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Mutation Spectrum of Cancer-Associated Genes in Patients With Early Onset of Colorectal Cancer.

ABSTRACT: Background: Colorectal cancer (CRC) incidence is rising worldwide, as well as in the Republic of Kazakhstan, while its occurrence is also increasing in the younger population. Hereditary forms associated with the development of colon and rectal cancer and early-onset CRC have never been studied in the population of Kazakhstan. The aim of this research was to investigate the spectrum of CRC-related gene mutations to determine which mutations cause early onset of CRC in the Kazakhstan population. Methods: The study included 125 unrelated patients from Kazakhstan (range 17-50 years in age) with early onset CRC. Genomic DNA was obtained from peripheral blood of the patients. Next-generation sequencing was performed using the TruSightCancer Kit on the MiSeq platform. The Studio Variant was used to annotate and interpret genetic variants. Results: Bioinformatics analysis of Next-generation sequencing data revealed 11,152 variants from 85 genes, of them, 3,790 missense, 6,254 synonymous variants, 44 3'UTR variants, 10 frameshift variants, five stop-gain variants, four in-frame deletions, two splice donors, one splice acceptor variant, and 1,042 intron or non-coding variants. APC, BRCA2/1, ALK, BRIP1, EGFR, FANCA, FANCD2, FANCI, HNF1A, MEN1, NSD1, PMS2, RECQL4, RET, SLX4, WRN, and XPC genes mutated most often. According to the ACMG guidelines and LOVD/ClinVar databases, 24 variants were pathogenic (10 frameshifts, five missenses, five stop-gain, one in-frame deletion, and three splice-site mutations), and 289 were VUS with population frequency <1%, 131 of them were attributed as deleterious. In the study, 50% of all pathogenic mutations found in Kazakhstani patients with early CRC onset were identified in the subgroups with a family history of CRC and primary multiple tumors. In APC, pathogenic mutations were most often (21%). Conclusion: Pathogenic and likely pathogenic mutations were found in 20 (16%) out of 125 patients. Eight novel pathogenic mutations detected in FANCI, APC, BMPR1, ATM, and DICER1 genes have not been reported in previous literature. Given the high frequency and wide spectrum of mutations, NGS analysis must be carried out in families with a history of CRC/CRC-related cancers with the purpose to identify cause-effective mutations, clarify the clinical diagnosis, and prevent the development of the disease in other family members.

SUBMITTER: Zhunussova G

PROVIDER: S-EPMC6688539 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Mutation Spectrum of Cancer-Associated Genes in Patients With Early Onset of Colorectal Cancer.

Zhunussova Gulnur G Afonin Georgiy G Abdikerim Saltanat S Jumanov Abai A Perfilyeva Anastassiya A Kaidarova Dilyara D Djansugurova Leyla L

Frontiers in oncology 20190802

<b>Background:</b> Colorectal cancer (CRC) incidence is rising worldwide, as well as in the Republic of Kazakhstan, while its occurrence is also increasing in the younger population. Hereditary forms associated with the development of colon and rectal cancer and early-onset CRC have never been studied in the population of Kazakhstan. The aim of this research was to investigate the spectrum of CRC-related gene mutations to determine which mutations cause early onset of CRC in the Kazakhstan popul ...[more]

PMID: 31428572

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Project description:Importance:Hereditary cancer syndromes infer high cancer risks and require intensive cancer surveillance, yet the prevalence and spectrum of these conditions among unselected patients with early-onset colorectal cancer (CRC) is largely undetermined. Objective:To determine the frequency and spectrum of cancer susceptibility gene mutations among patients with early-onset CRC. Design, Setting, and Participants:Overall, 450 patients diagnosed with colorectal cancer younger than 50 years were prospectively accrued from 51 hospitals into the Ohio Colorectal Cancer Prevention Initiative from January 1, 2013, to June 20, 2016. Mismatch repair (MMR) deficiency was determined by microsatellite instability and/or immunohistochemistry. Germline DNA was tested for mutations in 25 cancer susceptibility genes using next-generation sequencing. Main Outcomes and Measures:Mutation prevalence and spectrum in patients with early-onset CRC was determined. Clinical characteristics were assessed by mutation status. Results:In total 450 patients younger than 50 years were included in the study, and 75 gene mutations were found in 72 patients (16%). Forty-eight patients (10.7%) had MMR-deficient tumors, and 40 patients (83.3%) had at least 1 gene mutation: 37 had Lynch syndrome (13, MLH1 [including one with constitutional MLH1 methylation]; 16, MSH2; 1, MSH2/monoallelic MUTYH; 2, MSH6; 5, PMS2); 1 patient had the APC c.3920T>A, p.I1307K mutation and a PMS2 variant; 9 patients (18.8%) had double somatic MMR mutations (including 2 with germline biallelic MUTYH mutations); and 1 patient had somatic MLH1 methylation. Four hundred two patients (89.3%) had MMR-proficient tumors, and 32 patients (8%) had at least 1 gene mutation: 9 had mutations in high-penetrance CRC genes (5, APC; 1, APC/PMS2; 2, biallelic MUTYH; 1, SMAD4); 13 patients had mutations in high- or moderate-penetrance genes not traditionally associated with CRC (3, ATM; 1, ATM/CHEK2; 2, BRCA1; 4, BRCA2; 1, CDKN2A; 2, PALB2); 10 patients had mutations in low-penetrance CRC genes (3, APC c.3920T>A, p.I1307K; 7, monoallelic MUTYH). Importantly, 24 of 72 patients (33.3%) who were mutation positive did not meet established genetic testing criteria for the gene(s) in which they had a mutation. Conclusions and Relevance:Of 450 patients with early-onset CRC, 72 (16%) had gene mutations. Given the high frequency and wide spectrum of mutations, genetic counseling and testing with a multigene panel could be considered for all patients with early-onset CRC.

Project description:Background & aimsThe incidence of colorectal cancer (CRC) is increasing in individuals younger than 50 years, who do not usually undergo screening if they are of average risk. We sought to identify risk factors for CRC in this population.MethodsWe compared sociodemographic and medical characteristics of patients who received a diagnosis of CRC at an age of 18-49 years (early-onset) with patients who received a diagnosis of CRC at an age of 50 years or older (late-onset) and with age-matched, cancer-free individuals (controls) at a tertiary academic hospital. We collected data from all adult patients with a diagnosis of CRC from January 1, 2011 through April 3, 2017 from electronic health records. Associations with risk factors were assessed using univariable and multivariable logistic regression models.ResultsWe identified 269 patients with early-onset CRC, 2802 with late-onset CRC, and 1122 controls. Compared with controls, patients with early-onset CRC were more likely to be male (odds ratio [OR], 1.87; 95% CI, 1.39-2.51), have inflammatory bowel disease (IBD) (3% vs 0.4% for controls; univariable P < .01), and have a family history of CRC (OR, 8.61; CI, 4.83-15.75). Prevalence values of well-established modifiable CRC risk factors, including obesity, smoking, and diabetes, were similar. Compared to patients with late-onset CRC, patients with early-onset CRC were more likely to be male (OR, 1.44; 95% CI, 1.11-1.87), black (OR, 1.73; 95% CI, 1.08-2.65) or Asian (OR, 2.60; 95% CI, 1.57-4.15), and have IBD (OR, 2.97; 95% CI, 1.16-6.63) or a family history of CRC (OR, 2.87; 95% CI, 1.89-4.25). Sensitivity analyses excluding IBD and family history of CRC showed comparable results. Early-onset CRC was more likely than late-onset disease to be detected in the left colon or rectum (75% vs 59%, P = .02) and at a late stage of tumor development (77% vs 62%, P = .01).ConclusionsIn a retrospective study of patients with early-onset CRC vs late-onset CRC or no cancer, we identified non-modifiable risk factors, including sex, race, IBD, and family history of CRC, to be associated with early-onset CRC.

Project description:Background & aimsEarly-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.MethodsWe 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.ResultsOverall 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.ConclusionsIn 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.

Dataset Information

Mutation Spectrum of Cancer-Associated Genes in Patients With Early Onset of Colorectal Cancer.

Publications

Mutation Spectrum of Cancer-Associated Genes in Patients With Early Onset of Colorectal Cancer.

Similar Datasets

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