| Autor: |
Cannon-Albright LA; Genetic Epidemiology Group, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.; George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, UT 84148, USA.; Huntsman Cancer Institute, Salt Lake City, UT 84132, USA., Stevens J; Genetic Epidemiology Group, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84132, USA., Teerlink CC; Genetic Epidemiology Group, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.; George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, UT 84148, USA., Facelli JC; Department of Biomedical Informatics and Utah Clinical and Translational Science Institute, University of Utah School of Medicine, Salt Lake City, UT 84132, USA., Allen-Brady K; Genetic Epidemiology Group, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84132, USA., Welm AL; Huntsman Cancer Institute, Salt Lake City, UT 84132, USA.; Department of Oncological Sciences, University of Utah School of Medicine, Salt Lake City, UT 84132, USA. |
| Abstrakt: |
A significant fraction of breast cancer recurs, with lethal outcome, but specific genetic variants responsible have yet to be identified. Five cousin pairs with recurrent breast cancer from pedigrees with a statistical excess of recurrent breast cancer were sequenced to identify rare, shared candidate predisposition variants. The candidates were tested for association with breast cancer risk with UKBiobank data. Additional breast cancer cases were assayed for a subset of candidate variants to test for co-segregation. Three-dimensional protein structure prediction methods were used to investigate how the mutation under consideration is predicted to change structural and electrostatic properties in the mutated protein. One hundred and eighty-one rare candidate predisposition variants were shared in at least one cousin pair from a high-risk pedigree. A rare variant in MDH2 was found to segregate with breast-cancer-affected relatives in one extended pedigree. MDH2 is an estrogen-stimulated gene encoding the protein malate dehydrogenase, which catalyzes the reversible oxidation of malate to oxaloacetate. The molecular simulation results strongly suggest that the mutation changes the NAD + binding pocket electrostatics of MDH2 . This small sequencing study, using a powerful approach based on recurrent breast cancer cases from high-risk pedigrees, identified a set of strong candidate variants for inherited predisposition for breast cancer recurrence, including MDH2 , which should be pursued in other resources. |
