& nbsp;Small intestine-neuroendocrine tumors (SI-NETs) are one of the most common tumors of the small bowel. Despite an increasing incidence, the exact mechanisms driving underlying pathology... Show more& nbsp;Small intestine-neuroendocrine tumors (SI-NETs) are one of the most common tumors of the small bowel. Despite an increasing incidence, the exact mechanisms driving underlying pathology remain to be determined. Interestingly, recent studies linked the development of (SI-)NETs to both Lynch syndrome (LS) and MUTYH variants. If confirmed, these associations would have important consequences for treatment. In this study we therefore investigated the prevalence of mismatch repair (MMR) deficiency and MUTYH variants in 64 primary resected SI-NETs. Immunohistochemistry was used to assess the expression of the MMR genes, and competitive allele-specific PCR (KASPar) targeting two hotspot MUTYH variants [p.(Tyr179Cys), p.(Gly396Asp)] was performed to determine their prevalence in SI-NETs. Strikingly, all 64 SI-NETs stained positive for MSH6 and PMS2, indicating & nbsp;MMR proficiency. In addition, no MUTYH hotspot variant was found in any of the 64 SI-NETs. As such, these results do not support an association between SI-NET development and LS or MUTYH variants. In order to gain insight into SI-NET pathogenesis and optimally manage patients, future research should therefore focus on other candidate genes. (C) 2022 Published by Elsevier Inc Show less
Schubert, S.A.; Ruano, D.; Tiersma, Y.; Drost, M.; Wind, N. de; Nielsen, M.; ... ; Wezel, T. van 2020
We describe a family severely affected by colorectal cancer (CRC) where whole-exome sequencing identified the coinheritance of the germline variants encoding MSH6 p.Thr1100Met and MUTYH p.Tyr179Cys... Show moreWe describe a family severely affected by colorectal cancer (CRC) where whole-exome sequencing identified the coinheritance of the germline variants encoding MSH6 p.Thr1100Met and MUTYH p.Tyr179Cys in, at least, three CRC patients diagnosed before 60 years of age. Digenic inheritance of monoallelic MSH6 variants of uncertain significance and MUTYH variants has been suggested to predispose to Lynch syndrome-associated cancers; however, cosegregation with disease in the familial setting has not yet been established. The identification of individuals carrying multiple potential cancer risk variants is expected to rise with the increased application of whole-genome sequencing and large multigene panel testing in clinical genetic counseling of familial cancer patients. Here we demonstrate the coinheritance of monoallelic variants in MSH6 and MUTYH consistent with cosegregation with CRC, further supporting a role for digenic inheritance in cancer predisposition. Show less
Each year, approximately eleven thousand new colorectal cancer (CRC) patients are registered in the Netherlands. Half of these patients will eventually die of this disease. Consequently, it is of... Show moreEach year, approximately eleven thousand new colorectal cancer (CRC) patients are registered in the Netherlands. Half of these patients will eventually die of this disease. Consequently, it is of great importance to identify individuals with an increased risk for CRC. In this thesis, we evaluate the use of molecular pathology for identifying individuals with an increased risk for CRC based on their genetic makeup, and for generating insight into the tumorigenesis of familial CRC. We conclude that molecular pathology has a high potential for playing an active role in identifying individuals with CRC predisposing syndromes in a diagnostic setting as well as in studying tumorigenesis of CRC in a research setting. Tests which are readily applicable and straightforward, are now extensively used in our daily molecular pathology diagnostics. In the research setting, molecular pathology will be an important player in study the contribution to an increased CRC risk of the susceptibility alleles that are being identified. Furthermore, we now argue that the distinct tumor profiles that we found are convincing examples that molecular pathology approaches are also crucial in the characterization and elucidation of unresolved familial causes of CRC. Show less
