Dataset Information

Cumulative Burden of Colorectal Cancer-Associated Genetic Variants Is More Strongly Associated With Early-Onset vs Late-Onset Cancer.

ABSTRACT:

Background & aims

Early-onset colorectal cancer (CRC, in persons younger than 50 years old) is increasing in incidence; yet, in the absence of a family history of CRC, this population lacks harmonized recommendations for prevention. We aimed to determine whether a polygenic risk score (PRS) developed from 95 CRC-associated common genetic risk variants was associated with risk for early-onset CRC.

Methods

We studied risk for CRC associated with a weighted PRS in 12,197 participants younger than 50 years old vs 95,865 participants 50 years or older. PRS was calculated based on single nucleotide polymorphisms associated with CRC in a large-scale genome-wide association study as of January 2019. Participants were pooled from 3 large consortia that provided clinical and genotyping data: the Colon Cancer Family Registry, the Colorectal Transdisciplinary Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium and were all of genetically defined European descent. Findings were replicated in an independent cohort of 72,573 participants.

Results

Overall associations with CRC per standard deviation of PRS were significant for early-onset cancer, and were stronger compared with late-onset cancer (P for interaction = .01); when we compared the highest PRS quartile with the lowest, risk increased 3.7-fold for early-onset CRC (95% CI 3.28-4.24) vs 2.9-fold for late-onset CRC (95% CI 2.80-3.04). This association was strongest for participants without a first-degree family history of CRC (P for interaction = 5.61 × 10^-5). When we compared the highest with the lowest quartiles in this group, risk increased 4.3-fold for early-onset CRC (95% CI 3.61-5.01) vs 2.9-fold for late-onset CRC (95% CI 2.70-3.00). Sensitivity analyses were consistent with these findings.

Conclusions

In an analysis of associations with CRC per standard deviation of PRS, we found the cumulative burden of CRC-associated common genetic variants to associate with early-onset cancer, and to be more strongly associated with early-onset than late-onset cancer, particularly in the absence of CRC family history. Analyses of PRS, along with environmental and lifestyle risk factors, might identify younger individuals who would benefit from preventive measures.

SUBMITTER: Archambault AN

PROVIDER: S-EPMC7103489 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Cumulative Burden of Colorectal Cancer-Associated Genetic Variants Is More Strongly Associated With Early-Onset vs Late-Onset Cancer.

Archambault Alexi N AN Su Yu-Ru YR Jeon Jihyoun J Thomas Minta M Lin Yi Y Conti David V DV Win Aung Ko AK Sakoda Lori C LC Lansdorp-Vogelaar Iris I Peterse Elisabeth F P EFP Zauber Ann G AG Duggan David D Holowatyj Andreana N AN Huyghe Jeroen R JR Brenner Hermann H Cotterchio Michelle M Bézieau Stéphane S Schmit Stephanie L SL Edlund Christopher K CK Southey Melissa C MC MacInnis Robert J RJ Campbell Peter T PT Chang-Claude Jenny J Slattery Martha L ML Chan Andrew T AT Joshi Amit D AD Song Mingyang M Cao Yin Y Woods Michael O MO White Emily E Weinstein Stephanie J SJ Ulrich Cornelia M CM Hoffmeister Michael M Bien Stephanie A SA Harrison Tabitha A TA Hampe Jochen J Li Christopher I CI Schafmayer Clemens C Offit Kenneth K Pharoah Paul D PD Moreno Victor V Lindblom Annika A Wolk Alicja A Wu Anna H AH Li Li L Gunter Marc J MJ Gsur Andrea A Keku Temitope O TO Pearlman Rachel R Bishop D Timothy DT Castellví-Bel Sergi S Moreira Leticia L Vodicka Pavel P Kampman Ellen E Giles Graham G GG Albanes Demetrius D Baron John A JA Berndt Sonja I SI Brezina Stefanie S Buch Stephan S Buchanan Daniel D DD Trichopoulou Antonia A Severi Gianluca G Chirlaque María-Dolores MD Sánchez Maria-José MJ Palli Domenico D Kühn Tilman T Murphy Neil N Cross Amanda J AJ Burnett-Hartman Andrea N AN Chanock Stephen J SJ de la Chapelle Albert A Easton Douglas F DF Elliott Faye F English Dallas R DR Feskens Edith J M EJM FitzGerald Liesel M LM Goodman Phyllis J PJ Hopper John L JL Hudson Thomas J TJ Hunter David J DJ Jacobs Eric J EJ Joshu Corinne E CE Küry Sébastien S Markowitz Sanford D SD Milne Roger L RL Platz Elizabeth A EA Rennert Gad G Rennert Hedy S HS Schumacher Fredrick R FR Sandler Robert S RS Seminara Daniela D Tangen Catherine M CM Thibodeau Stephen N SN Toland Amanda E AE van Duijnhoven Franzel J B FJB Visvanathan Kala K Vodickova Ludmila L Potter John D JD Männistö Satu S Weigl Korbinian K Figueiredo Jane J Martín Vicente V Larsson Susanna C SC Parfrey Patrick S PS Huang Wen-Yi WY Lenz Heinz-Josef HJ Castelao Jose E JE Gago-Dominguez Manuela M Muñoz-Garzón Victor V Mancao Christoph C Haiman Christopher A CA Wilkens Lynne R LR Siegel Erin E Barry Elizabeth E Younghusband Ban B Van Guelpen Bethany B Harlid Sophia S Zeleniuch-Jacquotte Anne A Liang Peter S PS Du Mengmeng M Casey Graham G Lindor Noralane M NM Le Marchand Loic L Gallinger Steven J SJ Jenkins Mark A MA Newcomb Polly A PA Gruber Stephen B SB Schoen Robert E RE Hampel Heather H Corley Douglas A DA Hsu Li L Peters Ulrike U Hayes Richard B RB

Gastroenterology 20191219 5

<h4>Background & aims</h4>Early-onset colorectal cancer (CRC, in persons younger than 50 years old) is increasing in incidence; yet, in the absence of a family history of CRC, this population lacks harmonized recommendations for prevention. We aimed to determine whether a polygenic risk score (PRS) developed from 95 CRC-associated common genetic risk variants was associated with risk for early-onset CRC.<h4>Methods</h4>We studied risk for CRC associated with a weighted PRS in 12,197 participants ...[more]

PMID: 31866242

Similar Datasets

Project description:ImportanceThe understanding of the association between KRAS sequence variation status and clinical outcomes in colorectal cancer (CRC) has evolved over time.ObjectiveTo characterize the association of age at onset, tumor sidedness, and KRAS sequence variation with survival among patients diagnosed with CRC.Design, setting, and participantsThis cross-sectional study used data extracted from the Surveillance, Epidemiology, and End Results database. Patients diagnosed with adenocarcinoma of the colon or rectum from 2010 through 2015 were included and were classified as having young-onset (YO) cancer if diagnosed between ages 20 to 49 years and late-onset (LO) cancer if diagnosed at age 50 years or older. Data were analyzed from April 2021 through August 2023.Main outcomes and measuresCRC cause-specific survival (CSS) was summarized using Fine and Gray cumulative incidence and Kaplan-Meier curves. Estimation of subdistribution hazard ratios (sHRs) for the association of KRAS status, age at onset, and tumor location with CRC CSS was conducted using the Fine and Gray competing risk model. Cox proportional hazards regression was used to estimate and compare HRs.ResultsAmong 21 661 patients with KRAS sequence variation status (mean [SD] age at diagnosis, 62.50 [13.78] years; 9784 females [45.2%]), 3842 patients had YO CRC, including 1546 patients with KRAS variants, and 17 819 patients had LO CRC, including 7311 patients with KRAS variants. There was a significant difference in median CSS time between patients with variant vs wild-type KRAS (YO: 3.0 years [95% CI, 2.8-3.3 years] vs 3.5 years [95% CI, 3.3-3.9 years]; P = .02; LO: 2.5 years [95% CI, 2.4-2.7 years] vs 3.4 years [95% CI, 3.3-3.6 years]; P < .001). Tumors with variant compared with wild-type KRAS were associated with higher risk of CRC-related death (YO: sHR, 1.09 [95% CI, 1.01-1.18]; P = .03; LO: sHR, 1.06 [95% CI, 1.02-1.09]; P = .002). Among patients with YO cancer, mortality hazards increased by location, from right (sHR, 1.02 [95% CI, 0.88-1.17) to left (sHR, 1.15 [95% CI, 1.02-1.29) and rectum (sHR, 1.16 [95% CI, 0.99-1.36), but no trend by tumor location was seen for LO cancer.Conclusions and relevanceIn this study of patients diagnosed with CRC, KRAS sequence variation was associated with increased mortality among patients with YO and LO tumors. In YO cancer, variant KRAS-associated mortality risk was higher in distal tumors than proximal tumors.

Project description:ImportanceThe incidence of early-onset colorectal cancer (CRC) (age, <50 years) continues to increase globally within high-income countries.ObjectiveTo examine and compare rates of synchronous neoplasia found in patients at colonoscopic diagnosis of early-onset CRC with rates found at diagnosis of average-onset CRC.Design, setting, and participantsIn this multisite retrospective and cross-sectional study conducted at Mayo Clinic sites and in the Mayo Clinic Health System from January 1, 2012, to December 31, 2022, 150 randomly selected patients with early-onset CRC were identified from the electronic health record and matched with 150 patients with average-onset CRC based on sex and colonoscopic indication. Patients with known hereditary syndromes, past history of CRC, or inflammatory bowel disease were excluded.Main outcomes and measuresColonoscopic findings (polyp size, number, site) and related histopathologic findings (adenoma, advanced adenoma, sessile serrated polyp) were analyzed in association with cancer clinicopathologic features and molecular data (mismatch repair status, KRAS, and BRAFV600E).ResultsAmong 300 patients (156 men [52%]), the median age at diagnosis was 43 years (IQR, 39-47 years) for those with early-onset CRC and 67 years (IQR, 57-76) for those with average-onset CRC. Overall, 85% of patients were symptomatic at CRC diagnosis. Cancer stage, grade, molecular features, body mass index, and family history did not differ significantly between these groups. Among patients with colon cancer, the overall prevalence of synchronous neoplasia was similar, yet advanced adenomas were 3 times more frequent in those with early-onset vs average-onset cancers (31 of 75 [41%] vs 10 of 75 [13%]; P < .001). This difference was not associated with cancer stage or primary location. Among patients with rectal cancer, nonadvanced adenomas were less frequent among the early-onset group than the average-onset group (21 of 75 [28%] vs 36 of 75 [48%]), and although the prevalence of advanced adenomas was similar (11 of 75 [15%] vs 14 of 75 [19%]), they were more commonly located in the rectum (early onset, 5 of 11 [45%] vs average onset, 1 of 14 [7%]). Patients with early-onset cancer of the colon were significantly more likely than those with early-onset cancer of the rectum to have a synchronous advanced adenoma (31 of 75 [41%] vs 11 of 75 [15%]; P < .001).Conclusions and relevanceIn this cross-sectional study, synchronous advanced adenomas were more commonly found in patients with early-onset colon cancer compared with average-onset colon cancer, and they were distributed throughout the colon. In contrast, advanced adenomas were not increased in patients with rectal cancer and, when detected, were predominantly located in the rectum.

Project description:Grassland birds have undergone widespread global population declines due to loss and degradation of native grasslands. Activities associated with non-renewable energy derived from oil and natural gas extraction have substantially increased on grasslands. The cumulative disturbance generated by natural gas development creates a network of non-linear (e.g., bare ground and exotic plant species) and linear (e.g., roads, trails, pipelines) features that may degrade habitat quality for grassland species. We quantified grassland songbird abundance in two areas of southwestern Saskatchewan, Canada, to determine whether variation in abundance 1) depended on the type and amount of disturbance at two spatial extents, and 2) was more affected by the cumulative impacts of natural gas development than any single type of disturbance. We found that specific types of disturbances impacted the abundance of most species to varying degrees. The cover of different types of linear disturbance had the strongest effect on the most species. Natural gas disturbance within 450 m of point counts was more influential than disturbance within 200 m for nearly all species in both areas. Only Savannah sparrow (Passerculus sandwichensis) abundance was most strongly influenced by the cumulative amount of disturbance with abundance decreasing with increased disturbance. Overall, we detected few consistent patterns among species, or within species between our two study areas. Our results indicated that the impact of natural gas infrastructure can extend beyond the local influences associated with well sites and that relatively small amounts of disturbance (<2%) may impact grassland songbird abundance. We recommend that researchers use caution when studying well-density effects or combining individual types of disturbance without understanding the separate effects each type of disturbance has on the species or community of interest. Not doing so may lead to investing resources into management practices that do not have the greatest possible benefit for grassland songbirds.

Dataset Information

Cumulative Burden of Colorectal Cancer-Associated Genetic Variants Is More Strongly Associated With Early-Onset vs Late-Onset Cancer.

Background & aims

Methods

Results

Conclusions

Publications

Cumulative Burden of Colorectal Cancer-Associated Genetic Variants Is More Strongly Associated With Early-Onset vs Late-Onset Cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets