Fig. 3
Germline gene-based association results for multiple primary cancers combined or grouped by organ site. Burden tests were performed combining variants defined as pLOF with or without deleterious missense variants, defining deleteriousness by at least one (1/5) or all five (5/5) prediction algorithms used (Methods), at a MAF < 0.5%. Following a fixed-effects meta-analysis of Kaiser Permanente Research Bank and UK Biobank data, Bonferroni significant associations (p < 2.65 × 10−6 = 0.05/18,842) corrected for the number of genes tested were found for comparisons of cancer-free controls (n = 165,853) with all cases with any 2+ primary cancers (n = 6429) and with groups of cases defined by an index cancer for the following phenotypes: prostate + (n = 1977), breast + (n = 1874), and ovary + (n = 239). For each gene, the variant grouping with the smallest p-value was selected. The heatmap reflects the number of carriers of each associated variant, with the index (y-axis) and additional (x-axis) cancer over the total number of carriers, where the carrier is defined as having at least one alternate allele across all variants in a given gene, restricting to cancer cases. When the index and additional cancer are the same, the heatmap value represents all carriers with the specified cancer diagnosis divided by the total number of carriers. Abbreviations: OR, odds ratio; pLOF, predicted loss of function