期刊
GASTROENTEROLOGY
卷 152, 期 1, 页码 75-+出版社
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2016.09.041
关键词
Colon Cancer; Inherited; Germline; Exome Sequencing
资金
- Cancer Research UK Research [C1298/A8362]
- European Union (FP7) [258236]
- FP7 collaborative project SYSCOL
- Bloodwise
- National Cancer Research Network
- National Health Service
- Oxford Comprehensive Biomedical Research Centre (Wellcome Trust) [090532/Z/09/Z]
- Cancer Research UK [C348/A12076]
- Medical Research Council [MR/KO18647/1, WT095219MA, G1001799]
- Wellcome Trust
- COST Action [BM1206]
- MRC [MC_PC_U127527198, MC_U127527198, MR/N01104X/1, MR/N01104X/2, MR/K018647/1, G1001799] Funding Source: UKRI
- Cancer Research UK [15116, 18927, 12076, 16459] Funding Source: researchfish
- Medical Research Council [MC_PC_U127527198, MR/K018647/1, MR/N01104X/1, G1001799, MR/N01104X/2, MC_U127527198] Funding Source: researchfish
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.
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