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Background: Lynch‐like syndrome (LLS) represents around 50% of the patients fulfilling the Amsterdam Criteria II/revised Bethesda Guidelines, characterized by a strong family history of Lynch Syndrome (LS) associated cancer, where a causative variant was not identified during genetic testing for LS.Methods: Using data extracted from a larger gene panel, we have analyzed next‐generation sequencing data from 22 mismatch repair (MMR) genes (MSH3, PMS1, MLH3, EXO1, POLD1, POLD3 RFC1, RFC2, RFC3, RFC4, RFC5, PCNA, LIG1, RPA1, RPA2, RPA3, POLD2, POLD4, MLH1, MSH2, MSH6, and PMS2) in 274 LLS patients. Detected variants were annotated and filtered using ANNOVAR and FILTUS software.Results: Thirteen variants were revealed in MLH1, MSH2, and MSH6, all genes previously linked to LS. Five additional genes (EXO1, POLD1, RFC1, RPA1, and MLH3) were found to harbor 11 variants of unknown significance in our sample cohort, two of them being frameshift variants.Conclusion: We have shown that other genes associated with the process of DNA MMR have a high probability of being associated with LLS families. These findings indicate that the spectrum of genes that should be tested when considering an entity like Lynch‐like syndrome should be expanded so that a more inclusive definition of this entity can be developed. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc. DOI: 10.1002/mgg3.850

Background Many families with a high burden of colorectal cancer fulfil the clinical criteria for Lynch Syndrome. However, in about half of these families, no germline mutation in the mismatch repair genes known to be associated with this disease can be identified. The aim of this study was to find the genetic cause for the increased colorectal cancer risk in these unsolved cases. Materials and methods To reach the aim, we designed a gene panel targeting 112 previously known or candidate colorectal cancer susceptibility genes to screen 274 patient samples for mutations. Mutations were validated by Sanger sequencing and, where possible, segregation analysis was performed. Results We identified 73 interesting variants, of whom 17 were pathogenic and 19 were variants of unknown clinical significance in well-established cancer susceptibility genes. In addition, 37 potentially pathogenic variants in candidate colorectal cancer susceptibility genes were detected. Conclusion In conclusion, we found a promising DNA variant in more than 25 % of the patients, which shows that gene panel testing is a more effective method to identify germline variants in CRC patients compared to a single gene approach. © 2017 The Authors. Clinical Genetics published by John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

The American Women's Health Initiative study published in July 2002 caused considerable concern among hormone replacement therapy (HRT) users and prescribers in many countries. This study is an exploratory research comparing the genome-wide expression profile in whole-blood samples according to HRT use. Within the Norwegian Women and Cancer study, 100 postmenopausal women (50 HRT users and 50 non-HRT users) born between 1943 and 1949 with normal to high body mass index and no other medication use were selected. After total RNA extraction, amplification, and labeling, the samples were hybridized together with a common reference (Universal human reference RNA, Stratagen) to Agilent Human 1A oligoarrays (G4110b, Agilent Technologies) containing 20,173 unique genes. Differentially expressed genes were used to build a classifier using the nearest shrunken centroid method (PAM). Then, we tested the significant changes in single genes by different methods like t test, Significance Analysis of Microarrays, and Bayesian ANOVA analysis. Results did not reveal any distinct gene list which predicted accurately HRT exposure (error rate, 0.40). Classifier performance slightly improved (error rate, 0.26) including only women who were using continuous combined HRT treatment. According to the small amplitude of expression alterations observed in whole blood, more quantitative technique and larger sample sizes will be needed to be able to investigate whether significant single genes are differentially expressed in HRT versus non-HRT users. Taken cautiously, significant enrichments in biological process of genes with small changes after HRT use were observed (e.g., receptor and transporter activities, immune response, frizzled signaling pathway, actin filament organization, and glycogen metabolism). [Mol Cancer Ther 2006;5(4):868–76]

Background: microRNAs (miRNAs) exist in blood in an apparently stable form. We have explored whether serum miRNAs can be used as non-invasive early biomarkers of colon cancer. Methods: Serum samples from 30 patients with colon cancer stage IV and 10 healthy controls were examined for the expression of 375 cancer-relevant miRNAs. Based on the miRNA profile in this study, 34 selected miRNAs were measured in serum from 40 patients with stage I–II colon cancer and from 10 additional controls. Results: Twenty miRNAs were differentially expressed in serum from stage IV patients compared with controls (P

In some families there is an increased risk for colorectal cancer, caused by heritable, but often unidentified genetic mutations predisposing to the disease. We have identified the likely genetic cause for disease predisposition in a large family with high burden of colorectal adenomas and carcinomas, in addition to extra-colonic cancers. This family had previously been tested for known cancer susceptibility genes, with negative results. Exome sequencing was used to identify a novel mutation, c.1373A>T (p.Tyr458Phe), in the gene for DNA polymerase epsilon catalytic subunit (POLE). This mutation is located in the active site of the exonuclease domain of the enzyme, and affects a residue that has previously been shown to be important for exonuclease activity. The first predisposing mutation identified in POLE (c.1270C>G, p.Leu424Val) was associated with colorectal cancer only, but another mutation with a broader tumour spectrum (c.1089C>A, p.Asn363Lys) has recently been reported. In the family described in the present study, carriers generally have multiple colorectal adenomas and cancer of colon, pancreas, ovaries and small intestine which represents an important broadening of the tumour spectrum of POLE mutation carriers. We also observe a large phenotypic variation among the POLE mutation carriers in this family, most likely explained by modifying variants in other genes. One POLE mutation carrier has a novel variant in EXO1 (c.458C>T, p.Ala153Val), which may contribute to a more severe phenotype. The findings in this study will have important implications for risk assessment and surveillance of POLE mutation carriers. Electronic supplementary material The online version of this article (doi:10.1007/s10689-015-9803-2) contains supplementary material, which is available to authorized users.