Evaluation of genetic cancer predisposition and potential cancer genes

Abstract: Germline pathogenic TP53 variants are associated with a broad spectrum of hereditary cancers characterized from Li-Fraumeni syndrome (LFS) to hereditary breast cancer (HBC) outcomes, known as heritable TP53-related cancer (hTP53rc) syndrome. LFS is a rare inherited cancer syndrome characterized by premenopausal breast cancer, soft tissue sarcoma, brain tumor, osteosarcoma, and adrenocortical carcinoma. To identify carriers with high risk of LFS phenotype and explore stratifying clinical management for these carriers, we developed a phenotypic prediction model of LFS in relation to HBC risk based on predicted protein conformation changes for germline TP53 missense variants in the international agency for research on cancer (IARC) TP53 database and published papers in Paper I. This model was validated in our Swedish TP53 cohort with more reliable pedigree and clinical information in Paper II. Our results indicated that this tool could be considered helpful in the genetic counseling of families with hTP53rc, in particular as a psychological relief for families with a predominance of HBC phenotype. Also, we summarized the clinical characterization of all known TP53-carriers in hTP53rc families in Sweden and explored genotype-phenotype correlations. Except for the very high lifetime risk of a broad spectrum of tumor types in LFS families, chemo- and radiotherapy can increase these patients' risk of secondary tumors. Thus, efficient preventive treatment would be important to these tumor-prone carriers. We have seen an indication of delayed tumor onset using the mutant TP53-targeting compound APR-246 in a mouse model of LFS with R172H (amino acid change at residue 172 from arginine to histidine) mutant Trp53, and it had the potential to be used in the clinical study in Paper III. HBC is characterized by early-onset age of breast cancer, bilateral breast cancer, male breast cancer, and it can be accompanied by ovarian cancer or other cancer types. BRCA1 and BRCA2 are the most prevalent genes for HBC, however, most families are not associated with variants in any known breast cancer-related genes. We identified several potential high-risk genes that could contribute to breast cancer in three Swedish HBC families in Paper IV. In summary, this thesis enriches the knowledge of genetic predisposition and prevention of hereditary breast cancer syndromes and potential cancer genes.