Whole-Exome Sequencing of Germline Variants in Non-BRCA Families with Hereditary Breast Cancer.
Whole-Exome Sequencing of Germline Variants in Non-BRCA Families with Hereditary Breast Cancer.
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DOI：
10.3390/biomedicines10051004
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发表时间：
2022-04-26
期刊：
影响因子：
4.7
通讯作者：
中科院分区：
文献类型：
--
作者：
乳腺癌是全世界女性中最常见的恶性肿瘤，遗传性乳腺癌约占病例的5%-10%。目前已知的最常见的复发基因是BRCA1和BRCA2，约占家族性病例的25%。虽然已经在20多个易感基因中发现了数千个功能丧失的变异，但大多数家族性HBC病例仍然无法解释。本研究的目的是利用全外显子组测序和功能预测工具，在三个具有常染色体显性遗传模式的非BRCA家系中寻找新的HBC易感基因。已知的遗传性癌症相关基因中没有致病变异可以解释这些家庭中乳腺癌的易感性。在2122个外显子最大等位基因频率(MMAF)和0.1%的变异体中，有17-35个变异体具有联合注释相关缺失(CADD)和GT；20个与疾病分离的三个家系。选择的候选基因，即UBASH3A、MYH13、UTP11L和PAX7，进一步通过蛋白质表达分析进行了评估，但没有观察到与癌症相关的通路的变化。总而言之，使用全外显子组测序识别新的高危癌症基因比最初预期的更具挑战性，尽管选定的家庭有明显的乳腺癌家族史。相反，低风险和中等风险基因变异的组合可能会导致这些家庭对乳腺癌的易感性。
Breast cancer is the most prevalent malignancy among women worldwide and hereditary breast cancer (HBC) accounts for about 5–10% of the cases. Today, the most recurrent genes known are BRCA1 and BRCA2, accounting for around 25% of familial cases. Although thousands of loss-of-function variants in more than twenty predisposing genes have been found, the majority of familial cases of HBC remain unexplained. The aim of this study was to identify new predisposing genes for HBC in three non-BRCA families with autosomal dominant inheritance pattern using whole-exome sequencing and functional prediction tools. No pathogenic variants in known hereditary cancer-related genes could explain the breast cancer susceptibility in these families. Among 2122 exonic variants with maximum minor allele frequency (MMAF) < 0.1%, between 17–35 variants with combined annotation-dependent depletion (CADD) > 20 segregated with disease in the three analyzed families. Selected candidate genes, i.e., UBASH3A, MYH13, UTP11L, and PAX7, were further evaluated using protein expression analysis but no alterations of cancer-related pathways were observed. In conclusion, identification of new high-risk cancer genes using whole-exome sequencing has been more challenging than initially anticipated, in spite of selected families with pronounced family history of breast cancer. A combination of low- and intermediate-genetic-risk variants may instead contribute the breast cancer susceptibility in these families.
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影响因子：
30.8
作者：
Kircher, Martin;Witten, Daniela M.;Jain, Preti;O'Roak, Brian J.;Cooper, Gregory M.;Shendure, Jay
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Shendure, Jay
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通讯作者：
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2.6
作者：
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通讯作者：
Pilarski, Robert