BACKGROUND The Hereditary Breast and Ovarian Cancer Syndrome (HBOC) occurs in families with a history of breast/ovarian cancer, presenting an autosomal dominant inheritance pattern. BRCA1 and BRCA2 are high penetrance genes associated with an increased risk of up to 20-fold for breast and ovarian cancer. However, only 20-30% of HBOC cases present pathogenic variants in those genes, and other DNA repair genes have emerged as increasing the risk for HBOC. In Brazil, variants in ATM, ATR, CHEK2, MLH1, MSH2, MSH6, POLQ, PTEN, and TP53 genes have been reported in up to 7.35% of the studied cases. Here we screened and characterized variants in 21 DNA repair genes in HBOC patients. METHODS We systematically analyzed 708 amplicons encompassing the coding and flanking regions of 21 genes related to DNA repair pathways (ABRAXAS1, ATM, ATR, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MLH1, MRE11, MSH2, MSH6, NBN, PALB2, PMS2, PTEN, RAD50, RAD51, TP53 and UIMC1). A total of 95 individuals with HBOC syndrome clinical suspicion in Southeast Brazil were sequenced, and 25 samples were evaluated for insertions/deletions in BRCA1/BRCA2 genes. Identified variants were assessed in terms of population allele frequency and their functional effects were predicted through in silico algorithms. RESULTS We identified 80 variants in 19 genes. About 23.4% of the patients presented pathogenic variants in BRCA1, BRCA2 and TP53, a frequency higher than that identified among previous studies in Brazil. We identified a novel variant in ATR, which was predicted as pathogenic by in silico tools. The association analysis revealed 13 missense variants in ABRAXAS1, BARD1, BRCA2, CHEK2, CDH1, MLH1, PALB2, and PMS2 genes, as significantly associated with increased risk to HBOC, and the patients carrying those variants did not present large insertions or deletions in BRCA1/BRCA2 genes. CONCLUSIONS This study embodies the third report of a multi-gene analysis in the Brazilian population, and addresses the first report of many germline variants associated with HBOC in Brazil. Although further functional analyses are necessary to better characterize the contribution of those variants to the phenotype, these findings would improve the risk estimation and clinical follow-up of patients with HBOC clinical suspicion.

中文翻译：

---

与遗传性乳腺癌和卵巢癌综合症相关的DNA修复基因中的种系变异：巴西人群中21个基因组的分析。

背景技术遗传性乳腺癌和卵巢癌综合征（HBOC）发生在有乳腺癌/卵巢癌病史的家庭中，表现出常染色体显性遗传模式。BRCA1和BRCA2是高渗透性基因，与乳腺癌和卵巢癌的风险增加高达20倍有关。但是，只有20-30％的HBOC病例在这些基因中出现致病性变异，并且随着HBOC风险的增加，出现了其他DNA修复基因。在巴西，在多达7.35％的研究病例中已报道了ATM，ATR，CHEK2，MLH1，MSH2，MSH6，POLQ，PTEN和TP53基因的变异。在这里，我们筛选并鉴定了HBOC患者中21个DNA修复基因的变异。方法我们系统分析了708个扩增子，涵盖21个与DNA修复途径相关的基因（ABRAXAS1，ATM，ATR，BARD1，BRCA1，BRCA2，BRIP1，CDH1，CHEK2，MLH1，MRE11，MSH2，MSH6，NBN，PALB2，PMS2，PTEN，RAD50，RAD51，TP53和UIMC1）。测序了巴西东南部共95例具有HBOC综合征临床怀疑的个体，并对25个样本的BRCA1 / BRCA2基因进行了插入/缺失评估。根据群体等位基因频率评估已鉴定的变异体，并通过计算机模拟算法预测其功能效应。结果我们确定了19个基因中的80个变异体。约23.4％的患者呈现BRCA1，BRCA2和TP53的致病性变异，其发生频率高于巴西先前的研究。我们在ATR中鉴定了一种新型变异，通过计算机工具可以预测其致病性。关联分析显示ABRAXAS1，BARD1，BRCA2，CHEK2，CDH1，MLH1，PALB2和PMS2基因中有13个错义变体，与携带HBOC的风险显着相关，携带这些变异的患者在BRCA1 / BRCA2基因中并未出现大的插入或缺失。结论本研究体现了巴西人群中多基因分析的第三次报告，并涉及了与HBOC相关的许多种系变异的首次报告。尽管有必要进行进一步的功能分析以更好地表征这些变异对表型的影响，但这些发现将改善HBOC临床怀疑患者的风险估计和临床随访。结论本研究体现了巴西人群中多基因分析的第三次报告，并涉及了与HBOC相关的许多种系变异的首次报告。尽管有必要进行进一步的功能分析以更好地表征这些变异对表型的影响，但这些发现将改善HBOC临床怀疑患者的风险估计和临床随访。结论本研究体现了巴西人群中多基因分析的第三份报告，并涉及了与HBOC相关的许多种系变异的第一份报告。尽管有必要进行进一步的功能分析以更好地表征这些变异对表型的影响，但这些发现将改善HBOC临床怀疑患者的风险估计和临床随访。