THE EFFECT OF VARIANTS OF UNCLINICAL SIGNIFICANCE ON PROTEIN STRUCTURE AND DYNAMICS

“Using in silico methods and molecular dynamic (MD) simulations, Assoc. Prof. Mert Gür of the Mechanical Engineering Department is studying the effects of variants of unknown clinical significance (VUS) observed in breast and colon cancer on the structure, dynamics and thermodynamic properties of proteins playing key roles in the development of breast and colon cancer. Assoc. Prof. Mert Gür aims to improve the cancer related pathogenicity interpretation of genetic tests, by providing molecular level insight to the effect of VUS mutations on DNA repair and checkpoint proteins for VUS mutations determined by the genomic analyses in breast cancer patients at the Ümraniye Training and Research Hospital and Bahçeşehir University School of Medicine.

Cancer is a major public health and economic issue. Studies show that cancer-related deaths are the second primary cause of death in our country and in the world. Breast and colon cancers are among the most common and deadly types of cancer. About 3% to 10% of breast and colon cancer cases are thought to be hereditary. Studies show that the risk of developing cancer is carried by germinal (inherited from mother or father) pathogenic variants in cancer susceptibility genes. When individuals with a familial or individual cancer history are screened, it can be determined that they carry some pathogenic variants, thus providing the opportunity for early diagnosis and diagnosis as well as preventive medical treatment for the patient and their close relatives. Early diagnosis in breast and olon cancer is vital for both types of cancer. Studies show that with early diagnosis, the 5-year survival rate exceeds 90% for cancer in general, hence highlighting the importance for breast and colon cancer. Identifying individuals at risk for breast and colon cancer effectively with the help of creative decision support systems comprising innovative molecular analyses and statistical data analysis methods, would help to reduce cancer incidence, cancer death rates and cancer treatment costs.

Variations with unknown association disease risk and unclear significance to function are classified as variants of unknown clinical significance (VUS). The observation of VUS as a result of gene tests and sequencing emerges as a challenge in early diagnosis and diagnosis of cancer as they do not provide sufficient evidence to determine if the variant is related to disease or not. For this reason, it is important to collect more population data regarding the cancer type specific relevance of VUS and also conduct molecular studies to identify VUS affecting the functional mechanism of cancer related proteins. By investigating the effects of these mutations on proteins structure, dynamics and thermodynamics, Assoc. Prof. Mert Gür and his research group aim to identify the mutations among the VUS that are associated with colon and breast cancer occurrence in the Turkish population. Effect of the VUS detected by Ümraniye Training and Research Hospital and Bahçeşehir University School of Medicine on CHK2, MSH2 and MSH6 function are investigated via in silico methods to determine the mutations and hence VUS related to colon and breast cancer formation.

Assoc. Prof. Mert Gür is acting as the PI of the TÜBİTAK funded project titled “Development of an Early Detection System for Hereditary Colon and Breast Cancers and its Integration into e-Nabız Personal Health Record System” that investigates the effects of VUS mutations on CHK2, MSH2 and MSH6 protein structure, dynamics and thermodynamics with MD simulations and statistical thermodynamic calculations.

There is scarcity in information in the literature regarding the conformations sampled and functional conformational changes that takes place during CHK2 and Mutsa heterodimer, formed by MSH2 and MSH6, function and their thermodynamic cycles. As a first step, Assoc. Prof. Mert Gür and his team focused on revealing the conformational space and change for the wild type proteins in healthy individuals. For CHK2 66% of its thermodynamic cycle was completed via 14.5 μs of molecular dynamics simulations (Figure 1.)  As a next step the, 16 VUS for CHECK2 and 3 for Mutsa have been tested via MD simulations and conformational space and dynamics for the mutants were compared with WT. New sets of VUS are tested as they are determined by the genetic tests in Bahçeşehir University School of Medicine.

Figure 1. The mechanochemical cycle of the CHK2 protein.

Fundings:

TÜBİTAK (1003, Grant No: 318S129)

Collabrators:

Prof. Dr. Gizem Dinler Doğanay, Prof. Dr. Hamdi Levent Doğanay

Lab Members:

Clara Xazal Buran