Germline Pathogenic Variants in 7636 Japanese Patients With Prostate Cancer and 12 366 Controls

Abstract

Background Genetic testing has been conducted in patients with prostate cancer (PCa) using multigene panels, but no centralized guidelines for genetic testing exist. To overcome this limitation, we investigated the demographic and clinical characteristics of patients with pathogenic variants. Methods We sequenced eight genes associated with hereditary PCa in 7636 unselected Japanese patients with PCa and 12 366 male, cancer-free control individuals. We assigned clinical significance for all 1456 variants using the American College of Medical Genetics and Genomics guidelines and ClinVar. We compared the frequency of carriers bearing pathogenic variants between cases and control participants with calculated PCa risk in each gene and documented the demographic and clinical characteristics of patients bearing pathogenic variants. All statistical tests were two-sided. Results We identified 136 pathogenic variants, and 2.9% of patients and 0.8% of control individuals had a pathogenic variant. Association with PCa risk was statistically significant for variants in BRCA2 (P < .001, odds ratio [OR] = 5.65, 95% confidence interval [CI] = 3.55 to 9.32), HOXB13 (P < .001, OR = 4.73, 95% CI = 2.84 to 8.19), and ATM (P < .001, OR = 2.86, 95% CI = 1.63 to 5.15). We detected recurrent new pathogenic variants such as p.Gly132Glu of HOXB13. Patients with pathogenic variants were 2.0 years younger at diagnosis and more often had smoking and alcohol drinking histories as well as family histories of breast, pancreatic, lung, and liver cancers. Conclusions This largest sequencing study of PCa heredity provides additional evidence supporting the latest consensus among clinicians for developing genetic testing guidelines for PCa.

Rare germline genetic variants and risk of aggressive prostate cancer

“…Table 2 and Figure 1 illustrate the volume of genetic variation that is identified when using gene panel tests and that the data generated for the majority of genes included in these tests is currently uninterpretable. Interpretation of the genetic variation in genes such as BRCA1 , BRCA2 , HOXB13 and ATM , for which data has been accumulating for some time, is more advanced but a considerable proportion of the variants remain of uncertain significance 18,48,49 …”

Population-wide Screening for Germline Variants of Hereditary Cancer Genes in 12K Unselected Japanese Colorectal Cancers and 27K Controls

“…We selected 27 genes, including the 12 genes recommended by the NCCN guidelines whose rare germline variants were reported to show high penetrance for CRC and hereditary cancers (17). We analyzed the complete coding regions and 2-bp flanking intronic sequences of all 27 genes, except exons 10-15 of PMS2, (84,822 bp) by a multiplex PCR-based target sequence method (16,18). We called single nucleotide variants (SNVs) and insertion or deletion (INDELs) of each individual separately using UnifiedGenotyper and HaplotypeCaller of GATK, as described previously (16,18).…”

“…We analyzed the complete coding regions and 2-bp flanking intronic sequences of all 27 genes, except exons 10-15 of PMS2, (84,822 bp) by a multiplex PCR-based target sequence method (16,18). We called single nucleotide variants (SNVs) and insertion or deletion (INDELs) of each individual separately using UnifiedGenotyper and HaplotypeCaller of GATK, as described previously (16,18). Genotypes for all individuals were jointly determined for each variant based on the sequencing read ratio of reference and alternative alleles.…”

“…We assigned clinical significance (pathogenic, benign, or uncertain) for all variants, as in our previous study (16,18) with some modifications. Briefly, we determined clinical significance using the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines (19) as well as the pathogenicity assertions registered in ClinVar.…”

Analysis of Epigenetic Alterations in Homologous Recombination DNA Repair Genes in Male Breast Cancer

“…Indeed, the balance between BRCA2, RAD51 and RAD51 paralogs seems to be essential in HRR [8,12,13]. Mutations in HRR genes, either somatic and/ or in the germline occur in multiple conditions, including hereditary breast and ovarian cancer susceptibility syndromes, in which there is also increased male BC risk [2,8,[14][15][16][17]. Nonetheless, HRR deficiency may also be mediated by DNA repair gene aberrant promoter methylation.…”