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Lynch syndrome (LS) is a dominantly inherited cancer susceptibility syndrome defined by presence of pathogenic variants in DNA mismatch repair genes MLH1, MSH2, MSH6 and PMS2, or in deletions of the EPCAM gene. Although LS is present in about 1 in 400 people in the UK, it estimated that only 5% of people with this condition are aware of the diagnosis. Therefore, testing for LS in all new diagnoses of colorectal or endometrial cancers is now recommended in the UK, and gastroenterologists can offer ‘mainstreamed’ genetic testing for LS to patients with cancer. Because LS results in a high lifetime risk of colorectal, endometrial, gastric, ovarian, hepatobiliary, brain and other cancers, the lifelong care of affected individuals and their families requires a coordinated multidisciplinary approach. Interventions such as high-quality 2-yearly colonoscopy, prophylactic gynaecological surgery, and aspirin are proven to prevent and facilitate early diagnosis and prevention of cancers in this population, and improve patient outcomes. Recently, an appreciation of the mechanism of carcinogenesis in LS-associated cancers has contributed to the development of novel therapeutic and diagnostic approaches, with a gene-specific approach to disease management, with potential cancer-preventing vaccines in development. An adaptive approach to surgical or oncological management of LS-related cancers may be considered, including an important role for novel checkpoint inhibitor immunotherapy in locally advanced or metastatic disease. Therefore, a personalised approach to lifelong gene-specific management for people with LS provides many opportunities for cancer prevention and treatment which we outline in this review.

Background: Oesophageal (OeC) and gastric (GC) cancer patients are treated with similar multimodal therapy and have poor survival. There remains an urgent clinical need to identify biomarkers to individualise patient management and improve outcomes. Therapy with immune checkpoint inhibitors has shown promising results in other cancers. Proposed biomarkers to predict potential response to immune checkpoint inhibitors include DNA mismatch repair (MMR) and/ or EpsteineBarr virus (EBV) status. The aim of this study was to establish and compare EBV status and MMR status in large multi-centre series of OeC and GC. Methods: EBV was assessed by EBV-encoded RNA (EBER) in situ hybridisation and MMR protein expression by immunohistochemistry (IHC) in 988 OeC and 1213 GC from multiple centres. In a subset of OeC, microsatellite instability (MSI) was tested in parallel with MMR IHC. Results: Frequency of MMR deficiency (MMRdef) and MSI was low in OeC (0.8% and 0.6%, respectively) compared with GC (10.3%). None of the OeCs were EBER positive in contrast to 4.8% EBER positive GC. EBV positive GC patients were younger (p = 0.01), more often male (p = 0.001) and had a better overall survival (p = 0.012). MMRdef GC patients were older (p = 0.001) and showed more often intestinal-type histology (p = 0.022). Conclusions: This is the largest study to date indicating that EBV and MMRdef do not play a role in OeC carcinogenesis in contrast to GC. The potential clinical usefulness of determining MMRdef/EBV status to screen patients for eligibility for immune-targeting therapy differs between OeC and GC patients. (C) 2018 The Authors. Published by Elsevier Ltd.

Background Carcinomas of the small bowel are rare tumors usually with dismal prognosis. Most recently, some potentially treatable molecular alterations were described. We emphasize the growing evidence of individualized treatment options in small bowel carcinoma. Methods We performed a DNA- based multi-gene panel using ultra-deep sequencing analysis (including 14 genes with up to 452 amplicons in total; KRAS, NRAS, HRAS, BRAF, DDR2, ERBB2, KEAP1, NFE2L2, PIK3CA, PTEN, RHOA, BRCA1, BRCA2 and TP53) as well as an RNA-based gene fusion panel including ALK, BRAF, FGFR1, FGFR2, FGFR3, MET, NRG1, NTRK1, NTRK2, NTRK3, RET and ROS1 on eleven formalin fixed and paraffin embedded small bowel carcinomas. Additionally, mismatch-repair-deficiency was analyzed by checking the microsatellite status using the five different mononucleotide markers BAT25, BAT26, NR-21, NR-22 and NR-27 and loss of mismatch repair proteins using four different markers (MLH1, MSH6, MSH2, PMS2). Results In five out of eleven small bowel carcinomas we found potentially treatable genetic alterations. Three patients demonstrated pathogenic (class 5) BRCA1 or BRCA2 mutations – one germline-related in a mixed neuroendocrine-non neuroendocrine neoplasm (MiNEN). Two additional patients revealed an activating ERBB2 mutation or PIK3CA mutation. Furthermore two tumors were highly microsatellite-instable (MSI-high), in one case associated to Lynch-syndrome. We did not find any gene fusions. Conclusion Our results underscore, in particular, the relevance of potentially treatable molecular alterations (like ERBB2, BRCA and MSI) in small bowel carcinomas. Further studies are needed to proof the efficacy of these targeted therapies in small bowel carcinomas.

Introduction: Mismatch repair deficiency (dMMR) can be found in Lynch syndrome (LS)-associated colorectal carcinoma and in 15% of sporadic colorectal cancer (CRC). Outcome of MMR-deficiency testing is important for surgical decisions as extended colectomy is recommended in young LS-patients with CRC. Moreover, the finding of a dMMR tumour has consequences for the choices of adjuvant chemotherapy as MMR-deficient CRC is resistant to 5-fluorouracil (5-FU) monotherapy. Aims of our study are to evaluate whether MMR-deficiency testing leads to (1) identification of LS, (2) change in surgical treatment and (3) adjustment of systemic therapy in patients with dMMR CRC.Methods: We performed a multicentre, retrospective study, in a community hospital and a University Medical Centre. We included all CRC-patients between 2012 and 2016 who were tested for microsatellite instability. We collected clinical data such as gender, age, referral to clinical geneticist, surgical procedure and choice of chemotherapy.Results: We analysed 225 CRCs. Twenty-four (10.7%) of 225 CRC were MMR-deficient. Of the 24 patients with dMMR CRC, 18 (75%) were referred to the clinical geneticist and in nine (37%) patients a MMR mutation was identified. In one (4%) of the 24 patients, a subtotal colectomy was performed. In seven (35%) out of 20 MMR deficient patients, the chemotherapy regimen was adjusted.Conclusions: The finding of a dMMR CRC had consequences for decisions on chemotherapy in a relative high proportion of patients. We recommend testing in all patients with CRC independent of age at diagnosis, as proper treatment decisions and genetic counselling are very important.

The repertoire of coronavirus disease 2019 (COVID-19)-mediated adverse health outcomes has continued to expand in infected patients, including the susceptibility to developing long-COVID; however, the molecular underpinnings at the cellular level are poorly defined. In this study, we report that SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection triggers host cell genome instability by modulating the expression of molecules of DNA repair and mutagenic translesion synthesis. Further, SARS-CoV-2 infection causes genetic alterations, such as increased mutagenesis, telomere dysregulation, and elevated microsatellite instability (MSI). The MSI phenotype was coupled to reduced MLH1, MSH6, and MSH2 in infected cells. Strikingly, pre-treatment of cells with the REV1-targeting translesion DNA synthesis inhibitor, JH-RE-06, suppresses SARS-CoV-2 proliferation and dramatically represses the SARS-CoV-2-dependent genome instability. Mechanistically, JH-RE-06 treatment induces autophagy, which we hypothesize limits SARS-CoV-2 proliferation and, therefore, the hijacking of host-cell genome instability pathways. These results have implications for understanding the pathobiological consequences of COVID-19., Competing Interests: Declarations Competing interests “P.Z. and J.H. are inventors of a patent on JH-RE-06 for cancer therapy.”

Lynch syndrome (LS) is caused by a germline mutation in one of the mismatch repair (MMR) genes. The resulting loss of MMR gene function induces a strong mutator phenotype and predisposition to colorectal cancer (CRC). LS mutation carriers undergo regular colonoscopic surveillance and have extensive colonic resection in case of cancer because of the chance of metachronous tumors. Given the high risk and early onset of CRC, LS mutation carriers are good candidates for chemoprevention. Furthermore, evidence increases indicating that the response of MMR-deficient tumors to standard chemotherapy and radiotherapy differs from that of MMR-proficient tumors. Efforts should thus be directed at designing tailored strategies concerning both chemoprevention and medical cancer treatment for LS individuals. This review provides guidance for future studies in this field based on results from clinical and preclinical research. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

BRCA1-associated cancers differ from non-hereditary cancers for many factors, including somatic mutation. It can be a subject of discussion that the natural history and response to treatment also may differ between the hereditary and sporadic subgroups. Three frequent BRCA1 mutations (5382insC, 4153delA, C61G) in the Baltic countries (Lithuania, Latvia, Byelorussia and Poland) open a way for the chip test to select a subgroup from women with breast cancer. These women with BRCA1 breast cancer have a chance to get adequate treatment, including neo-adjuvant chemotherapy. So far many retrospective studies of survival, that used the same gold standard treatment for women with BRCA1 breast cancer and for women without a mutation, have not found a difference between these groups. Some studies show a worse survival result in women with a BRCA1 mutation than women without the mutation.

Objective To investigate if analysis of genetic alterations in the main pathways involved in endometrioid type carcinogenesis (PI3K–AKT, Wnt/β-catenin, P53-activation and MSI) improves the current risk assessment based on clinicopathological factors. Methods Formalin fixed paraffin embedded (FFPE) primary tumor samples of 65 patients with FIGO-stage I endometrioid type endometrial cancer (EEC) were selected from the randomized PORTEC-2 trial. Tumors were stained by immunohistochemistry for P53, PTEN and β-catenin. Tumor DNA was isolated for sequence analysis of TP53 (exons 4 to 8), hotspot mutation analysis of KRAS (exon 1) and PI3K (exon 9 and 20) and microsatellite-instability (MSI) analysis including MLH1 promotor-methylation status. Univariate and multivariate analyses for disease-free survival (DFS) using Cox regression models were performed. Results P53 status (HR 6.7, 95%CI 1.75–26.0, p=0.006) and MSI were the strongest single genetic prognostic factors for decreased DFS, while high PI3K–AKT pathway activation showed a trend and β-catenin was not prognostic. The combination of multiple activated pathways was the most powerful prognostic factor for decreased DFS (HR 5.0; 95%CI 1.59–15.6 p=0.006). Multiple pathway activation, found in 8% of patients, was strongly associated with aggressive clinical course. In contrast, 40% of patients had no alterations in the investigated pathways and had a very low risk of disease progression. Conclusions Activation of multiple oncogenic pathways in EEC was the most powerful prognostic factor for decreased DFS, resulting in an individual risk assessment superior to the current approach based on clinicopathological factors.

DNA mismatch repair suppresses gastrointestinal tumorgenesis. Four mammalian E. coli MutL homologues heterodimerize to form three distinct complexes: MLH1/PMS2, MLH1/MLH3, and MLH1/PMS1. To understand the mechanistic contributions of MLH3 and PMS2 in gastrointestinal tumor suppression, we generated Mlh3−/−;Apc1638N and Mlh3−/−;Pms2−/−;Apc1638N (MPA) mice. Mlh3 nullizygosity significantly increased Apc frameshift mutations and tumor multiplicity. Combined Mlh3;Pms2 nullizygosity further increased Apc base-substitution mutations. The spectrum of MPA tumor mutations was distinct from that observed in Mlh1−/−;Apc1638N mice, implicating the first potential role for MLH1/PMS1 in tumor suppression. Because Mlh3;Pms2 deficiency also increased gastrointestinal tumor progression, we used array-CGH to identify a recurrent tumor amplicon. This amplicon contained a previously uncharacterized Transducin enhancer of Split (Tle) family gene, Tle6-like. Expression of Tle6-like, or the similar human TLE6D splice isoform in colon cancer cells increased cell proliferation, colony-formation, cell migration, and xenograft tumorgenicity. Tle6-like;TLE6D directly interact with the gastrointestinal tumor suppressor RUNX3 and antagonize RUNX3 target transactivation. TLE6D is recurrently overexpressed in human colorectal cancers and TLE6D expression correlates with RUNX3 expression. Collectively, these findings provide important insights into the molecular mechanisms of individual MutL homologue tumor suppression and demonstrate an association between TLE mediated antagonism of RUNX3 and accelerated human colorectal cancer progression., Author Summary Approximately one million people every year are diagnosed with colorectal cancer worldwide, and about five hundred thousand of these people subsequently perish from the disease. Colorectal cancer is thought to develop through a series of early and later stages (called cancer initiation and progression, respectively). Deaths from colorectal cancer are particularly tragic because the disease can usually be cured if discovered before full-blown progression. However, our knowledge of how these tumors progress remains very limited. DNA mismatch repair is known to be an important process in preventing ∼15% of colorectal cancer initiation. In this study we describe how two of these genes (Mlh3 and Pms2) that have partial functional redundancy and therefore individually are rarely mutated are also important in preventing colorectal cancer progression. Additionally, we describe a new gene (Tle6-like) that, when overactive, makes these cancers progress more rapidly. The overall goal of this study is to understand colorectal cancer progression better so that we can come up with new ways to block it at the later stage.

Lynch syndrome (LS) is caused by a germline mutation in one of the mismatch repair (MMR) genes. The resulting loss of MMR gene function induces a strong mutator phenotype and predisposition to colorectal cancer (CRC). LS mutation carriers undergo regular colonoscopic surveillance and have extensive colonic resection in case of cancer because of the chance of metachronous tumors. Given the high risk and early onset of CRC, LS mutation carriers are good candidates for chemoprevention. Furthermore, evidence increases indicating that the response of MMR-deficient tumors to standard chemotherapy and radiotherapy differs from that of MMR-proficient tumors. Efforts should thus be directed at designing tailored strategies concerning both chemoprevention and medical cancer treatment for LS individuals. This review provides guidance for future studies in this field based on results from clinical and preclinical research. (C) 2010 Elsevier Ireland Ltd. All rights reserved.