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Gastroenterology. 2017 Jan;152(1):75-77.e4. doi: 10.1053/j.gastro.2016.09.041. Epub 2016 Oct 3.

Validation of Recently Proposed Colorectal Cancer Susceptibility Gene Variants in an Analysis of Families and Patients-a Systematic Review.

Author information

1
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
2
Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh.
3
Molecular and Population Genetics Laboratory and NIHR Biomedical Research Centre, Oxford Centre for Cancer Gene Research, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
4
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK; Division of Pathology, The Institute of Cancer Research, London, UK. Electronic address: richard.houlston@icr.ac.uk.

Abstract

High-throughput sequencing analysis has accelerated searches for genes associated with risk for colorectal cancer (CRC); germline mutations in NTHL1, RPS20, FANCM, FAN1, TP53, BUB1, BUB3, LRP6, and PTPN12 have been recently proposed to increase CRC risk. We attempted to validate the association between variants in these genes and development of CRC in a systematic review of 11 publications, using sequence data from 863 familial CRC cases and 1604 individuals without CRC (controls). All cases were diagnosed at an age of 55 years or younger and did not carry mutations in an established CRC predisposition gene. We found sufficient evidence for NTHL1 to be considered a CRC predisposition gene-members of 3 unrelated Dutch families were homozygous for inactivating p.Gln90Ter mutations; a Canadian woman with polyposis, CRC, and multiple tumors was reported to be heterozygous for the inactivating NTHL1 p.Gln90Ter/c.709+1G>A mutations; and a man with polyposis was reported to carry p.Gln90Ter/p.Gln287Ter; whereas no inactivating homozygous or compound heterozygous mutations were detected in controls. Variants that disrupted RPS20 were detected in a Finnish family with early-onset CRC (p.Val50SerfsTer23), a 39-year old individual with metachronous CRC (p.Leu61GlufsTer11 mutation), and a 41-year-old individual with CRC (missense p.Val54Leu), but not in controls. We therefore found published evidence to support the association between variants in NTHL1 and RPS20 with CRC, but not of other recently reported CRC susceptibility variants. We urge the research community to adopt rigorous statistical and biological approaches coupled with independent replication before making claims of pathogenicity.

KEYWORDS:

Colon Cancer; Exome Sequencing; Germline; Inherited

PMID:
27713038
PMCID:
PMC5860724
DOI:
10.1053/j.gastro.2016.09.041
[Indexed for MEDLINE]
Free PMC Article

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