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Abstract：
BACKGROUND: In Colombia and worldwide, breast cancer (BC) is the most frequently diagnosed neoplasia and the leading cause of death from cancer among women. Studies predominantly involve hereditary and familial cases, demonstrating a gap in the literature regarding the identification of germline mutations in unselected patients from Latin-America. Identification of pathogenic/likely pathogenic (P/LP) variants is important for shaping national genetic analysis policies, genetic counseling, and early detection strategies. The present study included 400 women with unselected breast cancer (BC), in whom we analyzed ten genes, using Whole Exome Sequencing (WES), know to confer risk for BC, with the aim of determining the genomic profile of previously unreported P/LP variants in the affected population. Additionally, Multiplex Ligation-dependent Probe Amplification (MLPA) was performed to identify Large Genomic Rearrangements (LGRs) in the BRCA1/2 genes. To ascertain the functional impact of a recurrent intronic variant (ATM c.5496 + 2_5496 + 5delTAAG), a minigene assay was conducted.
RESULTS: We ascertained the frequency of P/LP germline variants in BRCA2 (2.5%), ATM (1.25%), BRCA1 (0.75%), PALB2 (0.50%), CHEK2 (0.50%), BARD1 (0.25%), and RAD51D (0.25%) genes in the population of study. P/LP variants account for 6% of the total population analyzed. No LGRs were detected in our study. We identified 1.75% of recurrent variants in BRCA2 and ATM genes. One of them corresponds to the ATM c.5496 + 2_5496 + 5delTAAG. Functional validation of this variant demonstrated a splicing alteration probably modifying the Pincer domain and subsequent protein structure.
CONCLUSIONS: This study described for the first time the genomic profile of ten risk genes in Colombian women with unselected BC. Our findings underscore the significance of population-based research, advocating the consideration of molecular testing in all women with cancer.
RESULTS: We ascertained the frequency of P/LP germline variants in BRCA2 (2.5%), ATM (1.25%), BRCA1 (0.75%), PALB2 (0.50%), CHEK2 (0.50%), BARD1 (0.25%), and RAD51D (0.25%) genes in the population of study. P/LP variants account for 6% of the total population analyzed. No LGRs were detected in our study. We identified 1.75% of recurrent variants in BRCA2 and ATM genes. One of them corresponds to the ATM c.5496 + 2_5496 + 5delTAAG. Functional validation of this variant demonstrated a splicing alteration probably modifying the Pincer domain and subsequent protein structure.
CONCLUSIONS: This study described for the first time the genomic profile of ten risk genes in Colombian women with unselected BC. Our findings underscore the significance of population-based research, advocating the consideration of molecular testing in all women with cancer.
摘要：
背景：在哥伦比亚和全世界，乳腺癌（BC）是最常见的肿瘤形成，也是女性癌症死亡的主要原因。研究主要涉及遗传性和家族性病例，在来自拉丁美洲的未经选择的患者中鉴定种系突变的文献中显示出空白。致病性/可能致病性（P/LP）变异的鉴定对于制定国家遗传分析政策非常重要。遗传咨询,和早期检测策略。本研究包括400名患有未选择的乳腺癌（BC）的女性，我们分析了十个基因，使用全外显子组测序（WES），知道给BC带来风险，目的是确定受影响人群中先前未报告的P/LP变体的基因组谱。此外,进行多重连接依赖性探针扩增(MLPA)以鉴定BRCA1/2基因中的大基因组重排(LGRs)。为了确定复发性内含子变体（ATMc.5496+2_5496+5delTAAG）的功能影响，进行了小基因测定。
结果：我们确定了BRCA2中P/LP种系变异的频率（2.5％），ATM（1.25%），BRCA1（0.75%），PALB2(0.50%),CHEK2（0.50%），BARD1（0.25%），和RAD51D（0.25％）基因的研究人群。P/LP变体占所分析的总人口的6%。在我们的研究中没有检测到LGR。我们在BRCA2和ATM基因中鉴定了1.75％的复发变异。其中之一对应于ATMc.5496+2_5496+5delTAAG。该变体的功能验证表明剪接改变可能修饰了Pincer结构域和随后的蛋白质结构。
结论：这项研究首次描述了未选择BC的哥伦比亚女性中10个风险基因的基因组谱。我们的发现强调了基于人群的研究的重要性，提倡对所有癌症女性进行分子检测。
结果：我们确定了BRCA2中P/LP种系变异的频率（2.5％），ATM（1.25%），BRCA1（0.75%），PALB2(0.50%),CHEK2（0.50%），BARD1（0.25%），和RAD51D（0.25％）基因的研究人群。P/LP变体占所分析的总人口的6%。在我们的研究中没有检测到LGR。我们在BRCA2和ATM基因中鉴定了1.75％的复发变异。其中之一对应于ATMc.5496+2_5496+5delTAAG。该变体的功能验证表明剪接改变可能修饰了Pincer结构域和随后的蛋白质结构。
结论：这项研究首次描述了未选择BC的哥伦比亚女性中10个风险基因的基因组谱。我们的发现强调了基于人群的研究的重要性，提倡对所有癌症女性进行分子检测。
