We investigated a Spanish and Catalan family in which multiple cancer types tracked across three generations, but for which no genetic etiology had been identified. Whole exome sequencing of germline DNA from multiple affected family members was performed to identify candidate variants to explain this occurrence of familial cancer. We discovered in all cancer-affected family members a single rare heterozygous germline variant (I654V, rs1801201) in ERBB2/HER2 that is located in a transmembrane glycine zipper motif critical for ERBB2-mediated signaling and in complete linkage disequilibrium (D'=1) with a common polymorphism (I655V, rs1136201) previously reported in some populations as associated with cancer risk. Because multiple cancer types occurred in this family, we tested both the I654V and the I655V variants for association with cancer across multiple tumor types in 6,371 cases of Northern European ancestry drawn from The Cancer Genome Atlas and 6,647 controls, and found that the rare variant (I654V) was significantly associated with an increased risk for cancer (OR=1.40, p=0.021, 95% CI=1.05-1.89). Functional assays performed in HEK 293T cells revealed that both the I655V single mutant (SM) and the I654V;I655V double mutant (DM) stabilized ERBB2 protein and activated ERBB2 signaling, with the DM activating ERBB2 significantly more than the SM alone. Thus, our results suggest a model whereby heritable genetic variation in the transmembrane domain activating ERBB2 signaling is associated with both sporadic and familial cancer risk, with increased ERBB2 stabilization and activation associated with increased cancer risk.

中文翻译：

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功能性常见和罕见 ERBB2 种系变异在家族性和散发性癌症易感性中发挥作用


我们调查了一个西班牙和加泰罗尼亚家族，该家族在三代人中追踪到了多种癌症类型，但尚未确定其遗传病因。对多个受影响的家庭成员的种系 DNA 进行全外显子组测序，以确定解释家族性癌症发生的候选变异。我们在所有受癌症影响的家族成员中发现了 ERBB2/HER2 中的一个罕见杂合种系变异（I654V，rs1801201），该变异位于对 ERBB2 介导的信号传导至关重要的跨膜甘氨酸拉链基序中，并且处于完全连锁不平衡（D'=1）具有常见的多态性（I655V，rs1136201），之前在某些人群中报道与癌症风险相关。由于该家族中发生了多种癌症类型，因此我们在来自癌症基因组图谱的 6,371 例北欧血统病例和 6,647 例对照中测试了 I654V 和 I655V 变体与多种肿瘤类型的癌症的关联，并发现罕见变体（ I654V）与癌症风险增加显着相关（OR=1.40，p=0.021，95% CI=1.05-1.89）。在 HEK 293T 细胞中进行的功能测定显示，I655V 单突变体 (SM) 和 I654V;I655V 双突变体 (DM) 均稳定 ERBB2 蛋白并激活 ERBB2 信号传导，其中 DM 激活 ERBB2 的作用显着大于单独的 SM。因此，我们的结果提出了一个模型，即激活 ERBB2 信号传导的跨膜结构域中的可遗传遗传变异与散发性和家族性癌症风险相关，而 ERBB2 稳定性和激活的增加与癌症风险增加相关。