ATM, radiation, and the risk of second primary breast cancer

Abstract

Purpose: It was first suggested more than 40 years ago that heterozygous carriers for the human autosomal recessive disorder Ataxia-Telangiectasia (A-T) might also be at increased risk for cancer. Subsequent studies have identified the responsible gene, Ataxia-Telangiectasia Mutated (ATM), characterized genetic variation at this locus in A-T and a variety of different cancers, and described the functions of the ATM protein with regard to cellular DNA damage responses. However, an overall model of how ATM contributes to cancer risk, and in particular, the role of DNA damage in this process, remains lacking. This review considers these questions in the context of contralateral breast cancer (CBC).

Conclusions: Heterozygous carriers of loss of function mutations in ATM that are A-T causing, are at increased risk of breast cancer. However, examination of a range of genetic variants, both rare and common, across multiple cancers, suggests that ATM may have additional effects on cancer risk that are allele-dependent. In the case of CBC, selected common alleles at ATM are associated with a reduced incidence of CBC, while other rare and predicted deleterious variants may act jointly with radiation exposure to increase risk. Further studies that characterize germline and somatic ATM mutations in breast cancer and relate the detected genetic changes to functional outcomes, particularly with regard to radiation responses, are needed to gain a complete picture of the complex relationship between ATM, radiation and breast cancer.

Keywords:

• ATM
• breast cancer
• Ataxia-Telangiectasia
• radiation therapy
• allelic heterogeneity

Acknowledgements

The Women’s Environmental, Cancer, And Radiation Epidemiology (WECARE) Study Collaborative Group includes Memorial Sloan Kettering Cancer Center (Coordinating Center) Investigators and Staff: Jonine L. Bernstein Ph.D. (WECARE Study P.I.); Marinela Capanu Ph.D.; Xiaolin Liang M.D.; Irene Orlow Ph.D.; Anne S. Reiner M.P.H.; Mark Robson, M.D.; Meghan Woods M.P.H. Collaborative Site Investigators: Leslie Bernstein Ph.D.; John D. Boice Jr. Sc.D.; Jennifer Brooks Ph.D.; Patrick Concannon Ph.D.; Dave V. Conti Ph.D.; David Duggan Ph.D.; Joanne W. Elena Ph.D., M.P.H.; Robert W. Haile Dr.P.H.; Esther M. John Ph.D.; Julia A. Knight Ph.D.; Charles F. Lynch M.D., Ph.D.; Kathleen E. Malone Ph.D.; Lene Mellemkjær Ph.D.; Jørgen H. Olsen M.D. DMSc.; Daniela Seminara Ph.D. M.P.H.; Roy E. Shore Ph.D., Dr.P.H.; Marilyn Stovall Ph.D.; Daniel O. Stram Ph.D.; Marc Tischkowitz M.D., Ph.D.; Duncan C. Thomas Ph.D. Collaborative Site Staff: Kristina Blackmore M.Sc.; Anh T. Diep; Judy Goldstein; Irene Harris B.S., C.M.D.; Rikke Langballe M.P.H.; Cecilia O’Brien; Susan Smith M.P.H.; Rita Weathers M.S.; Michele West Ph.D.

Disclosure statement

No potential conflict of interest was reported by the authors.

Funding

Patrick Concannon was supported by grants from the NIEHS under Grant R01 ES027121 and the Defense Threat Reduction Agency under Grant 1-16-1-0048. This work was also supported by grants from the National Institutes of Health [U01 CA83178, R01 CA97397, R01 CA129639, R01 CA114236, and P30 CA008748].

Notes on contributors

Jonine L. Bernstein is an Attending Epidemiologist at Memorial Sloan Kettering Cancer Center with a research focus on the joint effects of genetics and radiation in cancer etiology, especially breast cancer. She is the Principal Investigator of the Women’s Environmental, Cancer, And Radiation Epidemiology (WECARE) Study.

Patrick Concannon is the Director of the University of Florida Genetics Institute. His research focuses on complex genetic disorders and gene-environment interactions, and includes studies of radiation sensitivity, breast cancer, malnutrition, and type 1 diabetes.