Lynch syndrome with deletion of exons 15–19 in MLH1 gene in residents of the Kabardino-Balkarian Republic: founder mutation or familial case?

Aim
Lynch syndrome (LS) is one of the most common tumor syndromes, characterized by a high risk of developing colorectal cancer (CRC) and endometrial cancer (EC). The search of recurrent ethnospecific lesions in the LS genes is one of the crucial areas of genetic research that allows to optimize the molecular genetic diagnostics. However, in some situations the difference between a founder mutation and a familial case of LS may be not so clear. The aim of this report is to illustrate several important aspects of molecular epidemiology, organization of molecular diagnostics and patient selection criteria for molecular diagnostics of LS by using clinical observation.
Materials and methods
The study included 3 patients with CRC/EC and 7 of their cancer-free relatives of Kabardian origin. Tumor DNA was analyzed for microsatellite instability. Targeted sequencing was used to exclude micromutations in the LS genes. The searching for large genomic rearrangements was carried out using Multiplex Ligase-dependent Probe Amplification (MLPA).
Results
A 60-year-old female patient of Kabardian origin with colorectal cancer and a family history of CRC and EC was referred to the molecular oncology laboratory of the N.N. Petrov National Medical Research Center of Oncology. The tumor demonstrated microsatellite instability, and despite the relatively late age of onset for LS a blood sample was requested to exclude the LS. MLPA revealed a deletion of 5 exons of the MLH1 gene, MLH1ex15-19del. Independently of this patient, a 45-year-old patient of Kabardian origin with CRC and no family history of cancer was admitted for routine diagnostics – he also had microsatellite instability and the MLH1ex15-19del mutation. After collecting genealogical data, it turned out that the patients were distantly related to each other.
Conclusion
Careful collection of family history data is necessary to identify cases of hereditary tumor syndromes and interpret test results correctly.