Lynch Syndrome-associated Genomic Variants
Robert Botea1, Madalina Piron-Dumitrascu1, Tiberiu Augustin Georgescu2
1Dept. of Obstetrics and Gynecology, Carol Davila University of Medicine and Pharmacy, Bucharest; Dept. of Obstetrics and Gynecology, Alessandrescu-Rusescu National Institute of Mother and Child Health, Bucharest, Romania.
Journal of Gastrointestinal and Liver Diseases : JGLD
|September 10, 2024
Summary
Lynch syndrome-associated endometrial cancers share genomic alterations with colorectal cancers, particularly in mismatch repair genes. Novel mutations in PIK3CA, PTEN, FBN1, and SPARC suggest new therapeutic targets for these hereditary cancers.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Lynch syndrome, a hereditary cancer predisposition, involves germline mutations in DNA mismatch repair (MMR) genes.
- While linked to colorectal cancer, its role in endometrial cancer and specific genomic drivers are not fully understood.
- Understanding these drivers is crucial for targeted therapies in Lynch syndrome-associated cancers.
Purpose of the Study:
- To comparatively analyze germline and somatic mutations in Lynch syndrome-associated endometrial cancer.
- To identify shared and unique genomic alterations with colorectal cancer.
- To elucidate the molecular pathways driving endometrial tumorigenesis in Lynch syndrome.
Main Methods:
- Whole exome sequencing of matched germline and tumor DNA from 13 patients.
- Bioinformatics analysis to identify and annotate pathogenic variants.
- Focus on mutations relevant to both endometrial and colorectal cancer.
Main Results:
- Identified 1,118 germline and 14,051 somatic variants, with 493 common.
- Confirmed pathogenic mutations in MMR genes (MLH1, MSH2, MSH6).
- Discovered frequent somatic mutations in PIK3CA and PTEN, implicating the PI3K/AKT/mTOR pathway, and novel mutations in FBN1 and SPARC.
Conclusions:
- Lynch syndrome-associated endometrial cancer shares oncogenic pathways with colorectal cancer.
- Specific genetic mutations offer potential therapeutic targets.
- Findings support developing combined treatment strategies for Lynch syndrome-associated malignancies.
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