Inherited mutations in BRCA1 and BRCA2 in an unselected multiethnic cohort of Asian patients with breast cancer and healthy controls from Malaysia

Abstract

BackgroundGenetic testing for BRCA1 and BRCA2 is offered typically to selected women based on age of onset and family history of cancer. However, current internationally accepted genetic testing referral guidelines are built mostly on data from cancer genetics clinics in women of European descent. To evaluate the appropriateness of such guidelines in Asians, we have determined the prevalence of germ line variants in an unselected cohort of Asian patients with breast cancer and healthy controls.MethodsGerm line DNA from a hospital-based study of 2575 unselected patients with breast cancer and 2809 healthy controls were subjected to amplicon-based targeted sequencing of exonic and proximal splice site junction regions of BRCA1 and BRCA2 using the Fluidigm Access Array system, with sequencing conducted on a Illumina HiSeq2500 platform. Variant calling was performed with GATK UnifiedGenotyper and were validated by Sanger sequencing.ResultsFifty-five (2.1%) BRCA1 and 66 (2.6%) BRCA2 deleterious mutations were identified among patients with breast cancer and five (0.18%) BRCA1 and six (0.21%) BRCA2 mutations among controls. One thousand one hundred and eighty-six (46%) patients and 97 (80%) carriers fulfilled the National Comprehensive Cancer Network guidelines for genetic testing.ConclusionFive per cent of unselected Asian patients with breast cancer carry deleterious variants in BRCA1 or BRCA2. While current referral guidelines identified the majority of carriers, one in two patients would be referred for genetic services. Given that such services are largely unavailable in majority of low-resource settings in Asia, our study highlights the need for more efficient guidelines to identify at-risk individuals in Asia.

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

“…Next we investigated the proportion of pathogenic variants shared between other Asian countries and this study to address how the Japanese data are relevant to other Asian populations. Two studies from China 18 and Malaysia 19 sequenced BRCA1/2 in >2000 selected and unselected breast cancer patients, respectively. The Chinese study identified 175 unique pathogenic variants in 247 of 2991 (8.3%) patients.…”

Hereditary breast and ovarian cancer (HBOC): review of its molecular characteristics, screening, treatment, and prognosis

“…Many recent reports have determined the frequency of BRCA1/2 mutation retention in patients with breast and ovarian cancers without selection bias, without considering family history, age of onset, and cancer subtype. Among all patients with breast cancer without selection bias, the BRCA1/2 mutation retention rate was 4.2-6.1% (BRCA1: 1.45-3.7%, BRCA2: 2.4-3.5%) [48][49][50][51][52]. Among patients with ovarian cancer, the retention rate of BRCA1/2 mutation was 8.3-14.7% (BRCA1: 3.4-9.9%, BRCA2: 4.7-5.3%) [53][54][55][56].…”

The relationship between BRCA-associated breast cancer and age factors: an analysis of the Japanese HBOC consortium database

“…This database includes 2054 female patients with breast cancer, 89 female patients with ovarian cancer patients, 62 female patients with both breast and ovarian cancers, 14 male breast cancer patients, and 147 individuals who had neither breast nor ovarian cancer. We compared the rate of each cohort with previous reports [23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] (Table 1).…”