Pilot study of gene mutations associated with Lynch syndrome in Slovak patients with breast cancer

Czech version

Authors: L. Krasničanová ¹; R. Saade ¹; Petra Priščáková ¹; H. Gbelcová ¹; K. Kaľavská ²; M. Karaba ³; J. Benca ^3,4; M. Mego ^2,5; Vanda Repiská ¹
Authors‘ workplace: Ústav lekárskej bio lógie, genetiky a klinickej genetiky Lekárskej fakulty Univerzity Komenského a Univerzitnej nemocnice Bratislava, Slovenská republika ¹; Jednotka translačného výskumu, Lekárska fakulta Univerzity Komenského a Národný onkologický ústav, Bratislava, Slovenská republika ²; Klinika chirurgickej onkológie, Národný onkologický ústav, Bratislava, Slovenská republika ³; Vysoká škola zdravotníctva a sociálnej práce sv. Alžbety, n. o., Bratislava, Slovenská republika ⁴; II. onkologická klinika, Lekárska fakulta Univerzity Komenského, Národný onkologický ústav, Bratislava, Slovenská republika ⁵
Published in: Klin Onkol 2023; 36(2): 130-134
Category: Original Articles
doi: https://doi.org/10.48095/ccko2023130

Overview

Background: Lynch syndrome (LS) is an autosomal dominant inherited disorder which causes an increased risk of cancer, especially colorectal and endometrial carcinomas. Recent studies have shown an association between LS and breast cancer as well. The aim of our study is to highlight the possible presence of mutations in genes associated with LS in patients with breast cancer and the need to include the examination of Lynch-associated genes in patients with a family history of breast cancer as well as in patients with recurrent breast cancer, as well as with the occurrence of other Lynch-associated cancer. Materials and methods: We analyzed tumor tissue samples from 78 patients with primary breast cancer. Our samples were tested with a gene panel associated with the risk of developing breast cancer, while in our study we focused primarily on the occurrence of mutations in mismatch-repair genes. DNA isolated from tumor tissue was sequenced using next generation sequencing (NGS) and analyzed using the Ingenuity Variant Analysis tool. To confirm the germline mutation, we examined the patient‘s blood sample using NGS sequencing. Results: As a result of our analysis, we managed to identify a mutation in the PMS2 gene in one patient‘s breast tumor tissue. The presence of this mutation indicates that the resulting cancer may be a consequence of LS. As for pathogenicity, this was probably a pathogenic variant, as we detected deletions in the exon region, which led to frameshift mutation. Moreover, we also identified single-nucleotide pathogenic variants in the TP53 and PIK3CA genes. To definitively establish the diagnosis of LS in the patient, we examined a blood sample, where we also identified a mutation of the PMS2 gene. Conclusion: LS is underdiagnosed in many Lynch-associated cancers. However, in the case of a familial occurrence of breast cancer and other Lynch-associated genes, it is important to think about a possible diagnosis of LS and, if the patient meets the diagnostic criteria, to carry out a genetic examination of Lynch-associated genes.

Keywords:

breast cancer – Lynch syndrome – MMR genes – MLH1 – MSH2 – MSH6 – PMS2

Sources

1. Dušek M, Hadravský L, Černá K et al. Diagnóza Lynchova syndromu od patologa. Klin Onkol 2016; 29 (3): 180–186. doi: 10.14735/amko2016180.

2. Vogelsang M. DNA alterations in Lynch syndrome. Dordrecht: Springer 2013.

3. Bonadona V, Bonaïti B, Olschwang S et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA 2011; 305 (22): 2304–2310. doi: 10.1001/jama.2011.743.

4. Roberts ME, Jackson SA, Susswein LR et al. MSH6 and PMS2 germ-line pathogenic variants implicated in Lynch syndrome are associated with breast cancer. Genet Med 2018; 20 (10): 1167–1174. doi: 10.1038/gim.2017.254.

5. Schwartz C, Da Silva EM, Marra A et al. Morphologic and genomic characteristics of breast cancers occurring in individuals with Lynch syndrome. Clin Cancer Res 2022; 28 (2): 404–413. doi: 10.1158/1078-0432.CCR-21-2027.

6. Sheehan M, Heald B, Yanda C et al. Investigating the link between Lynch syndrome and breast cancer. Eur J Breast Health 2020; 16 (2): 106–109. doi: 10.5152/ejbh.2020.5198.

7. Sung H, Ferlay J, Siegel RL et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021; 71 (3): 209–249. doi: 10.3322/caac.21660.

8. Nikitin AG, Chudakova DA, Enikeev RF et al. Lynch syndrome germline mutations in breast cancer: next generation sequencing case-control study of 1,263 participants. Front Oncol 2020; 10: 666. doi: 10.3389/fonc.2020.00 666.

9. Mego M, Karaba M, Sedlackova T et al. Circulating tumor cells and breast cancer-specific mutations in primary breast cancer. Mol Clin Oncol 2020; 12 (6): 565–573. doi: 10.3892/mco.2020.2026.

10. Lawrence MS, Stojanov P, Mermel CH et al. Discovery and saturation analysis of cancer genes across 21 tumor types. Nature 2014; 505 (7484): 495–501. doi: 10.1038/nature12912.

11. Duraturo F, Liccardo R, De Rosa M et al. Genetics, diagnosis and treatment of Lynch syndrome: old lessons and current challenges. Oncol Lett 2019; 17 (3): 3048–3054. doi: 10.3892/ol.2019.9945.

12. Strafford JC. Genetic testing for Lynch syndrome, an inherited cancer of the bowel, endometrium, and ovary. Rev Obstet Gynecol 2012; 5 (1): 42–49.

13. Ramsoekh D, Wagner A, van Leerdam ME et al. Cancer risk in MLH1, MSH2 and MSH6 mutation carriers; different risk profiles may influence clinical management. Hered Cancer Clin Pract 2009; 7 (1): 17. doi: 10.1186/1897-4287-7-17.

14. Evaluation of Genomic Applications in Practice and Prevention Working Group. Recommendations from the EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives. Genet Med 2009; 11 (1): 35–41. doi: 10.1097/GIM.0b013e31818fa2ff.