Lynch syndrome is a hereditary disease caused by mutations in DNA mismatch repair system (MMR), which includes ML1, MS2, MS6, PMS2, EPCAM genes. Clinical manifestation of the Lynch syndrome is usually colorectal cancer (CRC), endometrial cancer, ureteral cancer and kidney cancer. We aimed to analyze occurrence of mutations in MMR system genes in patients with hereditary breast and ovarian cancer.
We have analyzed 228 samples of blood from patients with hereditary breast (BC) and ovarian cancer (OC) in Tatarstan Regional Clinical Cancer Center, Russia. The criteria for inclusion was at least one out of three observations: Young age of manifestation of breast or ovarian cancer (before 50 y.o. for BC and 55 y.o. for OC), first or second-degree relatives with breast or ovarian cancer, primary-multiple BC and OC. The libraries for sequencing were prepared using NimblGen SepCapEZ Choice (Roche) with custom gene panel followed by sequencing on MiSeq platform.
Eight out of 101 (8%) patients with hereditary OC and five out of 127 (4%) patients with hereditary BC carried pathogenic mutation in one of MMR genes. Average age of manifestation of BC and OC in the patients with Lynch syndrome was 54 y.o. in case of OC and 56 y.o. in case of BC group: 50 y.o. Nine women had first and second-degree relatives with either BC, OC, colon or esophagus cancer. The distribution of affected genes in HBOC cohort was as follows: 3 patients with mutation in MSH6 gene, 4 patients with mutation in PMS2 gene, 2 patients with mutation in MSH2 gene, 3 patients with mutation in mlH1 gene. One patient carried mutation in EPCAM gene.
To date, the clinical standard for screening for Lynch syndrome is the Amsterdam criteria II, which are not oriented to the occurrence of OC and BC in patients, as well as to the presence of these cancers in a hereditary history in patients with colorectal cancer. However, our experience shows that patients with signs of hereditary OC and BC also can be carriers of mutations in the genes of the MMR system, which determine the Lynch syndrome. Thus, impact of Lynch syndrome-associated germline mutation on other types of cancer should be reconsidered and studied in detail.
Clinical trial identification
Legal entity responsible for the study
Tatarstan Cancer Center.
The work is supported by the Russian Foundation for Basic Research № 18-415-160009 r_a and according to the Russian Government Program of Competitive Growth of Kazan Federal University.
All authors have declared no conflicts of interest.