Two-stage Study of Familial Prostate Cancer by Whole-exome Sequencing and Custom Capture Identifies 10 Novel Genes Associated with the Risk of Prostate Cancer

Abstract

Background: Family history of prostate cancer (PCa) is a well-known risk factor, and both common and rare genetic variants are associated with the disease.

Objective: To detect new genetic variants associated with PCa, capitalizing on the role of family history and more aggressive PCa.

Design, setting, and participants: A two-stage design was used. In stage one, whole-exome sequencing was used to identify potential risk alleles among affected men with a strong family history of disease or with more aggressive disease (491 cases and 429 controls). Aggressive disease was based on a sum of scores for Gleason score, node status, metastasis, tumor stage, prostate-specific antigen at diagnosis, systemic recurrence, and time to PCa death. Genes identified in stage one were screened in stage two using a custom-capture design in an independent set of 2917 cases and 1899 controls.

Outcome measurements and statistical analysis: Frequencies of genetic variants (singly or jointly in a gene) were compared between cases and controls.

Results and limitations: Eleven genes previously reported to be associated with PCa were detected (ATM, BRCA2, HOXB13, FAM111A, EMSY, HNF1B, KLK3, MSMB, PCAT1, PRSS3, and TERT), as well as an additional 10 novel genes (PABPC1, QK1, FAM114A1, MUC6, MYCBP2, RAPGEF4, RNASEH2B, ULK4, XPO7, and THAP3). Of these 10 novel genes, all but PABPC1 and ULK4 were primarily associated with the risk of aggressive PCa.

Conclusions: Our approach demonstrates the advantage of gene sequencing in the search for genetic variants associated with PCa and the benefits of sampling patients with a strong family history of disease or an aggressive form of disease.

Patient summary: Multiple genes are associated with prostate cancer (PCa) among men with a strong family history of this disease or among men with an aggressive form of PCa.

Keywords: Custom-capture sequencing; Familial prostate cancer; Genetic risk variants; Whole-exome sequencing.

Fig. 1 –

Flow of samples excluded from stage one (primary and auxiliary samples) and stage two, resulting in sample sizes used in analyses at the bottom of the figure. QC = quality control; WES = whole-exome sequencing.

Fig. 2 –

Manhattan plots of stage-two associations of single variants with PCa. The x axes show the chromosomal positions and the y axes show the −log10 p value. (A) All PCa cases versus controls. (B) PCa cases with a positive family history versus controls. (C) Aggressive PCa cases versus controls; (D) Aggressive PCa cases versus nonaggressive PCa cases. Statistical analyses based on log-additive effects of alternate alleles. PCa = prostate cancer.

Fig. 3 –

Manhattan plots of stage-two SKAT-O gene-level associations with PCa. The x axes show the chromosomal positions and the y axes show the −log10 p value. (A) All PCa cases versus controls. (B) PCa cases with a positive family history versus controls. (C) Aggressive PCa cases versus controls. D) Aggressive PCa cases versus nonaggressive PCa cases. PCa = prostate cancer.