Comprehensive molecular characterization of human colon and rectal cancer

Abstract

Summary To characterize somatic alterations in colorectal carcinoma (CRC), we conducted genome-scale analysis of 276 samples, analyzing exome sequence, DNA copy number, promoter methylation, mRNA and microRNA expression. A subset (97) underwent low-depth-of-coverage whole-genome sequencing. 16% of CRC have hypermutation, three quarters of which have the expected high microsatellite instability (MSI), usually with hypermethylation and MLH1 silencing, but one quarter has somatic mismatch repair gene mutations. Excluding hypermutated cancers, colon and rectum cancers have remarkably similar patterns of genomic alteration. Twenty-four genes are significantly mutated. In addition to the expected APC, TP53, SMAD4, PIK3CA and KRAS mutations, we found frequent mutations in ARID1A, SOX9, and FAM123B/WTX. Recurrent copy number alterations include potentially drug-targetable amplifications of ERBB2 and newly discovered amplification of IGF2. Recurrent chromosomal translocations include fusion of NAV2 and WNT pathway member TCF7L1. Integrative analyses suggest new markers for aggressive CRC and important role for MYC-directed transcriptional activation and repression.

Mutation analysis of adenomas and carcinomas of the colon: Early and late drivers

“…The high mutation frequency is consistent with observations of other groups 19. One hundred and twenty‐one genes were found to be mutated in both of the MSI tumors in this study.…”

“…With the exception of OBSCN, this finding is consistent with the colon carcinoma sequencing results from The Cancer Genome Atlas Network (TCGA) 19. In addition, they saw less frequently mutated FBXW7 (11%), SMAD4 (10%), TCF7L2 (9%) and NRAS (9%).…”

Adenoma development in familial adenomatous polyposis and MUTYH‐associated polyposis: somatic landscape and driver genes

“…Captured material was indexed and sequenced on the Illumina platform at the Wellcome Trust Sanger Institute. Targeted capture sequencing was performed using baits designed against the genes APC , WTX/FAM123B , ATRNL1 , BCL9L , BRCA1 , BRCA2 , CXCR5 , DMD , FBXW7 , GPR112 , HUWE1 , KMT2C/MLL3 , NF1 , PTEN , SLFN5 , SMAD4 , SORCS1 , TP53 , UBR2 and ZNF37A , selected for sequencing on the basis of being recurrently mutated, or truncated, in the unfiltered whole‐exome sequencing data; these genes are also enriched for non‐silent mutations in the genome sequencing of sporadic CRC 9. A breakdown of the sequencing metrics for each sample is provided in Figure S1 (see supplementary material).…”

“…As a corollary, the multiplicity of tumours in patients with germline mutations in these genes differ and clinical outcomes and responses to therapy can vary, suggesting a complex interplay between the germline genetics of each patient and the somatic landscape of adenomas and tumours that develop within the bowel 8. Despite major initiatives to analyse sporadic colorectal cancers 9, little is known about the somatic landscape of tumours from patients with hereditary forms of the disease. Here we set out to profile somatic mutations in pre‐malignant adenomas in two hereditary colon cancer syndromes, FAP and MAP.…”

“…The Cancer Genome Atlas (TCGA) characterized the genomes of 276 sporadic colorectal cancers, focusing almost exclusively on invasive cancers and metastatic tumours 9. Other studies have analysed the exomes of microsatellite‐instable (MSI) primary cancers 18, while Nikolaev et al 19 performed a detailed and comprehensive analysis of 24 sporadic adenomas, revealing a signature of deamination (C → T at CpG sites), suggesting a role for replication stress in mutational acquisition.…”