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Rare loss of function variants in candidate genes and risk of colorectal cancer.

TitleRare loss of function variants in candidate genes and risk of colorectal cancer.
Publication TypeJournal Article
Year of Publication2018
AuthorsRosenthal EA, Shirts BH, Amendola LM, Horike-Pyne M, Robertson PD, Hisama FM, Bennett RL, Dorschner MO, Nickerson DA, Stanaway IB, Nassir R, Vickers KT, Li C, Grady WM, Peters U
Secondary AuthorsJarvik GP
Corporate AuthorsNHLBI GO Exome Sequencing Project
JournalHum Genet
Volume137
Issue10
Pagination795-806
Date Published2018 Oct
ISSN1432-1203
KeywordsAdolescent, Adult, Aged, Aged, 80 and over, BRCA2 Protein, Colorectal Neoplasms, Deoxyribonuclease (Pyrimidine Dimer), Fanconi Anemia Complementation Group Proteins, Female, Genetic Loci, Genetic Variation, Humans, Male, Middle Aged, Risk Factors, RNA Helicases
Abstract

Although ~ 25% of colorectal cancer or polyp (CRC/P) cases show familial aggregation, current germline genetic testing identifies a causal genotype in the 16 major genes associated with high penetrance CRC/P in only 20% of these cases. As there are likely other genes underlying heritable CRC/P, we evaluated the association of variation at novel loci with CRC/P. We evaluated 158 a priori selected candidate genes by comparing the number of rare potentially disruptive variants (PDVs) found in 84 CRC/P cases without an identified CRC/P risk-associated variant and 2440 controls. We repeated this analysis using an additional 73 CRC/P cases. We also compared the frequency of PDVs in select genes among CRC/P cases with two publicly available data sets. We found a significant enrichment of PDVs in cases vs. controls: 20% of cases vs. 11.5% of controls with ≥ 1 PDV (OR = 1.9, p = 0.01) in the original set of cases. Among the second cohort of CRC/P cases, 18% had a PDV, significantly different from 11.5% (p = 0.02). Logistic regression, adjusting for ancestry and multiple testing, indicated association between CRC/P and PDVs in NTHL1 (p = 0.0001), BRCA2 (p = 0.01) and BRIP1 (p = 0.04). However, there was no significant difference in the frequency of PDVs at each of these genes between all 157 CRC/P cases and two publicly available data sets. These results suggest an increased presence of PDVs in CRC/P cases and support further investigation of the association of NTHL1, BRCA2 and BRIP1 variation with CRC/P.

DOI10.1007/s00439-018-1938-4
Alternate JournalHum Genet
PubMed ID30267214
PubMed Central IDPMC6283057
Grant ListHHSN268201100046C / HL / NHLBI NIH HHS / United States
RC2 HL-102926 / HL / NHLBI NIH HHS / United States
U01 HG006507 / HG / NHGRI NIH HHS / United States
U24 HG007307 / HG / NHGRI NIH HHS / United States
UO1152756 / NH / NIH HHS / United States
HHSN268201100002I / HL / NHLBI NIH HHS / United States
HHSN268201600001C / HL / NHLBI NIH HHS / United States
HHSN268201100001I / HL / NHLBI NIH HHS / United States
RC2 HL102923 / HL / NHLBI NIH HHS / United States
RC2 HL-102924 / HL / NHLBI NIH HHS / United States
HHSN268201600002C / HL / NHLBI NIH HHS / United States
RC2 HL102926 / HL / NHLBI NIH HHS / United States
UO1 HG007307 / HG / NHGRI NIH HHS / United States
P30 CA015704 / CA / NCI NIH HHS / United States
P30 DK043351 / DK / NIDDK NIH HHS / United States
HHSN268201600018C / HL / NHLBI NIH HHS / United States
R01 CA189184 / CA / NCI NIH HHS / United States
RC2 HL-102923 / HL / NHLBI NIH HHS / United States
HHSN268201100003C / WH / WHI NIH HHS / United States
UO1 HG006507 / HG / NHGRI NIH HHS / United States
HHSN268201600003C / HL / NHLBI NIH HHS / United States
HHSN271201100004C / AG / NIA NIH HHS / United States
HHSN268201100002C / WH / WHI NIH HHS / United States
HHSN268201100004C / HL / NHLBI NIH HHS / United States
HHSN268201600004C / HL / NHLBI NIH HHS / United States
RO1CA194663 / CA / NCI NIH HHS / United States
2P30CA015704-40 / CA / NCI NIH HHS / United States
RC2 HL103010 / HL / NHLBI NIH HHS / United States
S10 OD020069 / OD / NIH HHS / United States
RC2 HL-102925 / HL / NHLBI NIH HHS / United States
U01 CA152756 / CA / NCI NIH HHS / United States
HHSN268201100001C / WH / WHI NIH HHS / United States
R01 CA194663 / CA / NCI NIH HHS / United States
RC2 HL-103010 / HL / NHLBI NIH HHS / United States
U01 HG007307 / HG / NHGRI NIH HHS / United States
X01-HG006196 / NH / NIH HHS / United States
RO1CA189184 / CA / NCI NIH HHS / United States