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& 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

In this thesis, we studied some of the genetic and molecular alterations that accompany the tumorigenesis of mismatch repair (MMR) and MUTYH deficient colorectal cancers, with focus on immune escape mechanisms. We discovered that loss of Human Leukocyte Antigen (HLA) class I expression was more frequent in those tumors than in the remaining spectrum of colorectal cancers (CRCs), and that distinct genetic mechanisms explained HLA class I abrogation in sporadic and hereditary mismatch repair deficient tumors. We then explored a potential association between the magnitude and quality of lymphocytic infiltration with the tumors__ HLA class I phenotypes and clinicopathological stages in a cohort of Lynch CRCs. Higher lymphocytic infiltration, particularly of cytotoxic lymphocytes, was observed in cancers presenting HLA class I defects and in tumors diagnosed at earlier stages, thus, supporting the role of the immune system in selecting immune evasive tumor traits and in counteracting cancer progression. Finally, we functionally characterized one of the most common genetic alterations that occur in MMR deficient CRCs. We demonstrated that TGFbeta signalling is active in these tumors and that TGFbeta activation occurs in a TGFBR2-dependent manner, despite the presence of truncating biallelic mutations in its gene in the majority of MMR deficient tumors.

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 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.