PhD Scientific Days 2026

Molecular Medicine 2.

Integrating germline and somatic testing in complex colorectal cancer predisposition

Name of the presenter

Horti-Oravecz, Klaudia

Institute/workplace of the presenter

National Institute of Oncology

Authors

Klaudia Horti-Oravecz^1,2,3,4,5, Anikó Bozsik^1,5,6, János Papp^1,5,6, Lőrinc Sándor Pongor^6,7, Erzsébet Csernák⁸, Tamás Strausz⁸, Erika Tóth^5,8, Henriett Butz^1,4,5,6,9, Attila Patócs^1,5,6,9, Vince Kornél Grolmusz^1,2,5,6
1: Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary
2: Lendület "Momentum" Hereditary Cancers Systems Biology Research Group, Hungarian Academy of Sciences - National Institute of Oncology, Budapest, Hungary
3: Doctoral College, Semmelweis University, Budapest, Hungary
4: Department of Oncology Biobank, National Institute of Oncology, Budapest, Hungary
5: National Tumorbiology Laboratory, National Institute of Oncology, Budapest, Hungary
6: HUN-REN-NIO-TTK-HCEMM Oncogenomics Research Group, Budapest, Hungary
7: Cancer Genomics and Epigenetics Core Group, Hungarian Center of Excellence for Molecular Medicine, Szeged, Hungary
8: Department of Surgical and Molecular Pathology, National Institute of Oncology, Budapest, Hungary
9: Department of Laboratory Medicine, Semmelweis University, Budapest, Hungary

Text of the abstract

Introduction
Hereditary colorectal cancer predisposition syndromes (HCPSs) are typically caused by a single pathogenic germline variant. Clinically challenging situations arise when patients harbor multiple variants independently influencing colorectal cancer (CRC) risk. This complexity confounds clinical interpretation and patient management. In such cases, mutational signature analysis may help to identify the dominant tumorigenic mechanism.
Aims
We aimed to assess how integrated germline and somatic analyses can resolve complex tumorigenic mechanisms in CRC patients with multiple germline pathogenic variants.
Method
Between September 2021 and March 2025, 364 CRC patients underwent multigene panel testing for HCPSs. Five individuals were identified with two pathogenic variants in CRC-associated genes. Variants were classified according to ACMG/AMP criteria. Functional validation included nonsense-mediated decay (NMD) inhibition at cDNA level. Somatic analyses comprised microsatellite instability (MSI), elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) testing and mutational signature profiling using large targeted sequencing panels.
Results
Distinct tumorigenic mechanisms were identified both between and within patients.
In two patients harboring germline APC and PMS2 pathogenic variants, tumor profiling revealed divergent pathways. In one case, a polyposis-associated CRC was followed by a rectal tumor with mismatch repair deficiency and an PMS2-deficiency-related SBS26 signature. In the other patient, only the second tumor showed MSI-high status with an SBS44 signature without macroscopic polyposis. A patient with biallelic MSH3 variants developed EMAST-positive, MSI-negative colorectal and endometrial tumors, supporting a non-classical mismatch repair deficiency mechanism. In additional cases, interpretation was limited by unavailable tumor material, including a patient with MSH6 and PMS2 variants and another with a homozygous NTHL1 variant.
Conclusion
Integrated germline and somatic profiling clarifies dominant tumorigenic mechanisms in complex HCPS cases and may support clinically relevant decision-making.
Funding
Supported by the Lendület–Momentum Grant (LP2025-21/2025), the National Research, Development and Innovation Office under grant NKFIH-FK-138377, and the HUN-REN Research Group Grant.