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

Archambault, Alexi; Su, Yu Ru; Jeon, Jihyoun; Thomas, Minta; Lin, Yi; Conti, David V.; Win, Aung Ko; Sakoda, Lori C.; Lansdorp–Vogelaar, Iris; Peterse, Elisabeth F. P.; Zauber, Ann G.; Duggan, David; Holowatyj, Andreana N.; Huyghe, Jeroen R.; Brenner, Hermann; Cotterchio, Michelle; Bézieau, Stéphane; Schmit, Stephanie L.; Edlund, Christopher K.; Southey, Melissa C.; MacInnis, Robert J.; Campbell, Peter T.; Chang‐Claude, Jenny; Slattery, Martha L.; Chan, Andrew T.; Joshi, Amit D.; Song, Mingyang; Cao, Yin; Woods, Michael O.; White, Emily; Weinstein, Stephanie J.; Ulrich, Cornelia M.; Hoffmeister, Michael; Bien, Stephanie A.; Harrison, Tabitha A.; Hampe, Jochen; Li, Christopher I.; Schafmayer, Clemens; Offit, Kenneth; Pharoah, Paul D.P.; Moreno, Vı́ctor; Lindblom, Annika; Wolk, Alicja; Wu, Anna H.; Li, Li; Gunter, Marc J.; Gsur, Andrea; Keku, Temitope O.; Pearlman, Rachel; Bishop, D. Timothy; Castellví–Bel, Sergi; Moreira, Letícia; Vodička, Pavel; Kampman, Ellen; Giles, Graham G.; Albanês, Demetrius; Baron, John A.; Berndt, Sonja I.; Brezina, Stefanie; Buch, Stephan; Buchanan, Daniel D.; Trichopoulou, Antonia; Severi, Gianluca; Chirlaque, María Dolores; Sánchez, María José; Palli, Domenico; Kühn, Tilman; Murphy, Neil; Cross, Amanda J.; Burnett‐Hartman, Andrea N.; Chanock, Stephen J.; Chapelle, Albert de la; Easton, Douglas F.; Elliott, Faye; English, Dallas R.; Feskens, Edith J. M.; FitzGerald, Liesel M.; Goodman, Phyllis J.; Hopper, John L.; Hudson, Thomas J.; Hunter, David J.; Jacobs, Eric J.; Joshu, Corinne E.; Küry, Sébastien; Markowitz, Sanford D.; Milne, Roger L.; Platz, Elizabeth A.; Rennert, Gad; Schumacher, Fredrick R.; Sandler, Robert S.; Seminara, Daniela; Tangen, Catherine M.; Thibodeau, Stephen N.; Toland, Amanda E.; Duijnhoven, Fränzel J.B. van; Visvanathan, Kala; Vodičková, Ľudmila; Potter, John D.; Männistö, Satu; Weigl, Korbinian; Figueiredo, Jane C.; Martín, Vicente; Larsson, Susanna C.; Parfrey, Patrick S.; Huang, Wen Yi; Lenz, Heinz Josef; Castelao, Jose E.; Gago‐Dominguez, Manuela; Muñoz-Garzón, Víctor; Mancao, Christoph; Haiman, Christopher A.; Wilkens, Lynne R.; Siegel, Erin M.; Barry, Elizabeth L.; Younghusband, Ban; Guelpen, Bethany Van; Harlid, Sophia; Zeleniuch‐Jacquotte, Anne; Liang, Peter S.; Du, Mengmeng; Casey, Graham; Lindor, Noralane M.; Marchand, Loı̈c Le; Gallinger, Steven; Jenkins, Mark A.; Newcomb, Polly A.; Gruber, Stephen B.; Schoen, Robert E.; Hampel, Heather; Corley, Douglas A.; Hsu, Li; Peters, Ulrike; Hayes, Richard B.

doi:10.1053/j.gastro.2019.12.012

Cited by 117 publications

(111 citation statements)

References 47 publications

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“…Syndromes are usually detected at an early age. However, sporadic CRC correlates with increasing age due to the accumulation of mutations in intestine cells [23,24]. In the study by Brenner et al [25], 10 years of cumulative risk of CRC among both sex with advanced adenomas increases from 25.4-25.2% at age 55 years to 42.9-39.7% at age 80 years.…”

Section: Sporadicmentioning

confidence: 99%

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Colorectal Adenomas—Genetics and Searching for New Molecular Screening Biomarkers

Siskova

Červená

Král

et al. 2020

IJMS

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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 stages. Research on CRC accomplished during the last decade has improved our understanding of the etiology and development of colorectal adenomas and revealed weaknesses in the general approach to their detection and elimination. Recent studies seek to find a reliable non-invasive biomarker detectable even in the blood. New candidate biomarkers could be selected on the basis of so-called liquid biopsy, such as long non-coding RNA, microRNA, circulating cell-free DNA, circulating tumor cells, and inflammatory factors released from the adenoma into circulation. In this work, we focused on both genetic and epigenetic changes associated with the development of colorectal adenomas into colorectal carcinoma and we also discuss new possible biomarkers that are detectable even in adenomas prior to cancer development.

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Section: Sporadicmentioning

confidence: 99%

“…Syndromes are usually detected at an early age. However, sporadic CRC correlates with increasing age due to the accumulation of mutations in intestine cells [23,24].…”

Section: Introductionmentioning

confidence: 99%

Colorectal Adenomas—Genetics and Searching for New Molecular Screening Biomarkers

Siskova

Červená

Král

et al. 2020

IJMS

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“…Data from GWASs on many cancers show that even collectively low-risk alleles explain a small proportion of the empirical familial risk [ 8 , 21 ]. It is known that usually low-risk alleles are moderately enriched in familial compared to sporadic cases, but even opposite results have been reported [ 22 , 23 ]. Improvement of risk prediction by adding a polygenetic risk score to prediction models that include the family history indicate only partial overlapping of these factors [ 24 , 25 ].…”

Section: Discussionmentioning

confidence: 99%

Cancer Predisposition Genes in Cancer-Free Families

Zheng

Catalano

Bandapalli

et al. 2020

Cancers

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Familial clustering, twin concordance, and identification of high- and low-penetrance cancer predisposition variants support the idea that there are families that are at a high to moderate excess risk of cancer. To what extent there may be families that are protected from cancer is unknown. We wanted to test genetically whether cancer-free families share fewer breast, colorectal, and prostate cancer risk alleles than the population at large. We addressed this question by whole-genome sequencing (WGS) of 51 elderly cancer-free individuals whose numerous (ca. 1000) family members were found to be cancer-free (‘cancer-free families’, CFFs) based on face-to-face interviews. The average coverage of the 51 samples in the WGS was 42x. We compared cancer risk allele frequencies in cancer-free individuals with those in the general population available in public databases. The CFF members had fewer loss-of-function variants in suggested cancer predisposition genes compared to the ExAC data, and for high-risk cancer predisposition genes, no pathogenic variants were found in CFFs. For common low-penetrance breast, colorectal, and prostate cancer risk alleles, the results were not conclusive. The results suggest that, in line with twin and family studies, random environmental causes are so dominant that a clear demarcation of cancer-free populations using genetic data may not be feasible.

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“…SNP-based Genetic Risk Score (GRS), an odds ratio (OR)-weighted and population-standardized polygenic risk score derived from well-established CRC risk-associated SNPs, has been consistently associated with CRC risk. [18][19][20][21][22][23] In brief, it is calculated by multiplying the per-allele OR for each SNP and normalizing the risk by the mean risk expected in the population. Such an approach has been successfully implemented for other malignancies in predicting risk for breast cancer, prostate cancer, CRC and other cancers.…”

Section: Introductionmentioning

confidence: 99%

Polygenic Risk Score is a Predictor of Adenomatous Polyps at Screening Colonoscopy 

Northcutt

Shi

Zijlstra

et al. 2020

Preprint

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Background: SNP-based polygenic risk scoring is predictive of colorectal cancer (CRC) risk. However, few studies have investigated the association of genetic risk score (GRS) with detection of adenomatous polyps at screening colonoscopy. Methods: We randomly selected 1,769 Caucasian subjects who underwent screening colonoscopy from the Genomic Health Initiative (GHI), a biobank of NorthShore University HealthSystem. Outcomes from initial screening colonoscopy were recorded. Twenty-two CRC risk-associated SNPs were obtained from the Affymetrix™ SNP array and used to calculate an odds ratio (OR)-weighted and population-standardized GRS. Subjects with GRS of <0.5, 0.5-1.5, and >1.5 were categorized as low, average and elevated risk.Results: Among 1,769 subjects, 520 (29%) had 1 or more adenomatous polyps. GRS was significantly higher in subjects with adenomatous polyps than those without; mean (95% confidence interval) was 1.02 (1.00-1.05) and 0.97 (0.95-0.99), respectively, p<0.001. The association remained significant after adjusting for age, gender, body mass index, and family history, p<0.001. The detection rate of adenomatous polyps was 10.8%, 29.0% and 39.7% in subjects with low, average and elevated GRS, respectively, p-trend <0.001. Higher GRS was also associated with early age diagnosis of adenomatous polyps, p<0.001. In contrast, positive family history was not associated with risk and age of adenomatous polyps.Conclusions: GRS was significantly associated with adenomatous polyps in subjects undergoing screening colonoscopy. This result may help in stratifying average risk patients and facilitating personalized colonoscopy screening strategies.

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

Cited by 117 publications

References 47 publications

Colorectal Adenomas—Genetics and Searching for New Molecular Screening Biomarkers

Colorectal Adenomas—Genetics and Searching for New Molecular Screening Biomarkers

Cancer Predisposition Genes in Cancer-Free Families

Polygenic Risk Score is a Predictor of Adenomatous Polyps at Screening Colonoscopy

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

Cited by 117 publications

References 47 publications

Colorectal Adenomas—Genetics and Searching for New Molecular Screening Biomarkers

Colorectal Adenomas—Genetics and Searching for New Molecular Screening Biomarkers

Cancer Predisposition Genes in Cancer-Free Families

Polygenic Risk Score is a Predictor of Adenomatous Polyps at Screening Colonoscopy&nbsp;

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Polygenic Risk Score is a Predictor of Adenomatous Polyps at Screening Colonoscopy