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Evaluating Cancer Epidemiologic Risk Factors Using Multiple Primary Malignancies

Kuligina, Ekatherinaa; Reiner, Anneb; Imyanitov, Evgeny N.a; Begg, Colin B.b

doi: 10.1097/EDE.0b013e3181cc8871
Methods: Original Article

Background: Several authors have proposed the use of patients with double primary malignancies affecting the same or contralateral organ as a genetically enriched resource of cases for epidemiologic case–control studies in cancer. Such an approach is based on the assumption that the factors that increase the risk of a second primary are the same ones which influence the risk of a first primary. The advantages for statistical power are premised on the assumption that relative risks in survivors of a first primary cancer are similar to relative risks in the unaffected population. We explore these assumptions theoretically and empirically using published data from breast cancer studies involving bilateral breast cancer.

Methods: We conducted a literature review to identify case–control studies of variants in 4 genes known to affect breast cancer risk: CHEK2*1100delC; multiple variants in BRCA1 and BRCA2; and FGFR2 rs2981582. Summary odds ratios were obtained for each of 3 study designs: a conventional case–control design, the design comparing bilateral cases with unilateral controls, and the design comparing bilateral cases with population controls.

Results: The data show strong patterns of steadily increasing prevalence of risk factors from healthy controls to primary cases to bilateral cases, as expected. Relative risks in survivors of unilateral breast cancer are either the same as in the general population, or modestly attenuated.

Conclusions: Patients with double primary malignancies are a very important underused resource for cancer epidemiologic investigation. Such patients are especially useful for broad genome-wide discovery studies, and for studies of rare, strong risk factors such as high penetrance genes.

From the aN. N. Petrov Institute of Oncology, Russian Federation, St. Petersburg, Russia; and bMemorial Sloan-Kettering Cancer Center, New York, NY.

Submitted 16 December 2008; accepted 24 November 2009; posted 18 March 2010.

Supported by an International Cancer Fellowship from the International Union Against Cancer (Application No ICR/08/140), by the National Cancer Institute (Awards CA131010 and CA124504), and by the Russian Foundation for Basic Research (grant numbers 09–04–90402; 08–04–00369–1; 07–04–00122) and the Government of Moscow (grant number 15/09).

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Editors' note: A commentary on this article appears on page 373.

Correspondence: Colin B. Begg, Memorial Sloan-Kettering Cancer Center, 307 East 63rd Street, New York, NY 10065. E-mail:

© 2010 Lippincott Williams & Wilkins, Inc.