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Observational Study
. 2020 Apr;158(5):1274-1286.e12.
doi: 10.1053/j.gastro.2019.12.012. Epub 2019 Dec 19.

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

Alexi N Archambault  1 , Yu-Ru Su  2 , Jihyoun Jeon  3 , Minta Thomas  2 , Yi Lin  2 , David V Conti  4 , Aung Ko Win  5 , Lori C Sakoda  6 , Iris Lansdorp-Vogelaar  7 , Elisabeth F P Peterse  7 , Ann G Zauber  8 , David Duggan  9 , Andreana N Holowatyj  10 , Jeroen R Huyghe  2 , Hermann Brenner  11 , Michelle Cotterchio  12 , Stéphane Bézieau  13 , Stephanie L Schmit  14 , Christopher K Edlund  4 , Melissa C Southey  15 , Robert J MacInnis  16 , Peter T Campbell  17 , Jenny Chang-Claude  18 , Martha L Slattery  19 , Andrew T Chan  20 , Amit D Joshi  21 , Mingyang Song  22 , Yin Cao  23 , Michael O Woods  24 , Emily White  25 , Stephanie J Weinstein  26 , Cornelia M Ulrich  10 , Michael Hoffmeister  27 , Stephanie A Bien  2 , Tabitha A Harrison  2 , Jochen Hampe  28 , Christopher I Li  2 , Clemens Schafmayer  29 , Kenneth Offit  30 , Paul D Pharoah  31 , Victor Moreno  32 , Annika Lindblom  33 , Alicja Wolk  34 , Anna H Wu  4 , Li Li  35 , Marc J Gunter  36 , Andrea Gsur  37 , Temitope O Keku  38 , Rachel Pearlman  39 , D Timothy Bishop  40 , Sergi Castellví-Bel  41 , Leticia Moreira  41 , Pavel Vodicka  42 , Ellen Kampman  43 , Graham G Giles  44 , Demetrius Albanes  45 , John A Baron  46 , Sonja I Berndt  45 , Stefanie Brezina  37 , Stephan Buch  10 , Daniel D Buchanan  47 , Antonia Trichopoulou  48 , Gianluca Severi  49 , María-Dolores Chirlaque  50 , Maria-José Sánchez  51 , Domenico Palli  52 , Tilman Kühn  53 , Neil Murphy  54 , Amanda J Cross  55 , Andrea N Burnett-Hartman  56 , Stephen J Chanock  45 , Albert de la Chapelle  57 , Douglas F Easton  58 , Faye Elliott  40 , Dallas R English  44 , Edith J M Feskens  43 , Liesel M FitzGerald  59 , Phyllis J Goodman  60 , John L Hopper  61 , Thomas J Hudson  62 , David J Hunter  63 , Eric J Jacobs  17 , Corinne E Joshu  64 , Sébastien Küry  65 , Sanford D Markowitz  34 , Roger L Milne  16 , Elizabeth A Platz  64 , Gad Rennert  66 , Hedy S Rennert  66 , Fredrick R Schumacher  67 , Robert S Sandler  38 , Daniela Seminara  68 , Catherine M Tangen  60 , Stephen N Thibodeau  69 , Amanda E Toland  57 , Franzel J B van Duijnhoven  43 , Kala Visvanathan  64 , Ludmila Vodickova  42 , John D Potter  2 , Satu Männistö  70 , Korbinian Weigl  71 , Jane Figueiredo  72 , Vicente Martín  73 , Susanna C Larsson  74 , Patrick S Parfrey  75 , Wen-Yi Huang  26 , Heinz-Josef Lenz  76 , Jose E Castelao  77 , Manuela Gago-Dominguez  78 , Victor Muñoz-Garzón  79 , Christoph Mancao  80 , Christopher A Haiman  4 , Lynne R Wilkens  81 , Erin Siegel  82 , Elizabeth Barry  83 , Ban Younghusband  24 , Bethany Van Guelpen  84 , Sophia Harlid  85 , Anne Zeleniuch-Jacquotte  1 , Peter S Liang  86 , Mengmeng Du  8 , Graham Casey  87 , Noralane M Lindor  88 , Loic Le Marchand  81 , Steven J Gallinger  89 , Mark A Jenkins  5 , Polly A Newcomb  90 , Stephen B Gruber  91 , Robert E Schoen  92 , Heather Hampel  39 , Douglas A Corley  93 , Li Hsu  94 , Ulrike Peters  95 , Richard B Hayes  96
Affiliations
Observational Study

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

Alexi N Archambault et al. Gastroenterology. 2020 Apr.

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.

Keywords: Colon Cancer; EOCRC; Penetrance; SNP.

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Figures

Figure 1:
Figure 1:
Risk estimates for early-onset versus late-onset CRC associated with a 95-SNP PRS in the discovery dataset. (A) Model includes all study participants regardless of first-degree family history of CRC. (B) Model includes study participants without a first-degree family history of CRC. (C) Model includes study participants with a first-degree family history of CRC. Models were adjusted for age, sex, principal components, genotype platform, and polygenic risk score. The interaction p-value reported was produced from a model including an interaction term with a continuous PRS (per SD) and age (<50 years versus ≥50 years).
Figure 2:
Figure 2:
Absolute risk estimates of being diagnosed with CRC across the age stratum by PRS percentile among individuals in the RPGEH cohort. (A) Among individuals with a first-degree relative with CRC. (B) Among individuals without a family history of CRC.
See this image and copyright information in PMC

Comment in

References

    1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016;66:7–30. - PubMed
    1. Phillips KA, Liang SY, Ladabaum U, et al. Trends in colonoscopy for colorectal cancer screening. Med Care 2007;45:160–7. - PubMed
    1. Cress RD, Morris C, Ellison GL, et al. Secular changes in colorectal cancer incidence by subsite, stage at diagnosis, and race/ethnicity, 1992–2001. Cancer 2006;107:1142–52. - PubMed
    1. Siegel RL, Torre LA, Soerjomataram I, et al. Global patterns and trends in colorectal cancer incidence in young adults. Gut 2019:gutjnl-2019–319511. - PubMed
    1. Yeo H, Betel D, Abelson JS, et al. Early-onset colorectal cancer is distinct from traditional colorectal cancer. Clin Colorectal Cancer 2017;16:293–299.e6. - PubMed

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