Germline mutations in many genes have been shown to increase the risk of developing cancer. This risk can vary across families who carry mutations in the same gene due to differences in the specific variants, gene–gene interactions, other susceptibility mutations, environmental factors, and behavioral factors. We develop an analytic tool to explore this heterogeneity using family history data. We propose to evaluate the ratio between the number of observed cancer cases in a family and the number of expected cases under a model where risk is assumed to be the same across families. We perform this analysis for both carriers and noncarriers in each family, using carrier probabilities when carrier statuses are unknown, and visualize the results. We first illustrate the approach in simulated data and then apply it to data on colorectal cancer risk in families carrying mutations in Lynch syndrome genes from Creighton University's Hereditary Cancer Center. We show that colorectal cancer risk in carriers can vary widely across families, and that this variation is not matched by a corresponding variation in the noncarriers from the same families. This suggests that the sources of variation in these families are to be found predominantly in variants harbored in the mutated MMR genes considered, or in variants interacting with them.

中文翻译：

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遗传易感家庭的癌症风险差异

许多基因的种系突变已被证明会增加患癌症的风险。由于特定变异、基因-基因相互作用、其他易感性突变、环境因素和行为因素的差异，这种风险可能因携带同一基因突变的家庭而异。我们开发了一种分析工具来使用家族史数据探索这种异质性。我们建议评估一个家庭中观察到的癌症病例数与假设风险在不同家庭之间相同的模型下的预期病例数之间的比率。我们对每个家庭中的携带者和非携带者执行此分析，使用携带者状态未知时的携带者概率，并可视化结果。我们首先在模拟数据中说明该方法，然后将其应用于来自 Creighton 大学遗传性癌症中心的携带 Lynch 综合征基因突变的家庭的结直肠癌风险数据。我们表明，携带者的结直肠癌风险在不同家庭之间可能存在很大差异，并且这种变化与来自同一家庭的非携带者的相应变化不匹配。这表明这些家族的变异来源主要存在于所考虑的突变 MMR 基因中的变异体中，或者与它们相互作用的变异体中。并且这种变化与来自同一家庭的非携带者的相应变化不匹配。这表明这些家族的变异来源主要存在于所考虑的突变 MMR 基因中的变异体中，或者与它们相互作用的变异体中。并且这种变化与来自同一家庭的非携带者的相应变化不匹配。这表明这些家族的变异来源主要存在于所考虑的突变 MMR 基因中的变异体中，或者与它们相互作用的变异体中。