Survival rates after surgical treatment of gastric, colon and rectal cancer can improve with preoperative and/or postoperative adjuvant treatment with chemo- and/or radiotherapy. The role of... Show moreSurvival rates after surgical treatment of gastric, colon and rectal cancer can improve with preoperative and/or postoperative adjuvant treatment with chemo- and/or radiotherapy. The role of epigenetic aberrancies such as DNA methylation is established to play a pivotal role in gastrointestinal carcinogenesis and malignant progression. This thesis describes novel epigenetic biomarkers that could tailor (neo)adjuvant treatment regimens to the patients who would benefit from them. The same markers could further be used to exclude those patients who would not gain more survival-years and would be unnecessarily exposed to the morbidity/mortality of additional chemo- and/or radiation therapy. Currently, nodal status is the single most important prognostic indicator in gastrointestinal cancers however this can only be reliably assessed by the pathologist after surgery. Currently, neoadjuvant regimens are more and more being studied and shown to be of benefit. This development necessitates biomarkers that are available before the operation. An important derived conclusion from this thesis is that the preoperative availability of primary tumor DNA methylation biomarkers holds great potential for tailoring neoadjuvant therapy. The thesis also describes technical advancements that will enable primary tumor DNA methylation assessment in small amounts of tissue as preoperative diagnostic tumor biopsies harvested during gastroscopy or colonoscopy Show less
Facioscapulohumeral muscular dystrophy is an autosomal dominant myopathy that is caused by a contraction of the D4Z4 repeat on the 4qA161 genetic variant of chromosome 4qter (FSHD1). FSHD1 patients... Show moreFacioscapulohumeral muscular dystrophy is an autosomal dominant myopathy that is caused by a contraction of the D4Z4 repeat on the 4qA161 genetic variant of chromosome 4qter (FSHD1). FSHD1 patients show loss of DNA methylation on the first D4Z4 repeat unit. Interestingly, a small group of patients with a myopathy clinically indistinguishable from FSHD1 but without a D4Z4 contraction (FSHD2) and patients suffering from the ICF (Immunodeficiency, Centromeric instability and Facial anomalies) syndrome also present with very low D4Z4 methylation. In this thesis studies are described that focused on the unraveling of the epigenetic disease mechanism responsible for FSHD development. These studies show that (1) the overlap between FSHD patients and ICF patients is restricted to low D4Z4 methylation levels, (2) FSHD1 and FSHD2 patients show loss of methyl groups on lysine 9 of histone protein H3 and a secondary loss of the proteins HP1? and cohesin at the D4Z4 repeat, (3) the combination of the 4qA161 genetic variant and low D4Z4 methylation is a necessary prerequisite for FSHD development and (4) supplementation with folic and methionine can raise the total amount of methyl groups present on the DNA but cannot restore D4Z4 methylation levels in FSHD1 and FSHD2 patients. Show less
