Gynaecological carcinomas (ovarian, endometrial, cervical, vaginal, vulvar and breast) are among the ones leading to the highest cancer-related deaths worldwide. The presence of germline pathogenic... Show moreGynaecological carcinomas (ovarian, endometrial, cervical, vaginal, vulvar and breast) are among the ones leading to the highest cancer-related deaths worldwide. The presence of germline pathogenic variants in the breast cancer susceptibility genes BRCA1 and BRCA2 is associated with an increased risk for breast and ovarian cancer as well as other cancers. The BRCA proteins play a crucial role in the homologous recombination (HR) pathway, which is the only DNA damage repair pathway that can repair DNA double-strand breaks error-free. The repair of DNA damage by HR is crucial to maintain genomic integrity. Patients whose tumors are HR-Deficient (HRD) are particularly sensitive to platinum-based chemotherapy and poly-ADP ribose polymerase inhibitors (PARPi). BRCA1/2 deficiency, but also (epi)genetic defects in other HR-related genes or other unknown factors can lead to HRD. However, BRCA1/2 deficiency, and not HRD, is still the leading prerequisite to be eligible for PARPi therapy. In this thesis, two functional RAD51-based HRD tests (RECAP and RAD51-FFPE test), were developed and validated using gynaecological carcinomas. These functional HRD tests were benchmarked with BRCA1/2 deficiency and with other DNA-based HRD tests measuring genomic scars and mutational signatures. In addition, the prevalence of functional HRD was explored among a variety of gynaecological carcinomas. Show less
The first part of this thesis evaluates the proportion of germline APC and MUTYH pathogenic variants in colorectal polyposis patients and subsequently identifies the substantial proportion... Show moreThe first part of this thesis evaluates the proportion of germline APC and MUTYH pathogenic variants in colorectal polyposis patients and subsequently identifies the substantial proportion polyposis patients remaining unexplained. Part II of this thesis elucidates the significance of APC mosaicism in these unexplained polyposis patients. Analysis of more than 400 patients resulted in a suggestion for both testing and surveillance guidelines. Moreover, chapter 4 describes the interesting finding of multiple APC mosaicism cases in one family with the family members having distinct mosaic patterns and phenotypes. The last part of this thesis assesses another explanation for the development of colorectal adenomatous polyps, namely the presence of pks+ E. coli and colibactin-associated mutational signatures. In this part we describe the common c.835-8A>G APC splice variant as fitting the mutational signature caused by colibactin, which is produced by pks+ E. coli. Moreover, we examine this mutational signature and fecal pks genes in a random selection of our cohort. Show less