The impact of coding germline variants on contralateral breast cancer risk and survival.
Morra A., Mavaddat N., Muranen TA., Ahearn TU., Allen J., Andrulis IL., Auvinen P., Becher H., Behrens S., Blomqvist C., Bojesen SE., Bolla MK., Brauch H., Camp NJ., Carvalho S., Castelao JE., Cessna MH., Chang-Claude J., Chenevix-Trench G., NBCS Collaborators None., Czene K., Decker B., Dennis J., Dörk T., Dorling L., Dunning AM., Ekici AB., Eriksson M., Evans DG., Fasching PA., Figueroa JD., Flyger H., Gago-Dominguez M., García-Closas M., Geurts-Giele WRR., Giles GG., Guénel P., Gündert M., Hahnen E., Hall P., Hamann U., Harrington PA., He W., Heikkilä P., Hooning MJ., Hoppe R., Howell A., Humphreys K., kConFab Investigators None., Jakubowska A., Jung AY., Keeman R., Kristensen VN., Lubiński J., Mannermaa A., Manoochehri M., Manoukian S., Margolin S., Mavroudis D., Milne RL., Mulligan AM., Newman WG., Park-Simon T-W., Peterlongo P., Pharoah PDP., Rhenius V., Saloustros E., Sawyer EJ., Schmutzler RK., Shah M., Spurdle AB., Tomlinson I., Truong T., van Veen EM., Vreeswijk MPG., Wang Q., Wendt C., Yang XR., Nevanlinna H., Devilee P., Easton DF., Schmidt MK.
Evidence linking coding germline variants in breast cancer (BC)-susceptibility genes other than BRCA1, BRCA2, and CHEK2 with contralateral breast cancer (CBC) risk and breast cancer-specific survival (BCSS) is scarce. The aim of this study was to assess the association of protein-truncating variants (PTVs) and rare missense variants (MSVs) in nine known (ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53) and 25 suspected BC-susceptibility genes with CBC risk and BCSS. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated with Cox regression models. Analyses included 34,401 women of European ancestry diagnosed with BC, including 676 CBCs and 3,449 BC deaths; the median follow-up was 10.9 years. Subtype analyses were based on estrogen receptor (ER) status of the first BC. Combined PTVs and pathogenic/likely pathogenic MSVs in BRCA1, BRCA2, and TP53 and PTVs in CHEK2 and PALB2 were associated with increased CBC risk [HRs (95% CIs): 2.88 (1.70-4.87), 2.31 (1.39-3.85), 8.29 (2.53-27.21), 2.25 (1.55-3.27), and 2.67 (1.33-5.35), respectively]. The strongest evidence of association with BCSS was for PTVs and pathogenic/likely pathogenic MSVs in BRCA2 (ER-positive BC) and TP53 and PTVs in CHEK2 [HRs (95% CIs): 1.53 (1.13-2.07), 2.08 (0.95-4.57), and 1.39 (1.13-1.72), respectively, after adjusting for tumor characteristics and treatment]. HRs were essentially unchanged when censoring for CBC, suggesting that these associations are not completely explained by increased CBC risk, tumor characteristics, or treatment. There was limited evidence of associations of PTVs and/or rare MSVs with CBC risk or BCSS for the 25 suspected BC genes. The CBC findings are relevant to treatment decisions, follow-up, and screening after BC diagnosis.