Familial Colorectal Cancer and Genetic Susceptibility: Colorectal Risk Variants in First-Degree Relatives of Patients With Colorectal Cancer.
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ABSTRACT: Introduction
Epidemiological studies estimate that having a first-degree relative (FDR) with colorectal cancer (CRC) increases 2-fold to 3-fold the risk of developing the disease. Because FDRs of CRC patients are more likely to co-inherit CRC risk variants, we aimed to evaluate potential differences in genotype distribution of single nucleotide polymorphisms (SNPs) related to CRC risk between FDRs of patients with nonsyndromic CRC (cases) and individuals with no family history of CRC (controls).Methods
We designed a case-control study comprising 750 cases and 750 Spanish Caucasian controls matched by sex, age, and histological findings after colonoscopy. Genomic DNA from all participants was genotyped for 88 SNPs associated with CRC risk using the MassArray (Sequenom) platform.Results
Ten of the 88 SNPs analyzed revealed significant associations (P < 0.05) with a family history of CRC in our population. The most robust associations were found for the rs17094983G>A SNP in the long noncoding RNA LINC01500 (odds ratio = 0.72; 95% confidence interval: 0.58-0.88, log-additive model), and the rs11255841T>A SNP in the long noncoding RNA LINC00709 (odds ratio = 2.04; 95% confidence interval: 1.19-3.51, dominant model). Of interest, the observed associations were in the same direction than those reported for CRC risk.Discussion
FDRs of CRC patients show significant differences in genotype distribution of SNPs related to CRC risk as compared to individuals with no family history of CRC. Genotyping of CRC risk variants in FDRs of CRC patients may help to identify subjects at risk that would benefit from stricter surveillance and CRC screening programs.
SUBMITTER: Gargallo-Puyuelo CJ
PROVIDER: S-EPMC7861964 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background & aimsDuring the last 15 years, several single-gene mendelian disorders have been discovered that might account for some of the familial aggregation detected in large population studies of colorectal cancer (CRC). Mutations in DNA mismatch repair (MMR) genes cause hereditary nonpolyposis colorectal cancer-Lynch syndrome, the most common of the recognized CRC-predisposition syndromes, in which one major feature is a young age for cancer onset. However, for young-onset microsatellite stable (MSS) CRC, the familial risk for CRC is unknown.MethodsPatients with CRC who were <50 years old were identified through Minnesota Cancer Surveillance System (MCSS) and Mayo Clinic, Rochester, MN. CRCs in which the DNA MMR function was deficient as evidenced by high level microsatellite instability and/or loss of expression of MMR gene product by immunostaining were excluded. A total of 278 probands (131 from MCSS; 147 from Mayo Clinic) were included. Data on 1862 relatives were collected, of whom 68 were found to have had CRC, and an additional 165 had primary cancers of other types.ResultsCompared with Surveillance Epidemiology and End Results program data, relatives of young-onset CRC probands had increased risks for CRC. This relative risk (RR) was increased among first-degree relatives (RR, 1.65; 95% confidence interval [CI], 1.29-2.07) and was greater for siblings (RR, 2.67; 95% CI, 1.50-4.41) than parents (RR, 1.5; 95% CI, 1.14-1.94).ConclusionsWe studied 278 probands with young-onset MSS CRC. We determined that the RR for CRC was greatest in siblings, which is consistent with an autosomal recessive inheritance pattern.
| S-EPMC2180165 | biostudies-literature
Project description:ObjectiveTo estimate risk of colorectal cancer (CRC) for first-degree relatives of CRC cases based on CRC molecular subtypes and tumour pathology features.DesignWe studied a cohort of 33,496 first-degree relatives of 4853 incident invasive CRC cases (probands) who were recruited to the Colon Cancer Family Registry through population cancer registries in the USA, Canada and Australia. We categorised the first-degree relatives into four groups: 28,156 of 4095 mismatch repair (MMR)-proficient probands, 2302 of 301 MMR-deficient non-Lynch syndrome probands, 1799 of 271 suspected Lynch syndrome probands and 1239 of 186 Lynch syndrome probands. We compared CRC risk for first-degree relatives stratified by the absence or presence of specific tumour molecular pathology features in probands across each of these four groups and for all groups combined.ResultsCompared with first-degree relatives of MMR-proficient CRC cases, a higher risk of CRC was estimated for first-degree relatives of CRC cases with suspected Lynch syndrome (HR 2.06, 95% CI 1.59 to 2.67) and with Lynch syndrome (HR 5.37, 95% CI 4.16 to 6.94), but not with MMR-deficient non-Lynch syndrome (HR 1.04, 95% CI 0.82 to 1.31). A greater risk of CRC was estimated for first-degree relatives if CRC cases were diagnosed before age 50 years, had proximal colon cancer or if their tumours had any of the following: expanding tumour margin, peritumoral lymphocytes, tumour-infiltrating lymphocytes or synchronous CRC.ConclusionsMolecular pathology features are potentially useful to refine screening recommendations for first-degree relatives of CRC cases and to identify which cases are more likely to be caused by genetic or other familial factors.
| S-EPMC4180004 | biostudies-literature
Project description:First-degree relatives (FDRs) of familial pancreatic cancer (FPC) patients have increased risk of developing pancreatic ductal adenocarcinoma (PDAC). Investigating and understanding the genetic basis for PDAC susceptibility in FPC predisposed families may contribute toward future risk-assessment and management of high-risk individuals. Using a Danish cohort of 27 FPC families, we performed whole-genome sequencing of 61 FDRs of FPC patients focusing on rare genetic variants that may contribute to familial aggregation of PDAC. Statistical analysis was performed using the gnomAD database as external controls. Through analysis of heterozygous premature truncating variants (PTV), we identified cancer-related genes and cancer-driver genes harboring multiple germline mutations. Association analysis detected 20 significant genes with false discovery rate, q < 0.05 including: PALD1, LRP1B, COL4A2, CYLC2, ZFYVE9, BRD3, AHDC1, etc. Functional annotation showed that the significant genes were enriched by gene clusters encoding for extracellular matrix and associated proteins. PTV genes were over-represented by functions related to transport of small molecules, innate immune system, ion channel transport, and stimuli-sensing channels. In conclusion, FDRs of FPC patients carry rare germline variants related to cancer pathogenesis that may contribute to increased susceptibility to PDAC. The identified variants may potentially be useful for risk prediction of high-risk individuals in predisposed families.
| S-EPMC9291090 | biostudies-literature
Project description:ObjectiveTo assess the risk of colorectal cancer (CRC) in first degree relatives (parents and full siblings) of patients with precursor lesions (polyps) for CRC.DesignCase-control study.SettingLinkage to the multi-generation register and gastrointestinal ESPRESSO (Epidemiology Strengthened by histoPathology Reports in Sweden) histopathology cohort in Sweden.Participants68 060 patients with CRC and 333 753 matched controls.Main outcome measuresMultivariable adjusted odds ratios of CRC according to the number of first degree relatives with a colorectal polyp and the histology of polyps and age at diagnosis in first degree relatives. Subgroup analysis was also performed according to age at CRC diagnosis and evaluated the joint association of family history of colorectal polyps and family history of CRC.ResultsAfter adjusting for family history of CRC and other covariates, having a first degree relative with a colorectal polyp (8.4% (5742/68 060) in cases and 5.7% (18 860/333 753) in controls) was associated with a higher risk of CRC (odds ratio 1.40, 95% confidence interval 1.35 to 1.45). The odds ratios ranged from 1.23 for those with hyperplastic polyps to 1.44 for those with tubulovillous adenomas. To better put this risk in perspective, the age specific absolute risk of colon and rectal cancers was estimated according to family history of polyps based on the 2018 national CRC incidence in Sweden. For example, the absolute risk of colon cancer in individuals aged 60-64 years with and without a family history of colorectal polyp was, respectively, 94.3 and 67.9 per 100 000 for men and 89.1 and 64.1 per 100 000 for women. The association between family history of polyps and CRC risk was strengthened by the increasing number of first degree relatives with polyps (≥2 first degree relatives: 1.70, 1.52 to 1.90, P<0.001 for trend) and decreasing age at polyp diagnosis (<50 years: 1.77, 1.57 to 1.99, P<0.001 for trend). A particularly strong association was found for early onset CRC diagnosed before age 50 years (≥2 first degree relatives: 3.34, 2.05 to 5.43, P=0.002 for heterogeneity by age of CRC diagnosis). In the joint analysis, the odds ratio of CRC for individuals with two or more first degree relatives with polyps but no CRC was 1.79 (1.52 to 2.10), with one first degree relative with CRC but no polyps was 1.70 (1.65 to 1.76), and with two or more first degree relatives with both polyps and CRC was 5.00 (3.77 to 6.63) (P<0.001 for interaction).ConclusionsAfter adjusting for family history of CRC, the siblings and children of patients with colorectal polyps are still at higher risk of CRC, particularly early onset CRC. Early screening for CRC might be considered for first degree relatives of patients with polyps.
| S-EPMC8083372 | biostudies-literature
Project description:Several guidelines recommend initiating colorectal cancer screening at age 40 for individuals with affected first-degree relatives, yet little evidence exists describing how often these individuals receive screening procedures.To determine the proportion of individuals in whom early initiation of colorectal cancer screening might be indicated and whether screening disparities exist.Population-based Supplemental Cancer Control Module to the 2000 National Health Interview Survey.Respondents, 5,564, aged 40 to 49 years were included within the analysis.Patient self-report of sigmoidoscopy, colonoscopy, or fecal occult blood test.Overall, 279 respondents (5.4%: 95% C.I., 4.7, 6.2) reported having a first-degree relative affected with colorectal cancer. For individuals with a positive family history, 67 whites (27.9%: 95% C.I., 21.1, 34.5) and 3 African American (9.3%: 95% C.I., 1.7, 37.9) had undergone an endoscopic procedure within the previous 10 years (P-value = .03). After adjusting for age, family history, gender, educational level, insurance status, and usual source of care, whites were more likely to be current with early initiation endoscopic screening recommendations than African Americans (OR = 1.38: 95% C.I., 1.01, 1.87). Having an affected first-degree relative with colorectal cancer appeared to have a stronger impact on endoscopic screening for whites (OR = 3.21: 95% C.I., 2.31, 4.46) than for African Americans (OR = 1.05: 95% C.I., 0.15, 7.21).White participants with a family history are more likely to have endoscopic procedures beginning before age 50 than African Americans.
| S-EPMC1824778 | biostudies-other
Project description:BackgroundFirst-degree relatives (FDR) of patients with colorectal cancer have a higher risk of developing colorectal cancer than the general population. For this reason, screening guidelines recommend colonoscopy every 5 or 10 y, starting at the age of 40, depending on whether colorectal cancer in the index-case is diagnosed at <60 or ≥60 y, respectively. However, studies on the risk of neoplastic lesions are inconclusive. The aim of this study was to determine the risk of advanced neoplasia (three or more non-advanced adenomas, advanced adenoma, or invasive cancer) in FDR of patients with colorectal cancer compared to average-risk individuals (i.e., asymptomatic adults 50 to 69 y of age with no family history of colorectal cancer).Methods and findingsThis cross-sectional analysis includes data from 8,498 individuals undergoing their first lifetime screening colonoscopy between 2006 and 2012 at six Spanish tertiary hospitals. Of these individuals, 3,015 were defined as asymptomatic FDR of patients with colorectal cancer ("familial-risk group") and 3,038 as asymptomatic with average-risk for colorectal cancer ("average-risk group"). The familial-risk group was stratified as one FDR, with one family member diagnosed with colorectal cancer at ≥60 y (n = 1,884) or at <60 y (n = 831), and as two FDR, with two family members diagnosed with colorectal cancer at any age (n = 300). Multiple logistic regression analysis was used for between-group comparisons after adjusting for potential confounders (age, gender, and center). Compared with the average-risk group, advanced neoplasia was significantly more prevalent in individuals having two FDR with colorectal cancer (odds ratio [OR] 1.90; 95% confidence interval [CI] 1.36-2.66, p < 0.001), but not in those having one FDR with colorectal cancer diagnosed at ≥60 y (OR 1.03; 95% CI 0.83-1.27, p = 0.77) and <60 y (OR 1.19; 95% CI 0.90-1.58, p = 0.20). After the age of 50 y, men developed advanced neoplasia over two times more frequently than women and advanced neoplasia appeared at least ten y earlier. Fewer colonoscopies by 2-fold were required to detect one advanced neoplasia in men than in women. Major limitations of this study were first that although average-risk individuals were consecutively included in a randomized control trial, this was not the case for all individuals in the familial-risk cohort; and second, the difference in age between the average-risk and familial-risk cohorts.ConclusionsIndividuals having two FDR with colorectal cancer showed an increased risk of advanced neoplasia compared to those with average-risk for colorectal cancer. Men had over 2-fold higher risk of advanced neoplasia than women, independent of family history. These data suggest that screening colonoscopy guidelines should be revised in the familial-risk population.
| S-EPMC4854417 | biostudies-literature
Project description:BackgroundGenomewide association studies have identified 10 low-penetrance loci that confer modestly increased risk for colorectal cancer (CRC). Although they underlie a significant proportion of CRC in the general population, their impact on the familial risk for CRC has yet to be formally enumerated. The aim of this study was to examine the combined contribution of the 10 variants, rs6983267, rs4779584, rs4939827, rs16892766, rs10795668, rs3802842, rs4444235, rs9929218, rs10411210, and rs961253, on familial CRC.MethodsThe population-based series of CRC samples included in this study consisted of 97 familial cases and 691 sporadic cases. Genotypes in the 10 loci and clinical data, including family history of cancer verified from the Finnish Cancer Registry, were available. The overall number of risk alleles (0-20) was determined, and its association with familial CRC was analyzed. Excess familial risk was estimated using cancer incidence data from the first-degree relatives of the cases.ResultsA linear association between the number of risk alleles and familial CRC was observed (P = 0.006). With each risk-allele addition, the odds of having an affected first-degree relative increased by 1.16 (95% confidence interval, 1.04-1.30). The 10 low-penetrance loci collectively explain approximately 9% of the variance in familial risk for CRC.ConclusionsThis study provides evidence to support the previous indirect estimations that these low-penetrance variants account for a relatively small proportion of the familial aggregation of CRC.ImpactOur results emphasize the need to characterize the remaining molecular basis of familial CRC, which should eventually yield in individualized targeting of preventive interventions.
| S-EPMC2883738 | biostudies-literature
Project description:BackgroundFamily history provides important information on risk of developing inflammatory bowel disease [IBD], and genetic profiling of first-degree relatives [FDR] of Crohn's disease [CD]- affected individuals might provide additional information. We aimed to delineate the genetic contribution to the increased IBD susceptibility observed in FDR.MethodsN = 976 Caucasian, healthy, non-related FDR; n = 4997 independent CD; and n = 5000 healthy controls [HC]; were studied. Genotyping for 158 IBD-associated single nucleotide polymorphisms [SNPs] was performed using the Illumina Immunochip. Risk allele frequency [RAF] differences between FDR and HC cohorts were correlated with those between CD and HC cohorts. CD and IBD genetic risk scores [GRS] were calculated and compared between HC, FDR, and CD cohorts.ResultsIBD-associated SNP RAF differences in FDR and HC cohorts were strongly correlated with those in CD and HC cohorts, correlation coefficient 0.63 (95% confidence interval [CI] 0.53 - 0.72), p = 9.90 x 10(-19). There was a significant increase in CD-GRS [mean] comparing HC, FDR, and CD cohorts: 0.0244, 0.0250, and 0.0257 respectively [p < 1.00 x 10(-7) for each comparison]. There was no significant difference in the IBD-GRS between HC and FDR cohorts [p = 0.81]; however, IBD-GRS was significantly higher in CD compared with FDR and HC cohorts [p < 1.00 x 10(-10) for each comparison].ConclusionFDR of CD-affected individuals are enriched with IBD risk alleles compared with HC. Cumulative CD-specific genetic risk is increased in FDR compared with HC. Prospective studies are required to determine if genotyping would facilitate better risk stratification of FDR.
| S-EPMC5007582 | biostudies-literature
Project description:BackgroundHaving a first-degree relative (FDR) with colorectal cancer (CRC) is a significant risk factor for CRC. Counseling for FDRs regarding CRC risk factors and personalized risk is important to improve knowledge and screening compliance.MethodsA 3-arm randomized controlled trial compared tailored in-person and telephone CRC counseling interventions with controls among FDRs who were not mutation carriers for known hereditary cancer syndromes, but who were considered to be at an increased risk based on family history. It was hypothesized that both telephone and in-person approaches would increase CRC knowledge, screening adherence, perceived risk accuracy, and psychosocial functioning compared with controls. The authors anticipated greater satisfaction with the in-person approach. CRC knowledge, risk perception, psychosocial functioning, and intention to screen were assessed at baseline and at 2-week and 2-month follow-ups (primary endpoint).ResultsA total of 278 FDRs (mean age, 47.4 years, standard deviation, 11.38 years) participated. At baseline, participants reported low to moderate CRC knowledge and overestimations of risk. Screening adherence was 73.7%. At 2 months, participants in the in-person arm and telephone arm demonstrated improvements in knowledge and perceived risk and were not found to be statistically different from each other. However, when comparing each intervention with controls, knowledge in the in-person arm was found to be statistically significantly higher, but the difference between the telephone and control arms was not. Cancer-related stress reduced over time in all groups. Intervention benefits were maintained at 1 year. Baseline screening intent/adherence were high, and therefore did not reach statistically significant improvement.ConclusionsTailored in-person or telephone formats for providing CRC risk counseling, incorporating behavioral interventions, appear to improve knowledge and risk perceptions, with high client satisfaction.
| S-EPMC6742581 | biostudies-literature
Project description:This comprehensive cross-sectional study aimed to identify factors contributing to familial aggregation of gastric cancer (GC). A total of 1058 GC patients and 1268 controls were analyzed separately according to the presence or absence of a first-degree relative of GC (GC-relative). Logistic regression analysis adjusted for age, gender, residence during childhood, smoking, alcohol intake, monthly income, spicy food ingestion, Helicobacter pylori status and host cytokine polymorphisms was performed. Cytotoxin-associated gene A (cagA) positivity was a distinctive risk factor for GC in the family history (FH)-positive group (odds ratio [OR], 2.39; 95% confidence interval [CI], 1.42-4.00), while current/ex-smoker, moderate to strong spicy food ingestion, and non-B blood types were more closely associated with GC in the FH-negative group. Among the FH-positive group, alcohol consumption showed a synergistic carcinogenic effect in the at least 2 GC-relatives group compared to the 1 GC-relative group (1.71 vs. 9.58, P for interaction = 0.026), and this was dose-dependent. In the subjects with ≥2 GC-relatives, TGFB1-509T/T was a risk factor for GC (OR 23.74; 95% CI 1.37-410.91), as were rural residency in childhood, alcohol consumption, spicy food ingestion, and cagA positivity. These results suggest that subjects with FH may be a heterogeneous group in terms of gastric cancer susceptibility. Especially, subjects with ≥2 GC-relatives should undergo risk stratification including TGFB1-509T/T and alcohol consumption.
| S-EPMC4902404 | biostudies-literature