P1296 - Incident Cancer Risk and Mutation Signatures Among Elderly MUTYH Carriers: Analysis of Population-Based and Genomic Cohorts

Award: Presidential Poster Award

Award: Presidential Poster Award

Jonathan M. Downie, MD, PhD¹, Moeen Riaz, PhD², Sophia Xie, PhD², Minyi Lee, BS¹, Andrew T. Chan, MD, MPH¹, Peter Gibbs, MBBS, MD³, Suzanne Orchard, PhD², Suzanne Mahady, MBBS, PhD², Robert Sebra, PhD⁴, Anne Murray, MD, MS⁵, Finlay Macrae, MBBS, MD⁶, Eric Schadt, PhD⁴, Robyn Woods, BSc, PhD², John McNeil, MBBS, PhD², Paul Lacaze, PhD², Manish Gala, MD^1
1Massachusetts General Hospital, Boston, MA; ²Monash University, Melbourne, Victoria, Australia; ³Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; ⁴Icahn School of Medicine at Mount Sinai, New York, NY; ⁵Berman Center for Outcomes & Clinical Research, Minneapolis, MN; ⁶University of Melbourne, Parkville, Victoria, Australia

Introduction: MUTYH carriers are at increased risk for colorectal cancer (CRC) and possibly extracolonic cancers. CRC screening guidelines exist for carriers with a personal or first-degree family history of CRC, whereas other carriers cease screening at age 75 due to a lack of population-based risk and formal recommendations. To address this, we sought to 1) determine CRC and overall cancer risk among elderly MUTYH carriers and 2) assess if cancers from MUTYH carriers demonstrate excessive G:C >T:A transversions as seen in those who inherit biallelic mutations.

Methods: Incident cancer events were obtained from a large population-based, prospective cohort derived from the ASPirin in Reducing Events in the Elderly (ASPREE) clinical trial, with enrollment from 2010 through 2014, and follow-up until June 2017 (mean 4.5 years). 13,131 ASPREE study participants underwent MUTYH sequencing to detect risk variants. Sex stratified colorectal cancer and all-cause cancer hazard ratios (HR) were calculated between MUTYH carriers and non-carriers by Cox regression adjusting for age, smoking status, alcohol use, baseline BMI, and aspirin use. Tumor single base substitution signatures of 10,483 individuals from The Cancer Genome Atlas (TCGA) and 2550 participants from the International Cancer Genome Consortium (ICGC) were calculated to determine the mutational profiles of these tumors.

Results: The demographics between MUTYH carriers and non-carriers were well matched. 1,328 cancers developed among sequenced study participants, among which 177 were CRCs. Among male MUTYH carriers, we observed an increased risk for cancer (HR 1.67, 95% CI [1.04, 2.68]; P = 0.035) and colorectal cancer (HR 3.53, 95% CI [1.42, 8.78]; P = 0.007). Female MUTYH carriers did not demonstrate a significantly increased risk in cancer (HR 1.47, 95% CI [0.85, 2.54]; P = 0.170) or CRC (HR 0.81, 95% CI [0.11, 5.79]; P = 0.831).

Genomic analysis of cancers from TCGA and ICGC MUTYH carriers revealed no significant contribution toward early mutagenesis from widespread G:C >T:A transversions among gastrointestinal epithelial cancers; but high contributions in pancreatic neuroendocrine tumors, adrenocortical carcinoma, and thymomas were seen.

Discussion: Elderly, male MUTYH carriers are at an increased risk for cancer, particularly CRC. Mutations associated with base-excision repair deficiency are uncommon in most tumors, suggestive of alternative mechanisms of carcinogenesis in monoallelic carriers compared to those who inherit biallelic mutations.


Disclosures:


Jonathan M. Downie, MD, PhD¹, Moeen Riaz, PhD², Sophia Xie, PhD², Minyi Lee, BS¹, Andrew T. Chan, MD, MPH¹, Peter Gibbs, MBBS, MD³, Suzanne Orchard, PhD², Suzanne Mahady, MBBS, PhD², Robert Sebra, PhD⁴, Anne Murray, MD, MS⁵, Finlay Macrae, MBBS, MD⁶, Eric Schadt, PhD⁴, Robyn Woods, BSc, PhD², John McNeil, MBBS, PhD², Paul Lacaze, PhD², Manish Gala, MD¹. P1296 - Incident Cancer Risk and Mutation Signatures Among Elderly MUTYH Carriers: Analysis of Population-Based and Genomic Cohorts, ACG 2021 Annual Scientific Meeting Abstracts. Las Vegas, Nevada: American College of Gastroenterology.