Title | Rare loss of function variants in candidate genes and risk of colorectal cancer. |
Publication Type | Journal Article |
Year of Publication | 2018 |
Authors | Rosenthal 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 Authors | Jarvik GP |
Corporate Authors | NHLBI GO Exome Sequencing Project |
Journal | Hum Genet |
Volume | 137 |
Issue | 10 |
Pagination | 795-806 |
Date Published | 2018 Oct |
ISSN | 1432-1203 |
Keywords | Adolescent, 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. |
DOI | 10.1007/s00439-018-1938-4 |
Alternate Journal | Hum Genet |
PubMed ID | 30267214 |
PubMed Central ID | PMC6283057 |
Grant List | HHSN268201100046C / 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 |