Early-onset colorectal cancer shows higher susceptibility to common

genetic risk factors Doug Corley on behalf of Alexi

Archambault (first author), Ulrike Peters, Richard Hayes and research group

The incidence of young-onset CRC is increasing and varies by race and location

Murphy, C, Gastroenterology, 2019

during 1992–1996 ( red circles ), during

2010–2014 ( blue circles )

Incidence is increasing for both local and advanced disease

Murphy, C, Gastroenterology, 2019

during 1992–1996 ( red circles ), during

2010–2014 ( blue circles )

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?Genetic contributions to CRC: Evaluated large discovery group

50,023 CRC patients and 58089 cancer-free controls 3 large consortia with clinical & genotyping data:

Colon Cancer Family Registry (CCFR), the Colorectal Transdisciplinary (CORECT) Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO)

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Analysis

• SNPs coded as 0, 1, or 2 copied of risk allele

• Polygenic risk score

– Weighted, from regression model with 95 SNPS, age, sex, principal components, genotype platform

• Logit for Risk Score vs. CRC

• Stratified by age (< vs. >50) and family h/o CRC

• Self-reported family history

• European descent

Colon Cancer Family Registry (CCFR), the Colorectal Transdisciplinary (CORECT) Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO)

Data acquired Limitations Genetic

• 95 CRC-risk-associated SNPs that reached genome-wide significance (p ≤ 5×10-8), in large-scale GWAS

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Replication group

KP Northern California and 200,000 people/samples: 72,573 genotyped with European Ancestry

KPNC Research Program on Genes, Environment and Health

Discovery dataset Replication dataset

Cases (N=50,023) Controls (N=58,039) All participants CRC Cases

<50 ≥50 <50 ≥50 Cohort CRC cases <50 ≥50

N 5479 44544 6718 51321 72573 1093 25 1068

Age, Mean 43.1 66.5 41.3 65.3 71.5 73.1 45.2 73.7

Male 50.5 41.6

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Different polygenic risk score distributions in both early & late

Discovery Cohort Risk Score vs. age of onset and family hx

Discovery Cohort Risk Score vs. age of onset and family hx

Discovery Cohort Risk Score vs. age of onset and cancer location

Conclusion: Early-onset has different genetic risk

• Polygenic risk score (per standard deviation)

– stronger for early-onset: 4th v 1st quartile risk

• 3.7-fold (95% CI: 3.28, 4.24) for early-onset

• 2.9-fold (95% CI: 2.80, 3.04) for late-onset CRC

– Strongest without a first-degree family history (p<0.01)

• 4th v 1st Q: 4.3-fold (3.61, 5.01) early; 2.9 (2.70, 3.00).

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Conclusion: Early-onset has different genetic risk • Polygenic risk score (per standard deviation)

– stronger for early-onset than for late-onset cancer

– 4th v 1st quartile risk • 3.7-fold (95% CI: 3.28, 4.24) for early-onset

• 2.9-fold (95% CI: 2.80, 3.04) for late-onset CRC

– Strongest for without a first-degree family history (p<0.01)

– 4th v 1st quartile risk • 4.3-fold (95% CI: 3.61, 5.01) early-onset; 2.9 (95% CI: 2.70, 3.00) for

late-onset CRC.

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• Alexi N Archambault1, Yu-Ru Su2, Jihyoun Jeon3, Minta Thomas2, Yi Lin2, David V Conti4, Aung Ko Win5, Lori C Sakoda2,6, Iris Lansdorp-Vogelaar7, Elisabeth FP Peterse7, Ann G Zauber8, David Duggan9, Andreana N Holowatyj10, Jeroen R Huyghe2, Hermann Brenner11-13, Michelle Cotterchio14, Stéphane Bézieau15, Stephanie L Schmit4,16, Christopher K Edlund4, Melissa C Southey17, Robert J MacInnis5,18, Peter T Campbell19, Jenny Chang-Claude20,21, Martha L Slattery22, Andrew T Chan23-28, Amit D Joshi25,27, Mingyang Song29, Yin Cao25,30, Michael O Woods31, Emily White2,32, Stephanie J Weinstein33, Cornelia M Ulrich34, Michael Hoffmeister11, Stephanie A Bien2, Tabitha A Harrison2, Jochen Hampe35, Christopher I Li2, Clemens Schafmayer36, Kenneth Offit37,38, Paul D Pharoah39, Victor Moreno40-42, Annika Lindblom43,44, Alicja Wolk45, Anna H Wu4, Li Li46, Marc J Gunter47, Andrea Gsur48, Temitope O Keku49, Heather Hampel50, D Timothy Bishop51, Sergi Castellví-Bel52, Leticia Moreira52, Pavel Vodicka53-55, Ellen Kampman56, Graham G Giles5,16, Demetrius Albanes32, John A Baron57, Sonja I Berndt32, Stefanie Brezina48, Stephan Buch34, Daniel D Buchanan5,58-60, Rachel Pearlman50, Antonia Trichopoulou61, Gianluca Severi62, María-Dolores Chirlaque41,63, Maria José Sánchez64, Domenico Palli65, Tilman Kühn20, Neil Murphy66, Amanda J Cross67, Andrea N Burnett-Hartman68, Stephen J Chanock32, Albert de la Chapelle69, Douglas F Easton38, Faye Elliott51, Dallas R English5,16, Edith JM Feskens56, Liesel M FitzGerald16,70, Phyllis J Goodman71, John L Hopper5,72, Thomas J Hudson73, David J Hunter27,74, Eric J Jacobs19, Corinne E Joshu75, Sébastien Küry18, Sanford D Markowitz45, Roger L Milne5,16, Elizabeth A Platz75, Gad Rennert76-78, Hedy S Rennert76-78, Fredrick R Schumacher79, Robert S Sandler49, Daniela Seminara80, Catherine M Tangen71, Stephen N Thibodeau81, Amanda E Toland69, Franzel JB van Duijnhoven56, Kala Visvanathan75, Ludmila Vodickova53-55, John D Potter2, Satu Männistö82, Korbinian Weigl11,83, Jane Figueiredo4,84, Vicente Martín41,85, Susanna C Larsson44, Patrick S Parfrey86, Wen-Yi Huang33, Heinz-Josef Lenz87, Jose Esteban Castelao4, Manuela Gago4, Victor Muñoz-Garzón88, Christoph Mancao89, Christopher A Haiman4, Lynne R Wilkens90, Erin Siegel16, Elizabeth Barry91, Ban Younghusband30, Bethany Van Guelpen92,93, Sophia Harlid93, Graham Casey94, Noralane M Lindor95, Loic Le Marchand90, Steven J Gallinger96, Mark A Jenkins5, Polly A Newcomb2,97, Stephen B Gruber4, Robert E Schoen98, Douglas A Corley6§, Li Hsu2,99§, Ulrike Peters2,31§, Richard B Hayes1§

Colon Cancer Family Registry (CCFR), the Colorectal Transdisciplinary (CORECT) Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO)

Thank you – to our teams The people who did the work Our Kaiser Permanente Team

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