Quantifying the Utility of Single Nucleotide Polymorphisms to Guide Colorectal Cancer Screening

Jenkins, Mark A.; Makalic, Enes; Dowty, James G.; Schmidt, Daniel F.; Dite, Gillian S.; MacInnis, Robert J.; Ouakrim, Driss Ait; Clendenning, Mark; Flander, Louisa; Stanesby, Oliver; Hopper, John L.; Win, Aung Ko; Buchanan, Daniel D.

doi:10.2217/fon.15.303

Cited by 42 publications

(60 citation statements)

References 41 publications

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“…For example, the current 45 independent susceptibility SNPs explain 22% of familial aggregation (20). It is likely this proportion will increase as larger studies are conducted, such as the OncoArray initiative, and as more informative statistical strategies are used to devise risk-prediction SNP-based scores other than the current highly conservative paradigm of considering each SNP individually and applying stringent penalties for multiple testing.…”

Section: Discussionmentioning

confidence: 99%

“…To help mitigate this weakness, we used estimates based on the largest studies available, and all used data from the same source, the Colon Cancer Family Registry (26, 32–34). Future studies should focus on incorporating the explicit effects of other colorectal cancer susceptibility genes such as STK11 (54) BMPR1A (55), SMAD4, PTEN (56), POLE and POLD1 (57) as well as the explicit effects of identified common low risk alleles(20). In addition to colorectal cancer risk, it is known that MMR gene mutations increase the risks of other cancers such as endometrial and ovarian cancer (58).…”

Section: Discussionmentioning

confidence: 99%

“…Genome-wide association studies have identified at least 45 independent genetic susceptibility markers (single-nucleotide polymorphisms, SNPs) that are reliably associated with small increments in the risk of developing colorectal cancer (20). …”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Prevalence and Penetrance of Major Genes and Polygenes for Colorectal Cancer

Win

Jenkins

Dowty

et al. 2017

Cancer Epidemiology, Biomarkers &Amp; Prevention

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387

268

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Background While high-risk mutations in identified major susceptibility genes (DNA mismatch repair genes and MUTYH) account for some familial aggregation of colorectal cancer, their population prevalence and the causes of the remaining familial aggregation are not known. Methods We studied the families of 5,744 colorectal cancer cases (probands) recruited from population cancer registries in the USA, Canada and Australia and screened probands for mutations in mismatch repair genes and MUTYH. We conducted modified segregation analyses using the cancer history of first-degree relatives, conditional on the proband’s age at diagnosis. We estimated the prevalence of mutations in the identified genes, the prevalence of and hazard ratio for unidentified major gene mutations, and the variance of the residual polygenic component. Results We estimated that 1 in 279 of the population carry mutations in mismatch repair genes (MLH1= 1 in 1946, MSH2= 1 in 2841, MSH6= 1 in 758, PMS2= 1 in 714), 1 in 45 carry mutations in MUTYH, and 1 in 504 carry mutations associated with an average 31-fold increased risk of colorectal cancer in unidentified major genes. The estimated polygenic variance was reduced by 30–50% after allowing for unidentified major genes and decreased from 3.3 for age <40 years to 0.5 for age ≥70 years (equivalent to sibling relative risks of 5.1 to 1.3, respectively). Conclusion Unidentified major genes might explain one-third to one-half of the missing heritability of colorectal cancer. Impact Our findings could aid gene discovery and development of better colorectal cancer risk prediction models.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Prevalence and Penetrance of Major Genes and Polygenes for Colorectal Cancer

Win

Jenkins

Dowty

et al. 2017

Cancer Epidemiology, Biomarkers &Amp; Prevention

Self Cite

387

268

View full text Add to dashboard Cite

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“…A recent systematic review identified 52 colorectal cancer prediction models3 with less than a third having reasonable ability to discriminate colorectal cases from those without colorectal cancer. This review and recent research has suggested utility of incorporating genetic factors in risk models including common variants such as single nucleotide polymorphisms (SNPs) 4. The second goal is development of risk tools to be simple to apply so that data on the at-risk person can be entered quickly and accurately.…”

Section: Commentarymentioning

confidence: 99%

Colorectal cancer screening is cost-effective in the elderly who have had less intense prior screening, high baseline risk of colorectal cancer and less comorbidities

Jenkins

2016

Evid Based Med

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“…They mostly employed an equation first proposed by Cox et al . in 2007, or slight modifications thereof that includes two major components: The relative risk attributable to a given SNP, commonly denoted as

λ * = \frac{p {(p r_{2} + q r_{1})}^{2} + q {(p r_{1} + q)}^{2}}{{((), p^{2} r_{2} + 2 italicpq r_{1} + q^{2})}^{2}}

, where p is the population frequency of the minor allele, q = 1−p , and r 1 and r 2 are the relative risks for heterozygotes and rare homozygotes relative to common homozygotes, and the overall familial relative risk estimated from epidemiological studies, commonly denoted as λ o . The share of the familial risk attributable to the SNP is then obtained as log λ * / λ o .…”

Section: Introductionmentioning

confidence: 99%

Establishing a valid approach for estimating familial risk of cancer explained by common genetic variants

Weigl

Chang‐Claude

Hsu

et al. 2019

Intl Journal of Cancer

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We critically examined existing approaches for the estimation of the excess familial risk of cancer that can be attributed to identified common genetic risk variants and propose an alternative, more straightforward approach for calculating this proportion using well‐established epidemiological methodology. We applied the underlying equations of the traditional approaches and the new epidemiological approach for colorectal cancer (CRC) in a large population‐based case–control study in Germany with 4,447 cases and 3,480 controls, who were recruited from 2003 to 2016 and for whom interview, medical and genomic data were available. Having a family history of CRC (FH) was associated with a 1.77‐fold risk increase in our study population (95% CI 1.52–2.07). Traditional approaches yielded estimates of the FH‐associated risk explained by 97 common genetics variants from 9.6% to 23.1%, depending on various assumptions. Our alternative approach resulted in smaller and more consistent estimates of this proportion, ranging from 5.4% to 14.3%. Commonly employed methods may lead to strongly divergent and possibly exaggerated estimates of excess familial risk of cancer explained by associated known common genetic variants. Our results suggest that familial risk and risk associated with known common genetic variants might reflect two complementary major sources of risk.

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Quantifying the Utility of Single Nucleotide Polymorphisms to Guide Colorectal Cancer Screening

Cited by 42 publications

References 41 publications

Prevalence and Penetrance of Major Genes and Polygenes for Colorectal Cancer

Prevalence and Penetrance of Major Genes and Polygenes for Colorectal Cancer

Colorectal cancer screening is cost-effective in the elderly who have had less intense prior screening, high baseline risk of colorectal cancer and less comorbidities

Establishing a valid approach for estimating familial risk of cancer explained by common genetic variants

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