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BackgroundColorectal cancer (CRC) is the second cause of cancer-related death in the Western world. Much of the CRC genetic risk remains unidentified and may be attributable to a large number of common, low-penetrance genetic variants. Genetic linkage studies in CRC families have reported additional association with regions 9q22-31, 3q21-24, 7q31, 11q, 14q and 22q. There are several plausible candidate genes for CRC susceptibility within the aforementioned linkage regions including PTCH1, XPA and TGFBR1 in 9q22-31, and EPHB1 and MRAS in 3q21-q24.MethodsCRC cases and matched controls were from EPICOLON, a prospective, multicentre, nationwide Spanish initiative, composed of two independent phases. Phase 1 corresponded to 515 CRC cases and 515 controls, whereas phase 2 consisted of 901 CRC cases and 909 controls. Genotyping was performed for 172 single-nucleotide polymorphisms (SNPs) in 84 genes located within regions 9q22-31 and 3q21-q24.ResultsNone of the 172 SNPs analysed in our study could be formally associated with CRC risk. However, rs1444601 (TOPBP1) and rs13088006 (CDV3) in region 3q22 showed interesting results and may have an effect on CRC risk.ConclusionsTOPBP1 and CDV3 genetic variants on region 3q22 may modulate CRC risk. Further validation and meta-analysis should be undertaken in larger CRC cohorts.

It is now recognised that a part of the inherited risk of colorectal cancer (CRC) can be explained by the co-inheritance of low-penetrance genetic variants. The accumulated experience to date in identifying these variants has served to highlight difficulties in conducting statistically and methodologically rigorous studies and follow-up analyses. The COGENT (COlorectal cancer GENeTics) consortium includes 20 research groups in Europe, Australia, the Americas, China and Japan. The overarching goal of COGENT is to identify and characterise low-penetrance susceptibility variants for CRC through association-based analyses. In this study, we review the rationale for identifying low-penetrance variants for CRC and our proposed strategy for establishing COGENT.

Context: The selection of individuals for hereditary nonpolyposis colorectal cancer (HNPCC) genetic testing is challenging. Recently, the National Cancer Institute outlined a new set of recommendations, the revised Bethesda guidelines, for the identification of individuals with HNPCC who should be tested for microsatellite instability. Objective: To establish the most effective and efficient strategy for the detection of MSH2/MLH1 gene carriers. Design, Setting, and Patients: A prospective, multicenter, nationwide study (the EPICOLON study) in 20 hospitals in the general community in Spain of 1222 patients with newly diagnosed colorectal cancer between November 1, 2000, and October 31, 2001. Interventions: Microsatellite instability testing and MSH2/MLH1 immunostaining in all patients regardless of age, personal or family history, and tumor characteristics. Patients whose tumors exhibited microsatellite instability and/or lack of protein expression underwent MSH2/MLH1 germline testing. Main Outcome Measures: Effectiveness and efficiency of both microsatellite instability testing and immunostaining, either directly or previous selection of patients according to the revised Bethesda guidelines, were evaluated with respect to the presence of MSH2/MLH1 germline mutations. Results: Two hundred eighty-seven patients (23.5%) fulfilled the revised Bethesda guidelines. Ninety-one patients (7.4%) had a mismatch repair deficiency, with tumors exhibiting either microsatellite instability (n = 83) or loss of protein expression (n = 81). Germline testing identified 11 mutations (0.9%) in either MSH2 (7 cases) or MLH1 (4 cases) genes. Strategies based on either microsatellite instability testing or immunostaining previous selection of patients according to the revised Bethesda guidelines were the most effective (sensitivity, 81.8% and 81.8%; specificity, 98.0% and 98.2%; positive predictive value, 27.3% and 29.0%, respectively) to identify MSH2/MLH1 gene carriers. Logistic regression analysis confirmed the revised Bethesda guidelines as the most discriminating set of clinical parameters (odds ratio, 33.3; 95% confidence interval, 4.3-250; P = .001). Conclusion: The revised Bethesda guidelines constitute a useful approach to identify patients at risk for HNPCC. In patients fulfilling these criteria, both microsatellite instability testing and immunostaining are equivalent and highly effective strategies to further select those patients who should be tested for MSH2/MLH1 germline mutations. [ABSTRACT FROM AUTHOR]

The main mutation responsible for the fragile X syndrome is the expansion of an untranslated CGG repeat in the first exon of the FMR1 gene, associated with the hypermethylation of the proximal CpG island and the CGG repeat region, and repression of transcription of FMR1. Fragile X syndrome mosaicism has been described as the coexistence of the full mutation and the permutation. We present here two cases of mosaicism for the full mutation in the FMR1 gene and deletions involving the CGG repeat region. In one case the deletion removed 113 bp proximal to the CGG repeat and part of the repeat itself, leaving 30 pure repeats, and representing 17% of lymphocytes of the patient. The 5' breakpoint of this deletion falls outside the putative hotspot for deletions in the CGG region of FMR1. In the second case the deleted region only involved the CGG sequence (leaving 15 pure repeats), with normal sequences flanking the repeat; this deleted ("normal") FMR1 was estimated to be in about 31% of blood lymphocytes. This second case can be considered a true regression of the CGG FMR1 expansion to a normal sized allele, although in mosaic form. [ABSTRACT FROM PUBLISHER]

Huntington's disease is an autosomal dominant neurodegenerative disorder caused by the expansion of a (CAG)n repeat in the IT15 gene. Three per cent of cases are sporadic and in those in which family studies have been performed, the origin of the mutation was always paternal. The first sporadic case of Huntington's disease is presented in which a premutated maternal allele of 37 CAG repeats was transmitted expanded to the proband (43 CAG repeats). Molecular analysis of the IT15 gene is extremely important in sporadic cases of Huntington's disease, providing correct diagnosis of the disorder and facilitating genetic counselling to the family members. [ABSTRACT FROM AUTHOR]

Huntington's disease is a neuropsychiatric disorder with late age of onset, caused by an elongation of a (CAG)n repeat in the IT15 gene. This trinucleotide repeat has been studied by polymerase chain reaction amplification in 86 members of 43 Spanish families with Huntington's disease and in 60 unrelated subjects from the general population. The number of (CAG)n repeats in Huntington's disease chromosomes varied from 40 to 85, with 49 and 52 repeats being the most common, whereas in normal chromosomes it ranged from 12 to 32 with 20 (CAG)n repeats being the most frequent allele. In four patients with juvenile onset the number of (CAG)n repeats was greater than 50 and only one was of maternal transmission. There was a clear inverse correlation between the number of repeats and the age of onset of the disease. The study contributed to the diagnosis of 10 patients in whom the clinical diagnosis was uncertain, and identified 41 "at risk" patients after a previous psychological-psychiatric evaluation. [ABSTRACT FROM AUTHOR]

We have used a non-isotopic PCR assay based on the chemiluminescent detection of blotted PCR products (CB-PCR) for two dynamic mutation diseases (Huntington's disease and spinocerebellar ataxia type 1). This gives an accurate sizing of alleles and permits a rapid analysis of at risk persons. The system involves PCR of the samples, separation of alleles on polyacrylamide gels, Southern blotting, and hybridisation with specific primers 3' labelled with fluorescein (F1)-dUTP as probes. CB-PCR retains the isotopic sensitivity for accurate allele determination, avoids isotopic manipulation, and provides the advantages of safety, long term storage of probes, and recycling of hybridisation solutions. [ABSTRACT FROM PUBLISHER]

Background: Colorectal cancer (CRC) is a common, fatal cancer. Identifying subgroups who may benefit more from intervention is of critical public health importance. Previous studies have assessed multiplicative interaction between genetic risk scores and environmental factors, but few have assessed additive interaction, the relevant public health measure., Methods: Using resources from colorectal cancer consortia including 45,247 CRC cases and 52,671 controls, we assessed multiplicative and additive interaction (relative excess risk due to interaction, RERI) using logistic regression between 13 harmonized environmental factors and genetic risk score including 141 variants associated with CRC risk., Results: There was no evidence of multiplicative interaction between environmental factors and genetic risk score. There was additive interaction where, for individuals with high genetic susceptibility, either heavy drinking [RERI = 0.24, 95% confidence interval, CI, (0.13, 0.36)], ever smoking [0.11 (0.05, 0.16)], high BMI [female 0.09 (0.05, 0.13), male 0.10 (0.05, 0.14)], or high red meat intake [highest versus lowest quartile 0.18 (0.09, 0.27)] was associated with excess CRC risk greater than that for individuals with average genetic susceptibility. Conversely, we estimate those with high genetic susceptibility may benefit more from reducing CRC risk with aspirin/NSAID use [-0.16 (-0.20, -0.11)] or higher intake of fruit, fiber, or calcium [highest quartile versus lowest quartile -0.12 (-0.18, -0.050); -0.16 (-0.23, -0.09); -0.11 (-0.18, -0.05), respectively] than those with average genetic susceptibility., Conclusions: Additive interaction is important to assess for identifying subgroups who may benefit from intervention. The subgroups identified in this study may help inform precision CRC prevention., Competing Interests: Conflict of Interest: SB Gruber: Brogent International LLC, co-founder, not related to submitted work. All other authors do not have any conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: CDH1 and CTNNA1 remain as the main genes for hereditary gastric cancer. However, they only explain a small fraction of gastric cancer cases with suspected inherited basis. In this study, we aimed to identify new hereditary genes for early-onset gastric cancer patients (EOGC; < 50 years old)., Methods: After germline exome sequencing in 20 EOGC patients and replication of relevant findings by gene-panel sequencing in an independent cohort of 152 patients, CTNND1 stood out as an interesting candidate gene, since its protein product (p120ctn) directly interacts with E-cadherin. We proceeded with functional characterization by generating two knockout CTNND1 cellular models by gene editing and introducing the detected genetic variants using a lentiviral delivery system. We assessed β-catenin and E-cadherin levels, cell detachment, as well as E-cadherin localization and cell-to-cell interaction by spheroid modeling., Results: Three CTNND1 germline variants [c.28&#95;29delinsCT, p.(Ala10Leu); c.1105C > T, p.(Pro369Ser); c.1537A > G, p.(Asn513Asp)] were identified in our EOGC cohorts. Cells encoding CTNND1 variants displayed altered E-cadherin levels and intercellular interactions. In addition, the p.(Pro369Ser) variant, located in a key region in the E-cadherin/p120ctn binding domain, showed E-cadherin mislocalization., Conclusions: Defects in CTNND1 could be involved in germline predisposition to gastric cancer by altering E-cadherin and, consequently, cell-to-cell interactions. In the present study, CTNND1 germline variants explained 2% (3/172) of the cases, although further studies in larger external cohorts are needed., (© 2024. The Author(s).)