PhD Scientific Days 2025

Molecular Medicine III.

Somatic analyses confirm DNA repair deficiency in MSH3-associated polyposis

Name of the presenter

Horti-Oravecz Klaudia

Institute/workplace of the presenter

Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary

Authors

Klaudia Horti-Oravecz^1,2,3,4, Anikó Bozsik^1,3,5, Tímea Pócza^5,6, István Kelemen^1,2,3,4, Erzsébet Csernák⁷, Tamás Strausz⁷, Erika Tóth^3,7, Butz Henriett^1,3,4,5,8, Attila Patócs^1,3,5,8, János Papp^1,3,5, Vince Kornél Grolmusz^3,5,9

1: Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary
2: Doctoral School, Semmelweis University, Budapest, Hungary
3: National Tumorbiology Laboratory, National Institute of Oncology, Budapest, Hungary
4: Department of Oncology Biobank, National Institute of Oncology, Budapest, Hungary
5: HUN-REN-NIO-TTK-HCEMM Oncogenomics Research Group, Budapest, Hungary
6: 1 Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary
7: Department of Molecular and Surgical Pathology, National Institute of Oncology, Budapest, Hungary
8: Department of Laboratory Medicine, Semmelweis University, Budapest, Hungary
9: Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary 2 Doctoral School, Semmelweis University, Budapest, Hungary

Text of the abstract

Introduction
Germline biallelic pathogenic variants in MSH3 are associated with MSH3-associated polyposis, a rare hereditary cancer predisposition characterized by elevated microsatellite alterations at selected tetranucleotide repeats (EMAST). Although benign and malignant colorectal tumors are the most frequent manifestations, it is unclear if additional organs exhibit elevated neoplastic potential.
Aims
In this case report we aimed to perform an extensive clinical and molecular genetic evaluation of a patient diagnosed with MSH3-associated polyposis.
Method
Following genetic counselling, multigene panel test was performed on DNA sample isolated from peripheral blood. Followed by identification of a biallelic MSH3 variant tumor-based analyses were employed to precisely detect microsatellite instability by comparing microsatellite repeat lengths in tumor and peripheral blood DNA. Eight EMAST-associated tetranucleotide microsatellite markers (MYCL1, D20S82, D2S443, D9S747, UT5037, D8S348, D8S321, D21S1436) were analyzed.
Result
Germline genetic test identified two germline pathogenic variants (MSH3 (NM_002439.5): c.1341-2A>G, p.(?) and c.2305delG, p.(Val769Ter)) in a 65-year old female patient with a history of multiple primary tumors (colorectal cancer (CRC) at the age of 53 years, colorectal cancer with additional three adenomatous polyps at the age of 55 years, endometrial cancer (EC) at the age of 59 years and breast cancer (BrC) at the age of 60 years). Cascade testing confirmed the biallelic nature of the two variants. Tumor testing identified that 6/8 markers in CRC53, 5/8 markers in CRC55, 5/8 markers in EC59 and 1/8 marker in BrC60 exhibited the EMAST phenotype, therefore confirming the direct impact of biallelic MSH3-deficiency on carcinogenesis.
Conclusion
Our results confirm the expanding spectrum of tumor types associated with MSH3-associated polyposis.
Funding
The project was implemented with the support from the National Research, Development and Innovation Fund of the Ministry of Culture and Innovation under the National Laboratories Program (2022-2.1.1-NL-2022-00010) and the Hungarian Thematic Excellence Program (TKP2021-EGA-44) Grant Agreements with the National Research, Development and Innovation Office. We would like to acknowledge the financial support of the National Research, Development and Innovation Office under grant NKFIH-FK-138377.