Mismatch repair (MMR) is a DNA repair system that corrects base-base misincorporations generated by the replicative DNA polymerases. Previous publications have shown the involvement of the MMR... Show moreMismatch repair (MMR) is a DNA repair system that corrects base-base misincorporations generated by the replicative DNA polymerases. Previous publications have shown the involvement of the MMR pathway in control of DNA damage responses. The work presented in this thesis suggests that the regulation of DNA damage induced mutagenesis and signaling may lie in the complex interplay between translesion synthesis (TLS), a subset of error-prone polymerases capable of replicating damaged DNA, and MMR. This thesis suggests that MMR may reduce DNA damage induced mutagenesis via two ways: (i) recruit the somewhat less error-prone TLS polymerases to the DNA lesion and (ii) post-replicative removal of mismatched nucleotides. Of note, inheriting a heterogenous defect in an MMR gene results in increased risk of developing cancer, in particular colorectal cancer. The reason for this specific cancer tropism is, as of yet, unclear. The colorectal tract is continuously exposed to DNA damaging agents and indeed data in this thesis shows that MMR is important in protecting against diet-derived DNA damaging agents by controlling DNA damage induced mutagenesis and signaling. As such the colorectal cancer tropism of MMR of LS may partly be explained by the role of MMR in controlling the DNA damage response. Show less
Werf-'t, A.S. van der; Terlouw, D.; Tops, C.M.; Kan, M.S. van; Hest, L.P. van; Gille, H.J.P.; ... ; Nielsen, M. 2023
Diagnosis of Lynch syndrome (LS) caused by a pathogenic germline MSH6 variant may be complicated by discordant immunohistochemistry (IHC) and/or by a microsatellite stable (MSS) phenotype. This... Show moreDiagnosis of Lynch syndrome (LS) caused by a pathogenic germline MSH6 variant may be complicated by discordant immunohistochemistry (IHC) and/or by a microsatellite stable (MSS) phenotype. This study aimed to identify the various causes of the discordant phenotypes of colorectal cancer (CRC) and endometrial cancer (EC) in MSH6-associated LS. Data were collected from Dutch family cancer clinics. Carriers of a (likely) pathogenic MSH6 variant diagnosed with CRC or EC were categorized based on an microsatellite instability (MSI)/IHC test outcome that might fail to result in a diagnosis of LS (eg, retained staining of all 4 mismatch repair proteins, with or without an MSS phenotype, and other staining patterns). When tumor tissue was available, MSI and/or IHC were repeated. Next-generation sequencing (NGS) was performed in cases with discordant staining patterns. Data were obtained from 360 families with 1763 (obligate) carriers. MSH6 variant carriers with CRC or EC (n = 590) were included, consisting of 418 CRCs and 232 ECs. Discordant staining was reported in 77 cases (36% of MSI/IHC results). Twelve patients gave informed consent for further analysis of tumor material. Upon revision, 2 out of 3 MSI/IHC cases were found to be concordant with the MSH6 variant, and NGS showed that 4 discordant IHC results were sporadic rather than LS-associated tumors. In 1 case, somatic events explained the discordant phenotype. The use of reflex IHC mismatch repair testing, the current standard in most Western countries, may lead to the misdiagnosis of germline MSH6 variant carriers. The pathologist should point out that further diagnostics for inheritable colon cancer, including LS, should be considered in case of a strong positive family history. Germline DNA analysis of the mismatch repair genes, preferably as part of a larger gene panel, should therefore be considered in potential LS patients. Show less
This thesis focuses on treatment outcomes of high risk endometrial cancer and corresponding patients’ and clinicians’ preferences regarding adjuvant treatment decisions; molecular studies on the... Show moreThis thesis focuses on treatment outcomes of high risk endometrial cancer and corresponding patients’ and clinicians’ preferences regarding adjuvant treatment decisions; molecular studies on the etiology of mismatch repair deficiency (MMRd) in intermediate and high risk endometrial cancer; and the combination of immunotherapy and PARP inhibition for the treatment of recurrent or metastatic endometrial cancer.The overall aims of this thesis were:• To evaluate health-related quality of life up to 5 years after chemoradiotherapy compared with pelvic radiotherapy alone in the adjuvant treatment of high risk endometrial cancer in the PORTEC-3 trial;• To investigate the preferences of patients and clinicians regarding the benefit-risk trade-off of the addition of chemotherapy to adjuvant pelvic radiotherapy;• To investigate the prevalence and prognosis of Lynch syndrome-associated endometrial cancer among MMRd endometrial cancers;• To evaluate the role of combined checkpoint inhibition and PARP inhibition in women with metastatic or recurrent endometrial cancer in terms of progression-free survival and toxicity in the DOMEC trial. Show less
Eikenboom, E.L.; Werf-'t Lam, A.S. van der; Rodriguez-Girondo, M.; Asperen, C.J. van; Dinjens, W.N.M.; Hofstra, R.M.W.; ... ; Nielsen, M. 2022
BACKGROUND & AIMS: Lynch syndrome is a form of hereditary colorectal cancer (CRC) caused by pathogenic germline variants (PV) in DNA mismatch repair (MMR) genes. Currently, many Western... Show moreBACKGROUND & AIMS: Lynch syndrome is a form of hereditary colorectal cancer (CRC) caused by pathogenic germline variants (PV) in DNA mismatch repair (MMR) genes. Currently, many Western countries perform universal immunohistochemistry testing on CRC to increase the identification of Lynch syndrome patients and their relatives. For a clear understanding of health benefits and costs, data on its outcomes are required: proportions of Lynch syndrome, sporadic MMR-deficient (MMRd) cases, and unexplained MMRd cases.METHODS: Ovid Medline, Embase, and Cochrane CENTRAL were searched for studies reporting on universal MMR immunohistochemistry, followed by MMR germline analysis, until March 20, 2020. Proportions were calculated, subgroup analyses were performed based on age and diagnostics used, and random effects meta-analyses were conducted. Quality was assessed using the Joanna Briggs Critical Appraisal Tool for Prevalence Studies.RESULTS: Of 2723 identified articles, 56 studies covering 58,580 CRCs were included. In 6.22% (95% CI, 5.08%-7.61%; I-2 = 96%) MMRd was identified. MMR germline PV was present in 2.00% (95% CI, 1.59%-2.50%; I-2 = 92%), ranging from 1.80% to 7.27% based on completeness of diagnostics and age restriction. Immunohistochemistry outcomes were missing in 11.81%, and germline testing was performed in 76.30% of eligible patients. In 7 studies, including 6848 CRCs completing all diagnostic stages, germline PV and biallelic somatic MMR inactivation were found in 3.01% and 1.75%, respectively; 0.61% remained unexplained MMRd.CONCLUSIONS: Age, completeness, and type of diagnostics affect the percentage of MMR PV and unexplained MMRd percentages. Complete diagnostics explain almost all MMRd CRCs, reducing the amount of subsequent multigene panel testing. This contributes to optimizing testing and surveillance in MMRd CRC patients and relatives. Show less
An estimated 15-25% of patients with colorectal cancer have a positive family history, but no known underlying genetic cause. In this thesis we aimed to detect the underlying genetic cause in... Show moreAn estimated 15-25% of patients with colorectal cancer have a positive family history, but no known underlying genetic cause. In this thesis we aimed to detect the underlying genetic cause in patients with suspected Lynch Syndrome, a familial disorder caused by mutations in the mismatch repair (MMR) genes. We hypothesized that these patients could be explained by missed MMR variants, somatic inactivation of the MMR genes, or variants in other genes, leading to secondary MMR-deficiency. In our cohort we found 10 patients with two somatic MMR variants in the tumor and 9 patients with a germline or somatic mutation in the POLE or POLD1 genes. Variants in the exonuclease domain of these genes results in highly mutated tumors. Additionally, we describe how to assess the effect of splice variants, and how to sequence the complex PMS2 gene with next generation sequencing. In the second part we aimed to detect the underlying genetic cause in patients with unexplained adenomatous polyposis. By testing multiple adenomas, we found that if two or more adenomas carry the same variant in the APC gene, this was indicative of an underlying mosaic genetic cause. Nine patients with 21-100 adenomas could be explained by APC mosaicism. Show less
