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

Published on Apr 1, 2020in Gastroenterology19.809
· DOI :10.1053/J.GASTRO.2019.12.012
Alexi N. Archambault1
Estimated H-index: 1
(NYU: New York University),
Yu Ru Su3
Estimated H-index: 3
(Fred Hutchinson Cancer Research Center)
+ 131 AuthorsRichard B. Hayes102
Estimated H-index: 102
(NYU: New York University)
Sources
Abstract
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=5.61x10–5). 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 preventative measures.
  • References (47)
  • Citations (3)
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References47
Newest
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#2Lindsey A. Torre (ACS: American Cancer Society)H-Index: 14
Last. Ahmedin Jemal (ACS: American Cancer Society)H-Index: 110
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Objective Early-onset colorectal cancer (CRC) is increasing in the USA despite rapid declines in older ages. Similar patterns are reported in Australia and Canada, but a comprehensive global analysis of contemporary data is lacking. Design We extracted long-term data from Cancer Incidence in Five Continents and supplemental sources to report on worldwide CRC incidence rates and trends by age (20–49 years and ≥50 years) through diagnosis year 2012 or beyond (Australia, Finland, New Zealand, Norwa...
21 CitationsSource
#1Stephanie L. Schmit (USF: University of South Florida)H-Index: 10
#2Christopher K. Edlund (USF: University of South Florida)H-Index: 24
Last. Stephen B. Gruber (SC: University of Southern California)H-Index: 67
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Author(s): Schmit, Stephanie L; Edlund, Christopher K; Schumacher, Fredrick R; Gong, Jian; Harrison, Tabitha A; Huyghe, Jeroen R; Qu, Chenxu; Melas, Marilena; Van Den Berg, David J; Wang, Hansong; Tring, Stephanie; Plummer, Sarah J; Albanes, Demetrius; Alonso, M Henar; Amos, Christopher I; Anton, Kristen; Aragaki, Aaron K; Arndt, Volker; Barry, Elizabeth L; Berndt, Sonja I; Bezieau, Stephane; Bien, Stephanie; Bloomer, Amanda; Boehm, Juergen; Boutron-Ruault, Marie-Christine; Brenner, Hermann; Bre...
17 CitationsSource
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#2Xue Qin Yu (Cancer Council New South Wales)H-Index: 20
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Background: Colorectal cancer is the third most commonly diagnosed cancer in Australia. Emerging evidence from several countries suggests increasing incidence in people aged Methods: We assessed colon and rectal cancer incidence trends in people aged 20+ in Australia from 1982 to 2014. We used data on 375,008 incident cases (248,162 colon and 126,846 rectal). We quantified the annual percentage change (APC) in rates by age group using Joinpoint regression. Results: For people aged 70 years) was ...
5 CitationsSource
#1Jeroen R. Huyghe (Fred Hutchinson Cancer Research Center)H-Index: 18
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Last. Ulrike Peters (UW: University of Washington)H-Index: 66
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To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined ...
17 CitationsSource
#1Caitlin Murphy (UNC: University of North Carolina at Chapel Hill)H-Index: 16
#2Amit G. Singal (UNC: University of North Carolina at Chapel Hill)H-Index: 42
Last. Robert S. Sandler (UNC: University of North Carolina at Chapel Hill)H-Index: 80
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: The increasing incidence of colorectal cancer in younger adults (aged <50 years) has been widely reported. Using data from the Surveillance, Epidemiology, and End Results Program, we found young-onset colorectal cancer incidence rates decreased from 1975 through about 1990. Decreases were more prominent in the colon, a contrast with more recent increases in rectal cancer. Incidence rates subsequently increased, differing by time period and 5-year age group. This inflection point is consistent ...
8 CitationsSource
#1Peter S. LiangH-Index: 8
#2James E. Allison (KP: Kaiser Permanente)H-Index: 26
Last. Samir GuptaH-Index: 18
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8 CitationsSource
6 CitationsSource
#1Andrew M.D. Wolf (UVA: University of Virginia)H-Index: 18
#2Elizabeth T. H. Fontham (LSU: Louisiana State University)H-Index: 50
Last. Robert A. Smith (ACS: American Cancer Society)H-Index: 82
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: In the United States, colorectal cancer (CRC) is the fourth most common cancer diagnosed among adults and the second leading cause of death from cancer. For this guideline update, the American Cancer Society (ACS) used an existing systematic evidence review of the CRC screening literature and microsimulation modeling analyses, including a new evaluation of the age to begin screening by race and sex and additional modeling that incorporates changes in US CRC incidence. Screening with any one of...
135 CitationsSource
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Last. Li Hsu (Fred Hutchinson Cancer Research Center)H-Index: 43
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Background & Aims Guidelines for initiating colorectal cancer (CRC) screening are based on family history but do not consider lifestyle, environmental, or genetic risk factors. We developed models to determine risk of CRC, based on lifestyle and environmental factors and genetic variants, and to identify an optimal age to begin screening. Methods We collected data from 9748 CRC cases and 10,590 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colorectal Transdisc...
34 CitationsSource
#1Darren R. Brenner (AHS: Alberta Health Services)H-Index: 17
#2Yibing Ruan (AHS: Alberta Health Services)H-Index: 5
Last. Robert J. Hilsden (U of C: University of Calgary)H-Index: 26
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Abstract Recent analyses in the United States have shown an overall decrease in the incidence of colorectal cancer despite contrasting increases in younger age groups. We examined whether these cohort trends are occurring in Canada. Age-specific trends in colon and rectal cancer incidence in Canada from the National Cancer Incidence Reporting System (1969–1992) and the Canadian Cancer Registry (1992–2012) were analyzed. We estimated annual percent changes (APC) with the Joinpoint Regression Prog...
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#1Mariona TerradasH-Index: 10
#2Gabriel CapelláH-Index: 60
Last. Laura ValleH-Index: 18
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In the past two decades, multiple studies have been undertaken to elucidate the genetic cause of the predisposition to mismatch repair (MMR)-proficient nonpolyposis colorectal cancer (CRC). Here, we present the proposed candidate genes according to their involvement in specific pathways considered relevant in hereditary CRC and/or colorectal carcinogenesis. To date, only pathogenic variants in RPS20 may be convincedly linked to hereditary CRC. Nevertheless, accumulated evidence supports the invo...
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#1Anna Siskova (First Faculty of Medicine, Charles University in Prague)H-Index: 1
#2Klara Cervena (First Faculty of Medicine, Charles University in Prague)H-Index: 2
Last. Veronika Vymetalkova (Charles University in Prague)H-Index: 12
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Colorectal cancer (CRC) is a malignant disease with an incidence of over 1.8 million new cases per year worldwide. CRC outcome is closely related to the respective stage of CRC and is more favorable at less advanced stages. Detection of early colorectal adenomas is the key to survival. In spite of implemented screening programs showing efficiency in the detection of early precancerous lesions and CRC in asymptomatic patients, a significant number of patients are still diagnosed in advanced stage...
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