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.
This study presents the first results of a molecular-genetic study of colorectal cancer (CRC) in Kazakhstan. Blood samples were collected from patients diagnosed with rectal or colon cancer (249 individuals) as well as a control cohort of healthy volunteers (245 individuals), taking into account the age, gender, ethnicity, and smoking habits of the CRC patients. Combined analysis of data obtained from individuals of either Kazakh or Russian decent showed a significant association with increased CRC risk in the following genotypes: DCC (32008376G/G and G/A versus A/A; OR = 3.45, 95 % confidence interval (95 %CI) = 1.75-6.81, χ (2) = 14.07, p < 0.0002), MLH1 (-93G/G versus G/A and A/A; OR = 1.45, 95 %CI = 1.02-2.07, χ (2) = 4.21, p < 0.04), TP53 (Pro72Pro; OR = 3.80, 95 %CI = 2.46-5.88, χ (2) = 61.27, p < 0.0001), combination GSTT1 deletions with heterozygotes versus normal homozygotes (OR = 1.43, 95 %CI = 1.00-2.04, χ (2) = 3.90, p < 0.05), and GSTM1 deletions (OR = 1.83, 95 %CI = 1.28-2.63, χ (2) = 11.04, p < .001). Analysis for ethnicity and smoking for each of the investigated polymorphisms showed that some genotypes can have a predictive value for susceptibility to CRC, at least those that demonstrate statistically significant ORs either for the combined mixed population of Kazakhstan or for both main ethnic groups separately (Kazakhs and Russians): TP53 Pro72Pro homozygous (for Kazakh-OR = 3.40, 95 %CI = 1.63-7.06, χ (2) = 11.35, p < 0.003; for Russian-OR = 4.69, 95 %CI = 2.53-8.66, χ (2) = 53.19, p < 0.0001) and GSTM1 deletions (for Kazakh-OR = 2.30, 95 %CI = 1.21-4.40, χ (2) = 8.42, p < 0.01; for Russian-OR = 1.64, 95 %CI = 1.01-2.66, χ (2) = 7.82, p < 0.02).
Relevance: In the Republic of Kazakhstan, colorectal cancer (CRC) ranks third in the structure of oncological pathology. In 2008-2019, the CRC incidence in the Republic was growing each year. There is an upward trend in CRC incidence among young people. Cohort studies show that, in young patients, CRC is characterized by distal localization of the tumor process, advanced stages of the disease, an aggressive course, and low tumor differentiation. The known association of phenotypic signs with clinical characteristics of the disease, such as the response to therapy and survival rates, urges addressing this problem. The phenotypic and molecular genetic aspects of CRC in young people have not been systematically studied in Kazakhstan. The purpose of the study was to compare the phenotypic features of hereditary and sporadic colorectal cancer in young patients and patients over 65 years. Results: The study involved 185 patients aged 17 to 50 years (Group 1) and 112 patients aged 65 to 85 (Group 2). In Group 1, a locally advanced process (stage III) was 14.8% more often than in Group 2; stage IV was 1.23 times more common in men; and multiple primary tumors were 3.1% more often, with a prevailing metachronous course. In Groups 1 & 2, most tumors were localized in the rectum; 84.8% and 78.6% of tumors, respectively, occurred in the left half of the colon. The frequency of right-sided tumors increased with age modified by gender (in Group 2). Hereditary burdened anamnesis was detected in 14.6% patients before 50 (6.57% more than in Group 2); family history of CRC – in 4.8% patients. The latter is consistent with published data. The studied syndromic variants met the diagnostic criteria for familial adenomatous polyposis, Lynch syndrome, Peutz-Jeghers syndrome, and familial type X colorectal cancer. Conclusion: The increase in CRC incidence at the age of 50-70 years is explained by the effectiveness of screening. However, the upward trend for the age below 50 needs a detailed study of etiological (dietary, environmental, behavioral, hereditary) factors. Effective early diagnostics requires considering the phenotypic characteristics and hereditary history associated with a high risk of CRC onset.
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