Evaluation of genetic cancer predisposition and potential cancer genes

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.

List of scientific papers

I. Association between predicted effects of TP53 missense variants on protein conformation and their phenotypic presentation as Li-Fraumeni syndrome or hereditary breast cancer. Yaxuan Liu, Olga Axell, Tom van Leeuwen, Robert Konrat, Pedram Kharaziha, Catharina Larsson, Anthony P H Wright, Svetlana Bajalica-Lagercrantz. International Journal of Molecular Sciences. 2021 Jun 14; 22 (12), 6345.
https://doi.org/10.3390/ijms22126345

II. Characterization of heritable TP53-related cancer syndrome in Sweden – a retrospective nationwide study of genotype-phenotype correlations in 98 families. Yaxuan Liu#, Meis Omran#,*, Alexander Sun Zhang, Marie Stenmark-Askmalm, Anna Rosén, Anna-Lotta Hallbeck, Anna Poluha, Fredrik Persson, Hafdis T. Helgadottir, Emma Tham, Svetlana Bajalica-Lagercrantz. [Manuscript]

III. Evaluation of the prophylactic use of APR-246 in a mouse model of the Li-Fraumeni syndrome with R172H mutant Trp53. Yaxuan Liu*, Charlotte Strandgren, Yajie Yang, Alexander Sun Zhang, Felix Haglund de Flon, Lennart Blomquist, Svetlana Bajalica-Lagercrantz, Klas G Wiman. [Manuscript]

IV. Whole exome sequencing of germline variants in non-BRCA families with hereditary breast cancer. Yaxuan Liu, Hafdis T. Helgadottir, Pedram Kharaziha, Jungmin Choi, Francesc Lopez-Giraldez, Shrikant M. Mane, Veronica Höiom, Carl Christofer Juhlin, Catharina Larsson, Svetlana Bajalica-Lagercrantz. biomedicines. 2022 April 26; 10 (5), 1004.
https://doi.org/10.3390/biomedicines10051004