Hereditary predisposition to breast cancer – evaluating the role of rare candidate alleles discovered by whole-exome sequencing
Thesis event information
Date and time of the thesis defence
Place of the thesis defence
Kontinkangas, Dentopolis, auditorium H1091
Topic of the dissertation
Hereditary predisposition to breast cancer – evaluating the role of rare candidate alleles discovered by whole-exome sequencing
Doctoral candidate
Master of Science Susanna Koivuluoma
Faculty and unit
University of Oulu Graduate School, Faculty of Medicine, Research Unit of Translational Medicine
Subject of study
Medicine
Opponent
Docent Eveliina Salminen, University of Helsinki
Custos
Professor Katri Pylkäs, University of Oulu
Hereditary predisposition to breast cancer – evaluating the role of rare candidate alleles discovered by whole-exome sequencing
This thesis aimed to identify novel rare breast cancer predisposing factors in Northern Finnish breast cancer cases with indication of inherited disease susceptibility. The main method in this study was whole-exome sequencing, which is a next-generation sequencing method focusing on the coding part of the genome.
Whole-exome sequencing revealed a mutation in SERPINA3 gene. This mutation was more common in breast cancer case cohorts compared to a healthy population control cohort. Based on the results, the carriers of this mutation have a moderate, approximately threefold risk of developing breast cancer. SERPINA3 gene functions as a serine protease inhibitor and it has been reported to have a role for example in inflammatory response and apoptosis.
This study also revealed a very rare protein truncating variant in TINF2 gene. Previous studies have reported similar mutations in TINF2 gene resulting in high cancer risk and other severe disorders. The mutation studied here was more common in breast cancer case cohorts compared to healthy controls and the results indicated that this mutation is at most a moderate-risk breast cancer allele. TINF2 gene is a part of the shelterin complex, which maintains and protects telomere length.
Additionally, the significance of a rare CHEK2 mutation in breast cancer was evaluated in this thesis. The mutation is enriched in North Ostrobothnia and classified as a variant of unknown significance. The results revealed that the prevalence of the mutation was nearly equal both in breast cancer case cohorts and healthy controls. These results suggested that the mutation is unlikely to predispose to breast cancer and its classification can be changed to likely benign. CHEK2 gene functions in DNA damage repair and it is an established breast cancer susceptibility gene.
Breast cancer is the most common malignancy among women, and the risk of developing the disease is strongly influenced by inherited predisposing mutations. Genes such as BRCA1, BRCA2 and PALB2 harbor variants that confer a high breast cancer risk, but despite extensive research, only about half of the hereditary component of the disease has been uncovered. The identification of novel predisposing alleles is imperative, as it enables better genetic counseling for the mutation carrier families and earlier cancer diagnosis.
Whole-exome sequencing revealed a mutation in SERPINA3 gene. This mutation was more common in breast cancer case cohorts compared to a healthy population control cohort. Based on the results, the carriers of this mutation have a moderate, approximately threefold risk of developing breast cancer. SERPINA3 gene functions as a serine protease inhibitor and it has been reported to have a role for example in inflammatory response and apoptosis.
This study also revealed a very rare protein truncating variant in TINF2 gene. Previous studies have reported similar mutations in TINF2 gene resulting in high cancer risk and other severe disorders. The mutation studied here was more common in breast cancer case cohorts compared to healthy controls and the results indicated that this mutation is at most a moderate-risk breast cancer allele. TINF2 gene is a part of the shelterin complex, which maintains and protects telomere length.
Additionally, the significance of a rare CHEK2 mutation in breast cancer was evaluated in this thesis. The mutation is enriched in North Ostrobothnia and classified as a variant of unknown significance. The results revealed that the prevalence of the mutation was nearly equal both in breast cancer case cohorts and healthy controls. These results suggested that the mutation is unlikely to predispose to breast cancer and its classification can be changed to likely benign. CHEK2 gene functions in DNA damage repair and it is an established breast cancer susceptibility gene.
Breast cancer is the most common malignancy among women, and the risk of developing the disease is strongly influenced by inherited predisposing mutations. Genes such as BRCA1, BRCA2 and PALB2 harbor variants that confer a high breast cancer risk, but despite extensive research, only about half of the hereditary component of the disease has been uncovered. The identification of novel predisposing alleles is imperative, as it enables better genetic counseling for the mutation carrier families and earlier cancer diagnosis.
Last updated: 23.1.2024