Abstract 1446: Genetic risk factors for the development of multiple primary cancers
Authors: Nierenberg Jovia L. , Kachuri Linda , Cavazos Taylor B. , Graff Rebecca E. , Hoffmann Thomas J. , Zhang Jie , Alexeeff Stacey , Habel Laurel , Corley Douglas , Van Den Eeden Stephen , Ziv Elad , Sakoda Lori C. , Witte John S. 
Published: June 2022

Abstract
Introduction: Individuals with one cancer are at greater risk of new primary cancers than the general population. While several hereditary cancer syndromes are known, genetic risk factors for multiple primary cancers in an individual are not well understood. Identification of susceptibility variants to multiple primary tumors could enhance screening for subsequent cancers among those at highest risk.
Methods: We conducted a pan-cancer genome-wide association study (GWAS) of multiple primary cancers among participants from 2 prospective cohorts: Kaiser Permanente and the UK Biobank. The primary GWAS within cohorts used logistic regression to estimate associations for diagnosis with ≥2 invasive or in situ primary cancers other than non-melanoma skin (N=11,773, 8,928 invasive only) compared to cancer-free controls (N=420,101). Case-case analyses were conducted to distinguish associations with multiple cancers from single-cancer (N=90,576) susceptibility signals. Regression models were adjusted for age, sex, first 10 genetic ancestry principal components, and array. Cohort-specific GWAS results were meta-analyzed. We highlight genome-wide significant (p&lt;5×10-8) results with consistent effect direction across the 2 studies.
Results: We identified 8 variants associated with multiple primary cancers.
Discussion: To our knowledge, rs192703567 has no previous cancer associations. Three identified variants are in known cancer predisposition genes (rs2293607 in TERC, rs6983267 in CASC8, rs35850753 in TP53). Three variants (rs34379047, rs612611, and rs9419958) are previously associated with multiple cancers, 2 (rs2293607 and rs6983267) with cancer pleiotropy, and 2 (rs283732 and rs35850753) with individual cancers. Most variants from the cancer-free control analyses had consistent effects in the single-cancer case-case analyses, suggesting pleiotropic mechanisms. Our preliminary findings offer insight into genetic risk factors associated with developing multiple primary cancers.
Multiple vs. none Multiple invasive vs. none Multiple vs. single Multiple invasive vs. single Chr Position rsID A1 A2 Gene OR P OR P OR P OR P 3 169482335 rs2293607 T C TERC 1.11 1.0×10-9 1.10 2.2×10-7 1.06 2.0×10-3 1.05 0.01 8 128281644 rs283732 C T Intergenic 1.09 2.3×10-7 1.11 9.2×10-9 1.06 3.8×10-4 1.09 3.9×10-5 8 128413305 rs6983267 G T CASC8 POU5F1B CCAT2 PCAT1 1.08 4.1×10-7 1.09 2.9×10-8 1.00 0.83 1.02 0.34 10 105644473 rs34379047 T A OBFC1 1.16 8.5×10-12 1.19 6.0×10-11 1.19 2.3×10-4 1.10 4.0×10-4 10 105675946 rs9419958 T C STN1 1.14 1.8×10-11 1.16 4.5×10-11 1.08 3.1×10-4 1.09 2.8×10-4 11 69307463 rs612611 G A Intergenic 1.11 3.7×10-8 1.10 5.3×10-6 1.06 9.6×10-4 1.05 0.02 17 7578671 rs35850753 T C TP53 1.27 4.9×10-7 1.34 1.6×10-8 1.16 2.8×10-3 1.24 8.8×10-5 22 40738280 rs192703567 C T Intergenic 1.37 5.2×10-8 1.37 1.8×10-6 1.43 4.9×10-9 1.43 2.8×10-7 Chr=Chromosome; A1=Effect allele; A2=Other allele; OR=Odds ratio.
Citation Format: Jovia L. Nierenberg, Linda Kachuri, Taylor B. Cavazos, Rebecca E. Graff, Thomas J. Hoffmann, Jie Zhang, Stacey Alexeeff, Laurel Habel, Douglas Corley, Stephen Van Den Eeden, Elad Ziv, Lori C. Sakoda, John S. Witte. Genetic risk factors for the development of multiple primary cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1446.