Supplementary Material for: Family history of breast cancer is associated with elevated risk of prostate cancer: evidence for shared genetic risks

Introduction: Although breast and prostate cancers arise in different organs and are more frequent in the opposite sex, multiple studies have reported an association between their family history. Analysis of single nucleotide polymorphism data, based on distant relatives, has revealed a small positive genetic correlation between these cancers explained by common variants. The estimate of genetic correlation based on close relatives reveals the extent to which shared genetic risks are explained by both common and rare variants. This estimate is unknown for breast and prostate cancer. Method: We estimated the relative risks, heritability, and genetic correlation of breast cancer and prostate cancer, based on the Minnesota Breast and Prostate Cancer Study, a family study of 141 families ascertained for breast cancer. Results: Heritability of breast cancer was 0.34 (95% credible interval: 0.23-0.49) and 0.65 (95% credible interval: 0.36-0.97) for prostate cancer, and the genetic correlation was 0.23. In terms of odds ratios, these values correspond to a 1.3 times higher odds of breast cancer among probands, given that the brother has prostate cancer. Conclusion: This study shows the inherent relation between prostate cancer and breast cancer; an incident of one in a family increases the risk of developing the other. The large difference between estimates of genetic correlation from distant and close relatives, if replicated, suggests that rare variants contribute to the shared genetic risk of breast and prostate cancer. However, the difference could steam from genotype-by-family effects shared between the two types of cancers.

引言：尽管乳腺癌与前列腺癌发生于不同器官，且在异性人群中发病率更高，但多项研究已报道二者存在家族史关联。基于远缘亲属的单核苷酸多态性（single nucleotide polymorphism, SNP）数据分析显示，这两种癌症间存在微弱的正向遗传相关性，该相关性可由常见变异解释。基于近缘亲属的遗传相关性估算值，可揭示共同和罕见变异分别解释共享遗传风险的程度，但目前尚无乳腺癌与前列腺癌的此类估算数据。
方法：本研究基于明尼苏达乳腺癌与前列腺癌研究（Minnesota Breast and Prostate Cancer Study）开展分析，该队列共纳入141个因乳腺癌招募的家系。我们估算了乳腺癌与前列腺癌的相对风险、遗传力（heritability）及遗传相关性。
结果：乳腺癌的遗传力为0.34（95%可信区间：0.23~0.49），前列腺癌的遗传力为0.65（95%可信区间：0.36~0.97），二者的遗传相关性为0.23。以比值比（odds ratio, OR）换算，若先证者（proband）的兄弟罹患前列腺癌，则该先证者患乳腺癌的风险升高1.3倍。
结论：本研究证实了前列腺癌与乳腺癌之间存在内在关联；家系中若出现其中一种癌症，则会升高另一种癌症的发病风险。若该结果得以重复，那么基于远缘与近缘亲属的遗传相关性估算值间的显著差异，提示罕见变异参与了乳腺癌与前列腺癌的共享遗传风险。不过该差异也可能源于两种癌症共有的基因型-家系交互效应。