 acts as tumor suppressor in a variety of cancers, the clinical relevance of Fat4 in GC remained unclear until now. We therefore examined the clinicopathological significance of Fat4 expression in 122 gastric cancer samples and 85 adjacent noncancerous samples based on immunohistochemistry (IHC) staining patterns.…”

“…Several studies using genome or exome sequencing have identified frequent, non-synonymous Fat4 mutations in esophageal squamous cell carcinoma (27%), 10,11 hepatocellular carcinoma (1/ 10), 12 melanoma (2/9) 13 and head and neck squamous cell carcinoma (2/32). 14 In colorectal cancer, 15 Fat4 mutation was observed in 14.4% of studied cases and was associated with poor prognosis. Fat4 promoter hypermethylation was observed in lung cancer (7/18) 16 and breast cancer.…”

Distinct Subtypes of Gastric Cancer Defined by Molecular Characterization Include Novel Mutational Signatures with Prognostic Capability

“…All samples were collected from patients diagnosed with primary gastric cancer with long-term survival data (15-60 months). Data were analyzed using a bioinformatic pipeline as previously described (31). All patients had given written informed consent, and the study protocol was approved by the clinical ethics committee of the Peking University Cancer Hospital & Institute (Beijing, China).…”

Revealing genomic profile that underlies tropism of myeloma cells using whole exome sequencing

“…Varscan2 which was used in our study for somatic variant calling is one of the most commonly used tools to detect somatic mutation along with MuTect [12,17]. In fact, many papers already published in the field of cancer genomics already used Varscan2 [18][19][20].…”