Combining genome-wide studies of breast, prostate, ovarian and endometrial cancers maps cross-cancer susceptibility loci and identifies new genetic associations

Kar, S. P.; Lindstroem, S.; Hung, R.; Lawrenson, K.; Schmidt, M.; O'Mara, T.; Glubb, D.; Tyrer, J.; Schildkraut, J.; Chang-Claude, J.; Alsulimani, A.; Anton, F.; Beeghly-Fadiel, A.; Bjorge, L.; Bodelon, C.; Brauch, H.; Burghaus, S.; Campa, D.; Carney, M.; Chen, Z.; Daly, M.; du Bois, A.; Ekici, A.; Ewing, A.; Fasching, P.; Flanagan, J. M.; Gawelko, J.; Giles, G.; Hamilton, R.; Harris, H.; Heitz, F.; Hildebrandt, M.; Hillemanns, P.; Huang, R.-Y.; Imaz, L.; Irmejs, A.; Jakubowska, A.; Jensen, A.; John, E.; Kannisto, P.; Karlan, B.; Khusnutdinova, E.; Kiemeney, L.; Kjaer, S.; Klapdor, R.; Kleiblo

doi:10.1101/2020.06.16.146803

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bioRxiv · 10.1101/2020.06.16.146803

Combining genome-wide studies of breast, prostate, ovarian and endometrial cancers maps cross-cancer susceptibility loci and identifies new genetic associations

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Abstract

We report a meta-analysis of breast, prostate, ovarian, and endometrial cancer genome-wide association data (effective sample size: 237,483 cases/317,006 controls). This identified 465 independent lead variants (P<5x10-8) across 192 genomic regions. Four lead variants were >1Mb from previously identified risk loci for the four cancers and an additional 23 lead variant-cancer associations were novel for one of the cancers. Bayesian models supported pleiotropic effects involving at least two cancers at 222/465 lead variants in 118/192 regions. Gene-level association analysis identified 13 shared susceptibility genes (P<2.6x10-6) in 13 regions not previously implicated in any of the four cancers and not uncovered by our variant-level meta-analysis. Several lead variants had opposite effects across cancers, including a cluster of such variants in the TP53 pathway. Fifty-four lead variants were associated with blood cell traits and suggested genetic overlaps with clonal hematopoiesis. Our study highlights the remarkable pervasiveness of pleiotropy across hormone-related cancers, further illuminating their shared genetic and mechanistic origins at variant- and gene-level resolution.

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Kar, S. P., Lindstroem, S., Hung, R., Lawrenson, K., Schmidt, M., O'Mara, T., Glubb, D., Tyrer, J., Schildkraut, J., Chang-Claude, J., Alsulimani, A., Anton, F., Beeghly-Fadiel, A., Bjorge, L., Bodelon, C., Brauch, H., Burghaus, S., Campa, D., Carney, M., Chen, Z., Daly, M., du Bois, A., Ekici, A., Ewing, A., Fasching, P., Flanagan, J. M., Gawelko, J., Giles, G., Hamilton, R., Harris, H., Heitz, F., Hildebrandt, M., Hillemanns, P., Huang, R.-Y., Imaz, L., Irmejs, A., Jakubowska, A., Jensen, A., John, E., Kannisto, P., Karlan, B., Khusnutdinova, E., Kiemeney, L., Kjaer, S., Klapdor, R., Kleiblo. 2020-06-19. Combining genome-wide studies of breast, prostate, ovarian and endometrial cancers maps cross-cancer susceptibility loci and identifies new genetic associations. https://doi.org/10.1101/2020.06.16.146803

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