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Genomic Signatures from Clinical Tumor Sequencing in Patients with Breast Cancer Having Germline BRCA1/2 Mutation

배수연|박경화|윤승규|정승필|강효은|유지영|최지미|김열홍|최윤지|김주원
대한암학회 (Korean Cancer Association)|2023.01|Cancer Research and Treatment|제55권 제1호|pp. 155-166|DOI 10.4143/crt.2021.1567

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Breast neoplasmsHigh-throughput nucleotide sequencingTumor mutation burdenGerm-line mutationBRCAGenomic landscape
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초록

Purpose<i>BRCA1</i> and <i>BRCA2</i> are among the most important genes involved in DNA repair via homologous recombination (HR). Germline <i>BRCA1/2</i> (<i>gBRCA1/2</i>)-related cancers have specific characteristics and treatment options but conducting <i>gBRCA1/2</i> testing and interpreting the genetic imprint are sometimes complicated. Here, we describe the concordance of <i>gBRCA1/2</i> derived from a panel of clinical tumor tissues using next-generation sequencing (NGS) and genetic aspects of tumors harboring <i>gBRCA1/2</i> pathogenic variants.Materials and MethodsTargeted sequencing was performed using available tumor tissue from patients who underwent <i>gBRCA1/2</i> testing. Comparative genomic analysis was performed according to <i>gBRCA1/2</i> pathogenicity.ResultsA total of 321 patients who underwent <i>gBRCA1/2</i> testing were screened, and 26 patients with <i>gBRCA1/2</i> pathogenic (<i>gBRCA1/2p</i>) variants, eight patients with <i>gBRCA1/2</i> variants of uncertain significance (VUS; <i>gBRCA1/2v</i>), and 43 patients with <i>gBRCA1/2</i> wild-type (<i>gBRCA1/2w</i>) were included in analysis. Mutations in <i>TP53</i> (49.4%) and <i>PIK3CA</i> (23.4%) were frequently detected in all samples. The number of single-nucleotide variants (SNVs) per tumor tissue was higher in the <i>gBRCA1/2w</i> group than that in the <i>gBRCA1/2p</i> group (14.81 vs. 18.86, p=0.278). Tumor mutation burden (TMB) was significantly higher in the <i>gBRCA1/2w</i> group than in the <i>gBRCA1/2p</i> group (10.21 vs. 13.47, p=0.017). Except for <i>BRCA1/2</i>, other HR-related genes were frequently mutated in patients with <i>gBRCA1/2w</i>.ConclusionWe demonstrated high sensitivity of <i>gBRCA1/2</i> in tumors analyzed by NGS using a panel of tumor tissues. TMB value and aberration of non-<i>BRCA1/2</i> HR-related genes differed significantly according to <i>gBRCA1/2</i> pathogenicity in patients with breast cancer.

Abstract

Purpose<i>BRCA1</i> and <i>BRCA2</i> are among the most important genes involved in DNA repair via homologous recombination (HR). Germline <i>BRCA1/2</i> (<i>gBRCA1/2</i>)-related cancers have specific characteristics and treatment options but conducting <i>gBRCA1/2</i> testing and interpreting the genetic imprint are sometimes complicated. Here, we describe the concordance of <i>gBRCA1/2</i> derived from a panel of clinical tumor tissues using next-generation sequencing (NGS) and genetic aspects of tumors harboring <i>gBRCA1/2</i> pathogenic variants.Materials and MethodsTargeted sequencing was performed using available tumor tissue from patients who underwent <i>gBRCA1/2</i> testing. Comparative genomic analysis was performed according to <i>gBRCA1/2</i> pathogenicity.ResultsA total of 321 patients who underwent <i>gBRCA1/2</i> testing were screened, and 26 patients with <i>gBRCA1/2</i> pathogenic (<i>gBRCA1/2p</i>) variants, eight patients with <i>gBRCA1/2</i> variants of uncertain significance (VUS; <i>gBRCA1/2v</i>), and 43 patients with <i>gBRCA1/2</i> wild-type (<i>gBRCA1/2w</i>) were included in analysis. Mutations in <i>TP53</i> (49.4%) and <i>PIK3CA</i> (23.4%) were frequently detected in all samples. The number of single-nucleotide variants (SNVs) per tumor tissue was higher in the <i>gBRCA1/2w</i> group than that in the <i>gBRCA1/2p</i> group (14.81 vs. 18.86, p=0.278). Tumor mutation burden (TMB) was significantly higher in the <i>gBRCA1/2w</i> group than in the <i>gBRCA1/2p</i> group (10.21 vs. 13.47, p=0.017). Except for <i>BRCA1/2</i>, other HR-related genes were frequently mutated in patients with <i>gBRCA1/2w</i>.ConclusionWe demonstrated high sensitivity of <i>gBRCA1/2</i> in tumors analyzed by NGS using a panel of tumor tissues. TMB value and aberration of non-<i>BRCA1/2</i> HR-related genes differed significantly according to <i>gBRCA1/2</i> pathogenicity in patients with breast cancer.

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