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Genetic variants in the mTOR pathway and interaction with body size and weight gain on breast cancer risk in African-American and European American women

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Abstract

Purpose

Positive energy imbalance and growth factors linked to obesity promote the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (mTOR) pathway. As the obesity–breast cancer associations differ between European American (EA) and African-American (AA) women, we investigated genetic variants in the mTOR pathway and breast cancer risk in these two racial groups.

Methods

We examined 400 single-nucleotide polymorphisms (SNPs) in 31 mTOR pathway genes in the Women’s Circle of Health Study with 1263 incident breast cancers (645 EA, 618 AA) and 1382 controls (641 EA, 741 AA). Multivariable logistic regression was performed separately within racial groups. Effect modification was assessed for measured body size and weight gain since age 20.

Results

In EA women, variants in FRAP1 rs12125777 (intron), PRR5L rs3740958 (synonymous coding), and CDKAL1 rs9368197 (intron) were associated with increased breast cancer risk, while variants in RPTOR rs9900506 (intron) were associated with decreased risk (nominal p-trend for functional and FRAP1 SNPs or p adjusted for correlated test [p ACT] < 0.05). For AA women, variants in RPTOR rs3817293 (intron), PIK3R1 rs7713645 (intron), and CDKAL1 rs9368197 were associated with decreased breast cancer risk. The significance for FRAP1 rs12125777 and RPTOR rs9900506 in EA women did not hold after correction for multiple comparisons. The risk associated with FRAP1 rs12125777 was higher among EAs who had body mass index ≥30 kg/m2 (odds ratio = 7.69, 95 % CI 2.11–28.0; p-interaction = 0.007) and gained weight ≥35 lb since age 20 (odds ratio = 3.34, 95 % CI 1.42–7.85; p-interaction = 0.021), compared to their counterparts.

Conclusions

The mTOR pathway may be involved in breast cancer carcinogenesis differently for EA and AA women.

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Acknowledgments

This work was supported in part by grants from the US National Institutes of Health (P01 CA151135, R01 CA100598, K22 CA138563, and P30 CA072720), US Army Medical Research and Material Command (DAMD-17-01-1-0334), the Breast Cancer Research Foundation, and a gift from the Philip L. Hubbell family. The study used shared resources supported by Roswell Park Cancer Institute’s Cancer Center Support Grant from the National Cancer Institute (P30CA016056). The New Jersey State Cancer Registry is supported by the National Program of Cancer Registries of the Centers for Disease Control and Prevention under cooperative agreement 1US58DP003931-01 awarded to the New Jersey Department of Health. The collection of New Jersey cancer incidence data is also supported by the Surveillance, Epidemiology, and End Results program of the National Cancer Institute under contract N01-PC-2010-0027 and the State of New Jersey. The authors thank Dr. Dana Bovbjerg, Ms. Lina Jandorf, and Ms. Edie Prescod for their contribution to the Women’s Circle of Health Study. We also thank our research personnel at the Cancer Institute of New Jersey (now Rutgers Cancer Institute of New Jersey), Roswell Park Cancer Institute, Mount Sinai School of Medicine (now Icahn School of Medicine at Mount Sinai), UMDNJ School of Public Health (now Rutgers School of Public Health), and the New Jersey State Cancer Registry, as well as our African-American breast cancer advocates and community partners, and all the women who generously donated their time to participate in the study.

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Authors and Affiliations

  1. Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Elm & Carlton Sts., Buffalo, NY, 14263, USA

    Ting-Yuan David Cheng, Gary Zirpoli, Chi-Chen Hong, Christine B. Ambrosone & Song Yao

  2. J. Craig Venter Institute, Rockville, MD, USA

    Jyoti Shankar

  3. Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, MA, USA

    Michelle R. Roberts

  4. Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA

    Elisa V. Bandera

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  1. Ting-Yuan David Cheng
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  2. Jyoti Shankar
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Cheng, TY.D., Shankar, J., Zirpoli, G. et al. Genetic variants in the mTOR pathway and interaction with body size and weight gain on breast cancer risk in African-American and European American women. Cancer Causes Control 27, 965–976 (2016). https://doi.org/10.1007/s10552-016-0774-x

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