Limited influence of germline genetic variation on all-cause mortality in women with early onset breast cancer

TY - JOUR

T1 - Limited influence of germline genetic variation on all-cause mortality in women with early onset breast cancer

T2 - evidence from gene-based tests, single-marker regression, and whole-genome prediction

AU - Scannell Bryan, Molly

AU - Argos, Maria

AU - Andrulis, Irene L

AU - Hopper, John L

AU - Chang-Claude, Jenny

AU - Malone, Kathleen E

AU - John, Esther M

AU - Gammon, Marilie D

AU - Daly, Mary B

AU - Terry, Mary-Beth

AU - Buys, Saundra

AU - Huo, Dezheng

AU - Olopade, Olofunmilayo

AU - Genkinger, Jeanine M

AU - Jasmine, Farzana

AU - Kibriya, Muhammad G

AU - Chen, Lin

AU - Ahsan, Habibul

PY - 2017/8

Y1 - 2017/8

N2 - PURPOSE: Women diagnosed with breast cancer have heterogeneous survival outcomes that cannot be fully explained by known prognostic factors, and germline variation is a plausible but unconfirmed risk factor.METHODS: We used three approaches to test the hypothesis that germline variation drives some differences in survival: mortality loci identification, tumor aggressiveness loci identification, and whole-genome prediction. The 2954 study participants were women diagnosed with breast cancer before age 50, with a median follow-up of 15 years who were genotyped on an exome array. We first searched for loci in gene regions that were associated with all-cause mortality. We next searched for loci in gene regions associated with five histopathological characteristics related to tumor aggressiveness. Last, we also predicted 10-year all-cause mortality on a subset of 1903 participants (3,245,343 variants after imputation) using whole-genome prediction methods.RESULTS: No risk loci for mortality or tumor aggressiveness were identified. This null result persisted when restricting to women with estrogen receptor-positive tumors, when examining suggestive loci in an independent study, and when restricting to previously published risk loci. Additionally, the whole-genome prediction model also found no evidence to support an association.CONCLUSION: Despite multiple complementary approaches, our study found no evidence that mortality in women with early onset breast cancer is influenced by germline variation.

AB - PURPOSE: Women diagnosed with breast cancer have heterogeneous survival outcomes that cannot be fully explained by known prognostic factors, and germline variation is a plausible but unconfirmed risk factor.METHODS: We used three approaches to test the hypothesis that germline variation drives some differences in survival: mortality loci identification, tumor aggressiveness loci identification, and whole-genome prediction. The 2954 study participants were women diagnosed with breast cancer before age 50, with a median follow-up of 15 years who were genotyped on an exome array. We first searched for loci in gene regions that were associated with all-cause mortality. We next searched for loci in gene regions associated with five histopathological characteristics related to tumor aggressiveness. Last, we also predicted 10-year all-cause mortality on a subset of 1903 participants (3,245,343 variants after imputation) using whole-genome prediction methods.RESULTS: No risk loci for mortality or tumor aggressiveness were identified. This null result persisted when restricting to women with estrogen receptor-positive tumors, when examining suggestive loci in an independent study, and when restricting to previously published risk loci. Additionally, the whole-genome prediction model also found no evidence to support an association.CONCLUSION: Despite multiple complementary approaches, our study found no evidence that mortality in women with early onset breast cancer is influenced by germline variation.

KW - Journal Article

U2 - 10.1007/s10549-017-4287-4

DO - 10.1007/s10549-017-4287-4

M3 - SCORING: Journal article

C2 - 28503721

VL - 164

SP - 707

EP - 717

JO - BREAST CANCER RES TR

JF - BREAST CANCER RES TR

SN - 0167-6806

IS - 3

ER -