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Rare loss of function variants in candidate genes and risk of colorectal cancer.
Wednesday,2018-10-03 18:41 America/Los_Angeles — ecterry
| 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, Jarvik, GP |
| Corporate/Institutional Authors | NHLBI GO Exome Sequencing Project |
| Journal | Hum Genet |
| Date Published | 2018 Sep 28 |
| ISSN | 1432-1203 |
| Abstract | <p>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.</p> |
| DOI | 10.1007/s00439-018-1938-4 |
| Alternate Journal | Hum. Genet. |
| PubMed ID | 30267214 |
| Grant List | UO1 HG006507 / / National Human Genome Research Institute / UO1 HG007307 / / National Human Genome Research Institute / HHSN268201600018C / / National Heart, Lung, and Blood Institute / HHSN268201600001C / / National Heart, Lung, and Blood Institute / HHSN268201600002C / / National Heart, Lung, and Blood Institute / HHSN268201600003C / / National Heart, Lung, and Blood Institute / HHSN268201600004C / / National Heart, Lung, and Blood Institute / HHSN268201100046C / / National Heart, Lung, and Blood Institute / HHSN268201100001C / / National Heart, Lung, and Blood Institute / HHSN268201100002C / / National Heart, Lung, and Blood Institute / HHSN268201100003C / / National Heart, Lung, and Blood Institute / HHSN268201100004C / / National Heart, Lung, and Blood Institute / HHSN271201100004C / / National Heart, Lung, and Blood Institute / RC2 HL-103010 / / National Heart, Lung, and Blood Institute / RC2 HL-102923 / / National Heart, Lung, and Blood Institute / RC2 HL-102924 / / National Heart, Lung, and Blood Institute / RC2 HL-102925 / / National Heart, Lung, and Blood Institute / RC2 HL-102926 / / National Heart, Lung, and Blood Institute / X01-HG006196 / / National Institutes of Health / UO1152756 / / National Institutes of Health / 2P30CA015704-40 / / National Cancer Institute / RO1CA194663 / / National Cancer Institute / RO1CA189184 / / National Cancer Institute / |
ePub date:
18/09