Discoveries beyond BRCA1/2: Multigene testing in an Asian multi-ethnic cohort suspected of hereditary breast cancer syndrome in the real world

Abstract

BackgroundDue to historically low uptake of genetic testing, the mutational spectrum of Asians with Hereditary Breast Cancer (HBC) is not well understood. This study sought to understand the incidence and spectrum of germline mutations in Asian patients with suspected HBC in a clinic setting.Methods1056 patients with suspected HBC were seen in our Cancer (CA) Genetics Clinic from 2000–2017, of which 460 underwent genetic testing.ResultsOf 460 probands tested, 93% were female, 61% Chinese, 90% had prior CA, with 19% (77/414) having ≥2 primary CA. Median age at CA-diagnosis was 43y (17–83); 70% had Breast CA (BC) and 25% Ovarian CA (OC). 34% had young-onset BC, 8% bilateral BC, and 4% BC/OC. Majority had family history of BC (53%) or OC (20%). 57% underwent multigene testing (14–49 genes), 34% targeted testing, and 8% predictive testing. 30% were found to have a pathogenic mutation: 80% in BRCA1/2 (8 novel mutations noted). Of 33 non-BRCA1/2 pathogenic mutations detected, 61% were in 11 BC genes while 39% were in non-BC genes suggestive of alternative CA syndromes. Testing beyond BRCA1/2 impacted management for 15.9% (22/138) of carriers, but extensive testing identified variants of uncertain significance (VUS) in up to 44.5% of probands. Restricting multigene panel testing to a guideline-based 20-gene panel including Lynch Syndrome genes was found to be most optimal, detecting 94.6% of mutation carriers while reducing VUS rate to 21.5%.ConclusionsEvolution of CA Genetics testing strategy to a multigene approach facilitated detection of pathogenic mutations in non-BRCA1/2 genes and aided management. Guideline-based panel testing is feasible and can be offered in Asians with suspected HBC.

Double heterozygous pathogenic variants in the BRCA1 and BRCA2 genes in a patient with bilateral metachronous breast cancer: a case report

“…One of the seven mentioned families is from Argentina [15][16]. It was also reported in two sisters with ovarian cancer at 39 and 57 years old from other Chinese family (17]. The BRCA1 variant of our patient was located outside the region bounded by positions c.2282 to c.4071 which is associated with a significantly higher breast cancer risk compared with mutations inside the region [1].…”

Characteristics of Germline Non-BRCA Mutation Status of High-Risk Breast Cancer Patients in China and Correlation with High-Risk Factors and Multigene Testing Suggestions

“…However, only a few studies to date report the prevalence of non- BRCA genes in the Chinese population. Samuel Guan Wei Ow et al analyzed 419 Asian patients suspected to have hereditary breast cancer syndrome who underwent genetic testing and found that the frequency of detrimental mutations in non- BRCA genes varied from 0 to 13.3% due to differences in ethnicity ( Ow et al, 2019 ). Using a 40 gene panel, another study found a non- BRCA gene mutation rate of 6.8% in a cohort of 937 Chinese breast cancer patients, with TP53 (1.9%), PALB2 (1.2%), CHEK2 (0.6%) and ATM (0.6%) being the major non- BRCA genes identified ( Li et al, 2019 ).…”

The management of BRCA1 and BRCA2 carriers in Singapore

“…This is especially important in a multiethnic population like Singapore, where there are often limited allelic frequency data available in the public domain for variant classification (37)(38)(39). Genetic data is lacking for much of Singapore's diverse Asian population and this results in a higher rate of VUS (40,41). Due to these limitations, all genetic test reports are discussed at a weekly family review meeting, where the genetics team reviews every report and ensure the correct interpretation of all variants, paying attention to the population source of the reported allelic frequencies.…”