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

Elisabeth A Rosenthal; Brian H Shirts; Laura M Amendola; Martha Horike-Pyne; Peggy D Robertson; Fuki M Hisama; Robin L Bennett; Michael O Dorschner; Deborah A Nickerson; Ian B Stanaway; Rami Nassir; Kathy T Vickers; Christopher Li; William M Grady; Ulrike Peters; Gail P Jarvik; NHLBI GO Exome Sequencing Project

doi:10.1007/s00439-018-1938-4

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

Journal article

Peer reviewed

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

Elisabeth A Rosenthal, Brian H Shirts, Laura M Amendola, Martha Horike-Pyne, Peggy D Robertson, Fuki M Hisama, Robin L Bennett, Michael O Dorschner, Deborah A Nickerson, Ian B Stanaway, …

Human genetics, Vol.137(10), pp.795-806

10/2018

DOI: 10.1007/s00439-018-1938-4

PMCID: PMC6283057

PMID: 30267214

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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.

Adolescent

Adult

Aged

Aged, 80 and over

BRCA2 Protein - genetics

Colorectal Neoplasms - genetics

Deoxyribonuclease (Pyrimidine Dimer) - genetics

Fanconi Anemia Complementation Group Proteins - genetics

Female

Genetic Loci

Genetic Variation

Humans

Male

Middle Aged

Risk Factors

RNA Helicases - genetics

Details

Title: Subtitle: Rare loss of function variants in candidate genes and risk of colorectal cancer
Creators: Elisabeth A Rosenthal - University of Washington Medical Center
Brian H Shirts - University of Washington
Laura M Amendola - University of Washington Medical Center
Martha Horike-Pyne - University of Washington Medical Center
Peggy D Robertson - University of Washington
Fuki M Hisama - University of Washington
Robin L Bennett - University of Washington Medical Center
Michael O Dorschner - University of Washington
Deborah A Nickerson - University of Washington
Ian B Stanaway - University of Washington
Rami Nassir - University of California, Davis
Kathy T Vickers - Fred Hutch Cancer Center
Christopher Li - Fred Hutch Cancer Center
William M Grady - University of Washington School of Medicine
Ulrike Peters - University of Washington
Gail P Jarvik - University of Washington
NHLBI GO Exome Sequencing Project
Contributors: Jennifer G Robinson (Contributor) - University of Iowa, Fraternal Order of Eagles Diabetes Research Center
Robert Wallace (Contributor) - University of Iowa, Internal Medicine
Resource Type: Journal article
Publication Details: Human genetics, Vol.137(10), pp.795-806
DOI: 10.1007/s00439-018-1938-4
PMID: 30267214
PMCID: PMC6283057
NLM abbreviation: Hum Genet
ISSN: 0340-6717
eISSN: 1432-1203
Grant note: HHSN271201100004C / NIA NIH HHS U01 CA152756 / NCI NIH HHS RO1CA189184 / NCI NIH HHS HHSN268201600003C / NHLBI NIH HHS P30 CA015704 / NCI NIH HHS R01 CA194663 / NCI NIH HHS RC2 HL-103010 / NHLBI NIH HHS RC2 HL102923 / NHLBI NIH HHS 2P30CA015704-40 / NCI NIH HHS T15 LM007442 / NLM NIH HHS HHSN268201600018C / NHLBI NIH HHS HHSN268201100002C / WHI NIH HHS X01-HG006196 / NIH HHS HHSN268201600002C / NHLBI NIH HHS RC2 HL-102926 / NHLBI NIH HHS HHSN268201100003C / WHI NIH HHS UO1152756 / NIH HHS RC2 HL103010 / NHLBI NIH HHS HHSN268201100002I / NHLBI NIH HHS RC2 HL-102923 / NHLBI NIH HHS HHSN268201100001C / WHI NIH HHS S10 OD020069 / NIH HHS HHSN268201600001C / NHLBI NIH HHS R01 CA189184 / NCI NIH HHS UO1 HG006507 / NHGRI NIH HHS RC2 HL102926 / NHLBI NIH HHS RO1CA194663 / NCI NIH HHS RC2 HL-102925 / NHLBI NIH HHS U01 HG006507 / NHGRI NIH HHS HHSN268201100046C / NHLBI NIH HHS U24 HG007307 / NHGRI NIH HHS HHSN268201100001I / NHLBI NIH HHS HHSN268201600004C / NHLBI NIH HHS HHSN268201100004C / NHLBI NIH HHS P30 DK043351 / NIDDK NIH HHS RC2 HL-102924 / NHLBI NIH HHS U01 HG007307 / NHGRI NIH HHS UO1 HG007307 / NHGRI NIH HHS
Language: English
Date published: 10/2018
Academic Unit: Epidemiology; Fraternal Order of Eagles Diabetes Research Center; Injury Prevention Research Center; Internal Medicine
Record Identifier: 9984364423602771

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