Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls

Abstract

Pathogenic variants in highly penetrant genes are useful for the diagnosis, therapy, and surveillance for hereditary breast cancer. Large-scale studies are needed to inform future testing and variant classification processes in Japanese. We performed a case-control association study for variants in coding regions of 11 hereditary breast cancer genes in 7051 unselected breast cancer patients and 11,241 female controls of Japanese ancestry. Here, we identify 244 germline pathogenic variants. Pathogenic variants are found in 5.7% of patients, ranging from 15% in women diagnosed <40 years to 3.2% in patients ≥80 years, with BRCA1/2, explaining two-thirds of pathogenic variants identified at all ages. BRCA1/2, PALB2, and TP53 are significant causative genes. Patients with pathogenic variants in BRCA1/2 or PTEN have significantly younger age at diagnosis. In conclusion, BRCA1/2, PALB2, and TP53 are the major hereditary breast cancer genes, irrespective of age at diagnosis, in Japanese women.

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

“…Clinical characteristics of CRC cases and controls were collected by interview or medical record survey using a standard questionnaire at the point of entry to Biobank Japan (15). We selected 12,606 CRC cases from this cohort and used the same 23,780 controls aged ≥ 60 years with no personal or family history of cancer from our previous study on breast cancer [16]. All participants provided written informed consent.…”

“…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.…”

Evaluation of ACMG Rules for In silico Evidence Strength Using An Independent Computational Tool Absent of Circularities on ATM and CHEK2 Breast Cancer Cases and Controls

“…Participants in this study were also screened against having a BRCA1/2 pathogenic variant. The third study was a large scale study performed on Japanese women from Biobank Japan published by Momozawa et al (2018). In the Momozawa et al data, one case subject was excluded for both genes as the subjects also had a pathogenic rMS variant in BRCA2, meaning the number of cases analyzed in this work for both genes was 7,050.…”