Systematic discovery of germline cancer predisposition genes through the identification of somatic second hits.

Eight of the 13 ALFRED genes with a nominally significant association between RDGVs and AI in at least one cancer type in the ALFRED analysis ( P < 0.05; Fig. 2d and Supplementary Data 5 ) also had an enrichment of RDGVs in a matched cancer type compared to in controls ( P < 0.05, Fig. 3d ; Supplementary Data 6 ): ATM in colon and rectum adenocarcinoma (COADREAD), lung adenocarcinoma (LUAD) and in PRAD, NSD1 in OV, and TPCN2 in uterine corpus endometrial carcinoma (UCEC).

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3c ) with one additional gene, NIPAL3 , marginally significant ( P = 0.07 by case-control analysis) (Fig. 3c ).

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