Leiden University Scholarly Publications

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Cunha Carvalho de Miranda, N.F. da (2013)

Mismatch repair and MUTYH deficient colorectal cancers : at the crossroad of genomic stability and immune escape

Doctoral Thesis
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...Show moreIn 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.Show less
Tumor infiltrating lymphocytes
Human Leukocyte Antigen
Immune escape
Mismatch repair
MUTYH
Microsatellite instability
TGFBR2
Transforming growth factor beta
Colorectal cancer
All authors
Cunha Carvalho de Miranda, N.F. da
Supervisor
Morreau, J.; Fleuren, G.J.
Co-supervisor
Wezel, T. van
Qualification
Doctor (dr.)
Awarding Institution
Leiden University Medical Center (LUMC), Leiden University
Date
2013-11-19
ISBN (print)
9789090279268

Funding

Sponsorship
The studies presented in this thesis were performed at the department of Pathology of the Leiden University Medical Centre. They have been partially funded by the Dutch Cancer Society (grant number 2000/2135) and the Bontius Stichting of the Leiden University Medical Centre through a generous gift from an alumnus.