A significant fraction of breast cancer recurs, with lethal outcome, but specific genetic variants responsible have yet to be identified. Five cousin pairs with recurrent breast cancer from pedigrees with a statistical excess of recurrent breast cancer were sequenced to identify rare, shared candidate predisposition variants. The candidates were tested for association with breast cancer risk with UKBiobank data. Additional breast cancer cases were assayed for a subset of candidate variants to test for co-segregation. Three-dimensional protein structure prediction methods were used to investigate how the mutation under consideration is predicted to change structural and electrostatic properties in the mutated protein. One hundred and eighty-one rare candidate predisposition variants were shared in at least one cousin pair from a high-risk pedigree. A rare variant inMDH2was found to segregate with breast-cancer-affected relatives in one extended pedigree.MDH2is an estrogen-stimulated gene encoding the protein malate dehydrogenase, which catalyzes the reversible oxidation of malate to oxaloacetate. The molecular simulation results strongly suggest that the mutation changes the NAD+binding pocket electrostatics ofMDH2. This small sequencing study, using a powerful approach based on recurrent breast cancer cases from high-risk pedigrees, identified a set of strong candidate variants for inherited predisposition for breast cancer recurrence, includingMDH2, which should be pursued in other resources.
相当比例的乳腺癌会复发并导致致命后果，但尚未确定导致复发的特定遗传变异。本研究对来自乳腺癌复发率显著偏高家系的五对患有复发性乳腺癌的表亲进行测序，以鉴定罕见且共有的候选易感变异。利用英国生物银行数据对这些候选变异与乳腺癌风险进行关联性检验。针对部分候选变异，在额外乳腺癌病例中进行检测以验证共分离现象。采用三维蛋白质结构预测方法，探究目标突变如何改变突变蛋白的结构与静电特性。研究共发现181个罕见候选易感变异在高风险家系的至少一对表亲中共享。其中MDH2基因的罕见变异在一个扩展家系中被发现与乳腺癌患病亲属存在分离现象。MDH2作为雌激素刺激基因，编码苹果酸脱氢酶，该酶催化苹果酸与草酰乙酸的可逆氧化反应。分子模拟结果强烈提示该突变改变了MDH2的NAD+结合口袋静电特性。这项小规模测序研究采用基于高风险家系复发性乳腺癌病例的有效策略，鉴定出一组包括MDH2在内的强候选遗传性乳腺癌复发易感变异，值得在其他资源中进一步验证。
肿瘤(癌症)患者之家