Identification of large genomic rearrangement of BRCA1/2 in high risk patients in Korea

Do-Hoon Kim,Gun Dong Lee,Soo Young Hur,Hyojin Chae,Woori Jang,Joonhong Park,Myungshin Kim,Irene Jo,Hyeyoung Lee,Byung Joo Chae,Yonggoo Kim,Jaeeun Yoo,Keun Ho Lee,Byung Joo Song,Dong-Seok Jeon

doi:10.1186/s12881-017-0398-3

Do-Hoon Kim, Gun Dong Lee + Show 13 more

Open Access

https://doi.org/10.1186/s12881-017-0398-3

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Abstract

BackgroundWhile the majority of germline inactivating mutations in BRCA1/2 are small-scale mutations, large genomic rearrangements (LGRs) are also detected in a variable proportion of patients. However, routine genetic methods are incapable of detecting LGRs, and comprehensive genetic testing algorithm is necessary.MethodsWe performed multiplex ligation-dependent probe amplification assay for small-scale mutation negative patients at high-risk for LGR, based on previously published LGR risk criteria. The inclusion criteria for the high-risk subgroup were personal history of 1) early-onset breast cancer (diagnosed at ≤36 years); 2) two breast primaries; 3) breast cancer diagnosed at any age, with ≥1 close blood relatives (includes first-, second-, or third-degree) with breast and/or epithelial ovarian cancer; 4) both breast and epithelial ovarian cancer diagnosed at any age; and 5) epithelial ovarian cancer with ≥1 close blood relatives with breast and/or epithelial ovarian cancer.ResultsTwo LGRs were identified. One was a heterozygous deletion of exon 19 and the other was a heterozygous duplication of exon 4–6. The prevalence of LGRs was 7% among Sanger-negative, high-risk patients, and accounted for 13% of all BRCA1 mutations and 2% of all patients. Moreover, LGRs reported in Korean patients, including our 2 newly identified cases, were found exclusively in families with at least one high-risk feature.ConclusionsOur result suggests that selective LGR screening for Sanger-negative, high-risk patients is necessary for Korean patients.

Highlights

While the majority of germline inactivating mutations in BRCA1/2 are small-scale mutations, large genomic rearrangements (LGRs) are detected in a variable proportion of patients
According to a large nationwide prospective Korean Hereditary Breast Cancer (KOHBRA) study, 153 distinct BRCA1/2 mutations have been identified in Korean breast cancer patients with a family history of breast/ovarian cancer resulting in a prevalence of 22.3% [3]
Large genomic rearrangement (LGR) of BRCA1 and BRCA2, which is another mechanism of gene inactivation, is responsible for a variable but significant proportion of BRCA mutations [5]

Summary

Introduction

While the majority of germline inactivating mutations in BRCA1/2 are small-scale mutations, large genomic rearrangements (LGRs) are detected in a variable proportion of patients. Routine genetic methods are incapable of detecting LGRs, and comprehensive genetic testing algorithm is necessary. Genetic counselling and genetic testing of BRCA1 and BRCA2 for the presence of germline inactivating mutations have been increasingly offered to identify individuals at elevated risk of breast and ovarian cancer in Korea. Kim et al BMC Medical Genetics (2017) 18:38 and insertions) Such mutations occur throughout the whole coding sequence and at the splice junctions of both genes. In Korea, reported LGR cases are few, and routine PCR-based genetic testing methods are not capable of detecting LGRs. an efficient genetic testing algorithm that incorporates LGR testing is necessary for accurate mutational screening of high-risk patients

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