Sonja Berndt

National Cancer Institute

Senior Investigator

PLCO (Learn more about this study)

PLCO-210

May 31, 2016

A Genome-Wide Scan to Detect Loci Associated with Multiple Primary Cancers

A recent National Cancer Institute monograph calculated that approximately 14% of cancer survivors will go on to develop a second malignancy by 25 years of follow-up [1]. Even among families without a known mutation [2, 3], family history of cancer is a strong determinant of individual cancer risk, indicating the contribution of a genetic mechanism to these cancers [4]. Large, population-based linked registries have demonstrated increased risk of cancer not only in families where the index case had an early-onset cancer, but also in families where the index case developed cancer at later ages [4, 5]. GWAS have been extremely successful in identifying common loci for cancers, such as breast [6] and prostate [7], but no genome-wide association study (GWAS) has yet been published for second primary cancers outside of survivors of Hodgkin lymphoma [8]. We therefore propose to take advantage of the existing GWAS data within PLCO to identify new loci associated with multiple primary cancers.
The proposed study will use a case-control design. Cases will be European-ancestry participants with genotype data and at least two pathologically confirmed cancers as defined by the SEER multiple primary rules. Controls will be all European-ancestry participants with genotype data who have never been diagnosed with any cancer, except non-melanoma skin cancer. With approximately 15,345 primary cancer diagnoses within GWAS data in PLCO, and assuming a 5.74% rate of second cancers, we expect around 881 cases of multiple primary cancers for our proposed analysis.
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2. Czene K, Lichtenstein P, Hemminki K: Environmental and heritable causes of cancer among 9.6 million individuals in the Swedish Family-Cancer Database. International journal of cancer Journal international du cancer 2002, 99(2):260-266.
3. Lichtenstein P, et al: Environmental and heritable factors in the causation of cancer–analyses of cohorts of twins from Sweden, Denmark, and Finland. The New England journal of medicine 2000, 343(2):78-85.
4. Kerber RA, O'Brien E: A cohort study of cancer risk in relation to family histories of cancer in the Utah population database. Cancer 2005, 103(9):1906-1915.
5. Kharazmi E, Fallah M, Sundquist K, Hemminki K: Familial risk of early and late onset cancer: nationwide prospective cohort study. Bmj 2012, 345:e8076.
6. Michailidou K, et al: Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer. Nature genetics 2015, 47(4):373-380.
7. Hoffmann TJ, et al: A large multiethnic genome-wide association study of prostate cancer identifies novel risk variants and substantial ethnic differences. Cancer discovery 2015, 5(8):878-891.
8. Best T, et al: Variants at 6q21 implicate PRDM1 in the etiology of therapy-induced second malignancies after Hodgkin's lymphoma. Nature medicine 2011, 17(8):941-943.