TY - JOUR
T1 - Observed evidence for guideline-recommended genes in predicting prostate cancer risk from a large population-based cohort
AU - Wei, Jun
AU - Yang, Wancai
AU - Shi, Zhuqing
AU - Lu, Lucy
AU - Wang, Qiang
AU - Resurreccion, W. Kyle
AU - Engelmann, Valentina
AU - Zheng, S. Lilly
AU - Hulick, Peter J.
AU - Cooney, Kathleen A.
AU - Isaacs, William B.
AU - Helfand, Brian T.
AU - Lu, Jim
AU - Xu, Jianfeng
N1 - Funding Information:
The authors are grateful to the Ellrodt-Schweighauser, Chez and Melman families for establishing Endowed Chairs of Cancer Genomic Research and Personalized Prostate Cancer Care at NorthShore University HealthSystem in support of Dr. Xu and Dr. Helfand. Likewise, the generous support from the Patrick C Walsh Hereditary Prostate Cancer program is gratefully acknowledged.
Publisher Copyright:
© 2021 Wiley Periodicals LLC
PY - 2021/9/15
Y1 - 2021/9/15
N2 - Background: Germline testing for prostate cancer (PCa) is now recommended by the National Comprehensive Cancer Network. While multi-gene testing has been proposed, evidence for their association with PCa risk is not well established. Methods: We tested associations of pathogenic/likely pathogenic mutations in 10 guideline-recommended genes (ATM, BRCA1, BRCA2, CHEK2, PALB2, MLH1, MSH2, MSH6, PMS2, and HOXB13) with PCa risk in the UK Biobank, a population-based cohort. Mutations were annotated based on prostate-specific transcripts using the American College of Medical Genetics and Genomics standards. Associations were tested in 4399 PCa cases and 85,403 unaffected male controls using logistic regression adjusting for age and genetic background. p <.005 was considered significant based on Bonferroni correction. Results: Among the 10 tested genes, significantly higher mutation carrier rates in PCa cases versus controls were found for four genes at p <.005; HOXB13, BRCA2, ATM, and CHEK2, with odds ratios (95% confidence interval) estimated at 4.96 (3.62–6.69), 3.23 (2.23–4.56), 2.95 (2.01–4.22), 1.94 (1.43–2.58), respectively. No significant association was found between mutation carrier status and age at PCa diagnosis or family history of PCa. Despite the large sample size of this study, statistical power remains limited, especially for genes where pathogenic mutation carrier rates are extremely rare (<0.03%). Conclusion: Observed evidence for PCa risk was found for four of the 10 guideline-recommended genes in this large population-based study. Mutations in these four genes can be interpreted with confidence in genetic counseling for PCa risk assessment. Evidence for the remaining six genes needs to be further evaluated in larger studies.
AB - Background: Germline testing for prostate cancer (PCa) is now recommended by the National Comprehensive Cancer Network. While multi-gene testing has been proposed, evidence for their association with PCa risk is not well established. Methods: We tested associations of pathogenic/likely pathogenic mutations in 10 guideline-recommended genes (ATM, BRCA1, BRCA2, CHEK2, PALB2, MLH1, MSH2, MSH6, PMS2, and HOXB13) with PCa risk in the UK Biobank, a population-based cohort. Mutations were annotated based on prostate-specific transcripts using the American College of Medical Genetics and Genomics standards. Associations were tested in 4399 PCa cases and 85,403 unaffected male controls using logistic regression adjusting for age and genetic background. p <.005 was considered significant based on Bonferroni correction. Results: Among the 10 tested genes, significantly higher mutation carrier rates in PCa cases versus controls were found for four genes at p <.005; HOXB13, BRCA2, ATM, and CHEK2, with odds ratios (95% confidence interval) estimated at 4.96 (3.62–6.69), 3.23 (2.23–4.56), 2.95 (2.01–4.22), 1.94 (1.43–2.58), respectively. No significant association was found between mutation carrier status and age at PCa diagnosis or family history of PCa. Despite the large sample size of this study, statistical power remains limited, especially for genes where pathogenic mutation carrier rates are extremely rare (<0.03%). Conclusion: Observed evidence for PCa risk was found for four of the 10 guideline-recommended genes in this large population-based study. Mutations in these four genes can be interpreted with confidence in genetic counseling for PCa risk assessment. Evidence for the remaining six genes needs to be further evaluated in larger studies.
KW - germline mutation
KW - guidelines
KW - prostate cancer
KW - risk
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U2 - 10.1002/pros.24195
DO - 10.1002/pros.24195
M3 - Article
C2 - 34254341
AN - SCOPUS:85109702691
SN - 0270-4137
VL - 81
SP - 1002
EP - 1008
JO - Prostate
JF - Prostate
IS - 13
ER -