scholarly journals Exome sequencing of early-onset patients supports genetic heterogeneity in colorectal cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
C. Fernández-Rozadilla ◽  
M. Álvarez-Barona ◽  
I. Quintana ◽  
A. López-Novo ◽  
J. Amigo ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Genetic Variants ◽  
Early Onset ◽  
Complex Disease ◽  
High Impact ◽  
Molecular Heterogeneity ◽  
Risk Alleles ◽  
High Penetrance ◽  
Predisposing Genes ◽  
Functional Analyses

AbstractColorectal cancer (CRC) is a complex disease that can be caused by a spectrum of genetic variants ranging from low to high penetrance changes, that interact with the environment to determine which individuals will develop the disease. In this study, we sequenced 20 early-onset CRC patients to discover novel genetic variants that could be linked to the prompt disease development. Eight genes, CHAD, CHD1L, ERCC6, IGTB7, PTPN13, SPATA20, TDG and TGS1, were selected and re-sequenced in a further 304 early onset CRC patients to search for rare, high-impact variants. Although we found a recurring truncating variant in the TDG gene shared by two independent patients, the results obtained did not help consolidate any of the candidates as promising CRC predisposing genes. However, we found that potential risk alleles in our extended list of candidate variants have a tendency to appear at higher numbers in younger cases. This supports the idea that CRC onset may be oligogenic in nature and may show molecular heterogeneity. Further, larger and robust studies are thus needed to unravel the genetics behind early-onset CRC development, coupled with novel functional analyses and omic approaches that may offer complementary insight.

scholarly journals Non-Lynch Familial and Early-Onset Colorectal Cancer Explained by Accumulation of Low-Risk Genetic Variants

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3857
Author(s):  
Pilar Mur ◽  
Nuria Bonifaci ◽  
Anna Díez-Villanueva ◽  
Elisabet Munté ◽  
Maria Henar Alonso ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Risk Score ◽  
Early Onset ◽  
Low Risk ◽  
Polygenic Risk Score ◽  
Polygenic Risk ◽  
Pathogenic Variants ◽  
Predisposing Genes ◽  
The Mean ◽  
Early Onset Colorectal Cancer

A large proportion of familial and/or early-onset cancer patients do not carry pathogenic variants in known cancer predisposing genes. We aimed to assess the contribution of previously validated low-risk colorectal cancer (CRC) alleles to familial/early-onset CRC (fCRC) and to serrated polyposis. We estimated the association of CRC with a 92-variant-based weighted polygenic risk score (wPRS) using 417 fCRC patients, 80 serrated polyposis patients, 1077 hospital-based incident CRC patients, and 1642 controls. The mean wPRS was significantly higher in fCRC than in controls or sporadic CRC patients. fCRC patients in the highest (20th) wPRS quantile were at four-fold greater CRC risk than those in the middle quantile (10th). Compared to low-wPRS fCRC, a higher number of high-wPRS fCRC patients had developed multiple primary CRCs, had CRC family history, and were diagnosed at age ≥50. No association with wPRS was observed for serrated polyposis. In conclusion, a relevant proportion of mismatch repair (MMR)-proficient fCRC cases might be explained by the accumulation of low-risk CRC alleles. Validation in independent cohorts and development of predictive models that include polygenic risk score (PRS) data and other CRC predisposing factors will determine the implementation of PRS into genetic testing and counselling in familial and early-onset CRC.

scholarly journals Genetic variants in the cell cycle control pathways contribute to early onset colorectal cancer in Lynch syndrome

2009 ◽  
Vol 20 (9) ◽  
pp. 1769-1777 ◽  
Author(s):  
Jinyun Chen ◽  
Carol J. Etzel ◽  
Christopher I. Amos ◽  
Qing Zhang ◽  
Nancy Viscofsky ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Lynch Syndrome ◽  
Genetic Variants ◽  
Early Onset ◽  
Cell Cycle Control ◽  
Early Onset Colorectal Cancer

scholarly journals Susceptibility genetic variants associated with early-onset colorectal cancer

2012 ◽  
Vol 33 (3) ◽  
pp. 613-619 ◽  
Author(s):  
María Dolores Giráldez ◽  
Adriana López-Dóriga ◽  
Luis Bujanda ◽  
Anna Abulí ◽  
Xavier Bessa ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Genetic Variants ◽  
Early Onset ◽  
Early Onset Colorectal Cancer

scholarly journals Genetic variants in germline TP53 and MDM2 SNP309 are not associated with early onset colorectal cancer

2008 ◽  
Vol 97 (7) ◽  
pp. 621-625 ◽  
Author(s):  
Sajid A. Khan ◽  
Kamran Idrees ◽  
Ann Forslund ◽  
Zhaoshi Zeng ◽  
Shoshana Rosenberg ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Genetic Variants ◽  
Early Onset ◽  
Mdm2 Snp309 ◽  
Early Onset Colorectal Cancer

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

2020 ◽  
Vol 158 (5) ◽  
pp. 1274-1286.e12 ◽  
Author(s):  
Alexi N. Archambault ◽  
Yu-Ru Su ◽  
Jihyoun Jeon ◽  
Minta Thomas ◽  
Yi Lin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Genetic Variants ◽  
Early Onset ◽  
Late Onset

scholarly journals Su1813 Susceptibility Genetic Variants Associated With Early-Onset Colorectal Cancer

2012 ◽  
Vol 142 (5) ◽  
pp. S-510
Author(s):  
María Dolores Giráldez ◽  
Adriana López-Dóriga ◽  
Luis Bujanda ◽  
Anna Abulí ◽  
Xavier Bessa ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Genetic Variants ◽  
Early Onset ◽  
Early Onset Colorectal Cancer

Has the time come to integrate genetic risk scores into clinical practice?

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
F.V Moniz Mendonca ◽  
M.I Mendonca ◽  
A Pereira ◽  
J Monteiro ◽  
J Sousa ◽  
...  
Keyword(s):  
Risk Factors ◽  
Clinical Practice ◽  
Genetic Variants ◽  
Genetic Risk ◽  
Odds Ratio ◽  
Risk Scores ◽  
Cumulative Number ◽  
Genetic Risk Scores ◽  
Risk Alleles ◽  
Cad Risk

Abstract Background The risk for Coronary Artery Disease (CAD) is determined by both genetic and environmental factors, as well as by the interaction between them. It is estimated that genetic factors could account for 40% to 55% of the existing variability among the population (inheritability). Therefore, some authors have advised that it is time we integrated genetic risk scores into clinical practice. Aim The aim of this study was to evaluate the magnitude of the association between an additive genetic risk score (aGRS) and CAD based on the cumulative number of risk alleles in these variants, and to estimate whether their use is valuable in clinical practice. Methods A case-control study was performed in a Portuguese population. We enrolled 3120 participants, of whom 1687 were CAD patients and 1433 were normal controls. Controls were paired to cases with respect to gender and age. 33 genetic variants known to be associated with CAD were selected, and an aGRS was calculated for each individual. The aGRS was further subdivided into deciles groups, in order to estimate the CAD risk in each decile, defined by the number of risk alleles. The magnitude of the risk (odds ratio) was calculated for each group by multiple logistic regression using the 5th decile as the reference group (median). In order to evaluate the ability of the aGRS to discriminate susceptibility to CAD, two genetic models were performed, the first with traditional risk factors (TRF) and second with TRF plus aGRS. The AUC of the two ROC curves was calculated. Results A higher prevalence of cases over controls became apparent from the 6th decile of the aGRS, reflecting the higher number of risk alleles present (see figure). The difference in CAD risk was only significant from the 6th decile, increasing gradually until the 10th decile. The odds ratio (OR) for the last decile related to 5th decile (median) was 1.87 (95% CI:1.36–2.56; p<0.0001). The first model yielded an AUC=0.738 (95% CI:0.720–0.755) and the second model was slightly more discriminative for CAD risk (AUC=0.748; 95% CI:0.730–0.765). The DeLong test was significant (p=0.0002). Conclusion Adding an aGRS to the non-genetic risk factors resulted in a modest improvement in the ability to discriminate the risk of CAD. Such improvement, even if statistically significant, does not appear to be of real value in clinical practice yet. We anticipate that with the development of further knowledge about different SNPs and their complex interactions, and with the inclusion of rare genetic variants, genetic risk scores will be better suited for use in a clinical setting. Funding Acknowledgement Type of funding source: None

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