Lynch syndrome as a manifestation of hereditary ovarian cancer: a case report of treatment of a patient with platinum-sensitive recurrent ovarian cancer

When we talk about hereditary ovarian cancer, we usually mean BRCA – associated cancer. Detection of hereditary ovarian cancer is important for the prevention of cancer in blood relatives of mutation carriers, and also makes it possible to use PARP inhibitors as maintenance therapy in BRCA – associated ovarian cancer.Due to the widespread introduction of modern molecular genetic technologies and the expansion of the diagnostic panel, mutations in genes other than BRCA 1/2 have begun to be detected in individuals with suspected hereditary ovarian cancer. Lynch’s syndrome is one of the most common and studied hereditary cancer syndromes. Interest in this syndrome in recent years is due to the emergence of the possibility of using checkpoint inhibitors – pembrolizumab and nivolumab for the treatment of colorectal cancer, stomach and endometrial cancer. To date, the definition of mutations in the genes of the MMR – system in ovarian cancer has not yet been applied in practice. Proband is a 69-year-old female with stage IIIC ovarian cancer at the time of diagnosis. The family history is burdened by 2 cases: lung cancer in the father and pancreatic cancer in the mother after the age of 60 years. Despite the advanced oncological process at the time of diagnosis, the start of combined treatment with 5 courses of neoadjuvant chemotherapy, incomplete cytoreduction, the patient’s overall survival during the follow-up period was 92 months. The clinical course of the disease was characterized as BRCA-associated ovarian cancer: long overall and relapse-free survival, long free-ofcharge interval with several relapses of more than 6 months; burdened family history; response to therapy with platinum and gemcitabine. However, when testing a patient with platinum-sensitive relapse by PCR, no mutations in the BRCA genes 1 and 2 were detected. To search for causal mutations, genetic testing was carried out using NGS technologies at the second stage. A germline mutation in the EPCAM gene involved in Lynch syndrome has been identified. 

1. Lynch H.T., Shaw M.W., Magnuson C.W., Larsen A.L., Krush A.J. Hereditary Factors in Cancer. Study of Two Large Midwestern Kindreds. Arch Intern Med. 1966;117(2):206–212.doi:10.1001/archinte.1966.03870080050009.

2. Lynch H.T., Lynch J.F., Lynch P.M., Attard T. Hereditary Colorectal Cancer Syndromes: Molecular Genetics, Genetic Counseling, Diagnosis and Management. Fam Cancer. 2008;7(1):27–39.doi: 10.1007/s10689-007-9165-5.

3. Hereditary Cancer Syndromes and Risk Assessment: ACOG COMMITTEE OPINION SUMMARY, Number 793. Obstet Gynecol. 2019;134(6):1366–1367. doi: 10.1097/AOG.0000000000003563.

4. Rahner N., Steinke V., Schlegelberger B., Olschwang S., Eisinger F., Hutter P. Clinical Utility Gene Card for: LYNCH Syndrome (MLH1, MSH2, MSH6, PMS2). Eur J Hum Genet. 2010;18(9). doi: 10.1038/ejhg.2009.232.

5. Bolton K.L., Ganda C., Berchuck A., Pharaoh P.D., Gayther S.A. Role of Common Genetic Variants in Ovarian Cancer Susceptibility and Outcome: Progress to Date from the Ovarian Cancer Association Consortium (OCAC). J Intern Med. 2012;271(4):366–78. doi: 10.1111/j.1365-2796.2011.02509.x.

6. Sankila R., Aaltonen L.A., Järvinen H.J., Mecklin J.P. Better Survival Rates in Patients with MLH1-Associated Hereditary Colorectal Cancer. Gastroenterology. 1996;110(3):682–687. doi: 10.1053/gast.1996.v110. pm8608876.

7. Varga D., Deniz M., Schwentner L., Wiesmüller L. Ovarian Cancer: in Search of Better Marker Systems Based on DNA Repair Defects. Int J Mol Sci. 2013;14(1):640–673. doi: 10.3390/ijms14010640.

8. Singh S., Resnick K.E. Lynch Syndrome and Endometrial Cancer. South Med J. 2017;110(4):265–269. doi: 10.14423/SMJ.0000000000000633.

9. Tanakaya K. Current Clinical Topics of Lynch Syndrome. Int J Clin Oncol. 2019;24(9):1013–1019. doi: 10.1007/s10147-018-1282-7 .

10. Keller L., Werner S., Pantel K. Biology and Clinical Relevance of EpCAM. Cell Stress. 2019;3(6):165–180. doi: 10.15698/cst2019.06.188.

11. Kempers M.J., Kuiper R.P., Ockeloen C.W., Chappuis P.O., Hutter P., Rahner N. et al. Risk of Colorectal and Endometrial Cancers in EPCAM DeletionPositive Lynch Syndrome: A Cohort Study. Lancet Oncol. 2011;12(1):49–55. doi: 10.1016/S1470-2045(10)70265-5.

12. Pathak S.J., Mueller J.L., Okamoto K., Das B., Hertecant J., Greenhalgh L. et al. EPCAM Mutation Update: Variants Associated with Congenital Tufting Enteropathy and Lynch Syndrome. Hum Mutat. 2019;40(2):142–161. doi: 10.1002/humu.23688.

13. Tutlewska K., Lubinski J., Kurzawski G. Germline Deletions in the EPCAM Gene as a Cause of Lynch Syndrome –Literature Review. Hered Cancer Clin Pract. 2013;11(1):9. doi: 10.1186/1897-4287-11-9.