Characterization of Large Genomic Rearrangements in BRCA1 and BRCA2 Genes in a Chinese High-Risk Cohort

Abstract

<p>Large genomic rearrangements (LGRs) account for at least 10% of the mutations in <em>BRCA1</em> and 5% of <em>BRCA2</em> mutations in outbred families with hereditary breast and ovarian cancer. A total of 21 probands with breast cancer who carried <em>BRCA1</em> or <em>BRCA2</em> LGRs were identified from a cohort of 4678 Chinese patients. There was a total of 13 <em>BRCA1</em> LGR carriers and 8 <em>BRCA2</em> LGR carriers, including 12 large genomic deletions and 1 duplication. Ten and three specific breakpoints from <em>BRCA1</em> and <em>BRCA2</em>, respectively, were identified by either whole-genome sequencing by nanopore sequencing or long-range PCR. Five of these LGRs were recurrent LGRs. Three LGRs were novel founder LGRs in the southeast Chinese population. Chinese LGR carriers exhibited clinical phenotypes that were generally similar to those of non-LGR mutation carriers. However, there was a notable tendency for triple-negative breast cancer to be more prevalent among Chinese LGR carriers (<em>P</em> = 0.007), largely because of the predominance of <em>BRCA1</em> mutations. This suggests a potential association that warrants further investigation.</p><p>Large genomic rearrangements (LGRs) account for at least 10% of mutations in <em>BRCA1</em> and 5% in <em>BRCA2</em> among outbred families with hereditary breast and ovarian cancer.<a href="https://www.jmdjournal.org/article/S1525-1578(25)00240-5/fulltext#">¹</a> LGRs in <em>BRCA1</em> are responsible for up to 27% of all <em>BRCA1</em> disease-causing mutations identified in numerous populations.<a href="https://www.jmdjournal.org/article/S1525-1578(25)00240-5/fulltext#">²</a> On average, LGRs make up 10% of all worldwide <em>BRCA1</em> mutations,<a href="https://www.jmdjournal.org/article/S1525-1578(25)00240-5/fulltext#">^3–6</a> but significantly higher rates were observed in the Netherlands (36%), Italy (19%), and the United Kingdom (20%).<a href="https://www.jmdjournal.org/article/S1525-1578(25)00240-5/fulltext#">^7–9</a> A large cohort study from Hungary indicated that LGRs in <em>BRCA1</em> represented approximately 10% of total <em>BRCA1</em> mutations, whereas LGRs in <em>BRCA2</em> accounted for <0.5%.<a href="https://www.jmdjournal.org/article/S1525-1578(25)00240-5/fulltext#">³</a> LGRs comprised 16.1% (5 of 31) of pathogenic <em>BRCA1</em> variants in Chinese patients with hereditary breast and ovarian cancer.<a href="https://www.jmdjournal.org/article/S1525-1578(25)00240-5/fulltext#">¹⁰</a></p><p>LGRs frequently span multiple exons and may also impact nearby functional genes, such as <em>NBR1</em> and <em>NBR2</em>. This raises the question of whether LGRs are associated with more severe disease manifestations. Given that most LGRs involve the <em>BRCA1</em> gene, some studies have found no significant differences in various pathologic features between LGR carriers and non-LGR <em>BRCA1</em> mutation carriers.<a href="https://www.jmdjournal.org/article/S1525-1578(25)00240-5/fulltext#">⁶</a> Contrasting views suggest that LGRs are more often linked to bilateral breast cancer, diagnoses before the age of 40 years, ovarian cancer, and male breast cancer.<a href="https://www.jmdjournal.org/article/S1525-1578(25)00240-5/fulltext#">¹</a></p><p>Despite advancements in copy-number sensitive methods, such as multiplex ligation-dependent probe amplification (MLPA),<a href="https://www.jmdjournal.org/article/S1525-1578(25)00240-5/fulltext#">¹¹</a> quantitative multiplex PCR of short fluorescent fragments,<a href="https://www.jmdjournal.org/article/S1525-1578(25)00240-5/fulltext#">¹²</a> and the assessment of aligned read counts from next-generation sequencing (NGS),<a href="https://www.jmdjournal.org/article/S1525-1578(25)00240-5/fulltext#">¹³</a> most of these methods are laborious, are time-consuming, and exhibit variable sensitivity. The detection of LGRs remains challenging because of extensive chromosomal rearrangements. These rearrangements often include large breakpoints spanning exons and introns, exceeding the read lengths typical of standard Sanger sequencing and NGS technologies. Furthermore, some breakpoints are located in deep introns, where neither conventional Sanger sequencing nor NGS can read. The presence of repetitive elements in introns complicates alignment, further hindering LGR detection for clinical applications. In contrast, third-generation nanopore sequencing by the MinION (Oxford Nanopore Technologies, Oxford, UK) offers a long-read capacity of up to megabases.<a href="https://www.jmdjournal.org/article/S1525-1578(25)00240-5/fulltext#">¹⁴</a> This technology significantly enhances LGR detection with improved accuracy and precision, making it more suitable for clinical use. Consequently, family studies and founder mutation investigations become more effective and feasible, paving the way for better genetic counseling and management strategies.</p><p>The objective of this study was to investigate the prevalence of genomic rearrangements within an Asian population consisting of familial and early-onset breast and ovarian cancer cases. A thorough analysis of the LGRs identified in the patients was conducted, examining their locations, frequencies, and pathogenicity. The phenotypic characteristics in families carrying LGRs were assessed to evaluate whether these rearrangements are associated with more severe disease compared with mutations limited to short or single-base alternation. One practical advantage of determining precise LGR breakpoints is that it allows laboratories to design a cost-effective and technically simpler method for studying family members. These data provide further insight into the correlation between genotype and phenotype of LGR <em>BRCA1</em> and <em>BRCA2</em> mutations.</p>