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<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.
TPS3631 Background: Adenomatous polyps are the acknowledged precursors of colorectal cancer (CRC). Identification and removal of adenomas is the mechanism by which screening is effective in reducing CRC incidence and mortality. Patients with 1-2 non-advanced adenomas ( < 1 cm with neither villous components nor high grade dysplasia) are recommended to return at a timing ranging from 5-10 yrs. However, evidence for the benefit, optimal timing, and recommended frequency of surveillance colonoscopy is not available. A randomized, clinical trial to demonstrate the difference in results between 5- or 10-yr surveillance for participants with non-advanced adenoma can guide clinical practice. Methods: NRG-CC005/FORTE is a prospective, randomized, non-blinded, Phase III, non-inferiority clinical trial comparing CRC incidence in participants randomized to recommendation for a 5- and 10-yr vs. a 10-yr only surveillance colonoscopy exam schedule. Other pre-defined exploratory endpoints include incidence of advanced adenomas, CRC mortality, and incidence of stage III-IV CRCs. Stratification factors include age, gender, and time from qualifying colonoscopy to randomization. Participants ≥50 and < 70 yrs of age at the time of randomization with a first-time diagnosis of 1-2 non-advanced tubular adenomas from the qualifying colonoscopy within 4 yrs prior to randomization will be eligible. Participants with a clinical diagnosis of a significant genetic risk for CRC or with a family history of CRC diagnosed at ≤60 yrs in a first degree relative or in two first degree relatives diagnosed at any age are ineligible. Other ineligibility criteria include prior history of CRC or colorectal adenomas, a hyperplastic polyp measuring ≥1 cm or traditional serrated adenomas, or life expectancy < 10 yrs due to comorbid conditions. Collection of blood, stool, and tissue samples is planned. Statistics: The primary endpoint for the trial is CRC incidence. The trial is focused on CRCs diagnosed between year 5 and year 10. By incorporating a window of +/- 1 yr to allow for somewhat earlier and later procedures, as typically occurs in clinical medicine, the primary endpoint will include incident cancers identified in years 4 through 11. A crude 4- to 11-yr incidence rate of 0.387% is assumed for the 5- and 10-yr schedule arm. The study is powered at 90% to detect a non-inferiority margin difference of 0.387% at alpha 5% in CRC incidence rate between two schedules. 9,500 participants are to be enrolled. Support: U10CA180868, -180822, UG1CA189867, U24CA196067 Clinical trial information: NCT05080673.
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