Abstract
Background
Lynch syndrome (LS) is associated with germline mutations in one of the mismatch repair genes or EPCAM. The majority of the causative alterations are point mutations. Large genomic rearrangements represent only 5–20%. Hypothetically, the allelic imbalance, like the loss of heterozygosity, may be another high penetrance risk factor.
Case presentation
We describe the case of a patient who developed 5 tumors during her lifetime and with a family history characterized by a high frequency of tumors associated with LS. The proband was tested for mutations and copy number alterations with a panel of hereditary cancer genes and by SNP array. She showed a 187 Kb duplication including EPCAM and the first 7 exons of MSH2, plus two loss of heterozygosity (LOHs) in chromosome 20 and one in chromosome X which include many tumor suppressor genes.
Conclusion
We found a novel large EPCAM-MSH2 duplication associated with LS and the presence of LOHs in regions containing numerous tumor suppressors, raising the hypothesis that these alterations could contribute to cancer susceptibility. Our results underline the importance to deepen the knowledge of molecular mechanisms in order to determine the role in cancer predisposition of novel genetic alterations.
Similar content being viewed by others
Data availability
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
References
InSiGHT-Variant database https://www.insight-group.org/variants/databases/ (archived on 3 May 2017)
Therkildsen C, Jönsson G, Dominguez-Valentin M et al (2013) Gain of chromosomal region 20q and loss of 18 discriminates between Lynch syndrome and familial colorectal cancer. Eur J Cancer 49:1226–1235. https://doi.org/10.1016/j.ejca.2012.11.011
Vasen HF, Watson P, Mecklin JP, Lynch HT (1999) New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology 116:1453–1456
Umar A, Richard Boland C, Terdiman JP et al (2004) Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer 18:261–268
Cancer T, Atlas G (2012) Comprehensive molecular characterization of human colon and rectal cancer. Nature 487:330–337. https://doi.org/10.1038/nature11252
Peng Z, Zhou C, Zhang F, Ling Y, Tang H, Bai S, Liu W, Qiu GHL (2002) Loss of heterozygosity of chromosome 20 in sporadic colorectal cancer. Chin Med J 115(10):1529–1532
Flores-Rozas H, Clark D, Kolodner RD (2000) Proliferating cell nuclear antigen and Msh2p-Msh6p interact to form an active mispair recognition complex. Nat Genet 26:375
Genschel J, Kadyrova LY, Iyer RR, Dahal BK, Kadyrov FA, Modrich P (2017) Interaction of proliferating cell nuclear antigen with PMS2 is required for MutLα activation and function in mismatch repair. Proc Natl Acad Sci 114:4930–4935. https://doi.org/10.1073/pnas.1702561114
Akino K, Toyota M, Suzuki H, Mita H, Sasaki Y, Ohe-Toyota M, Issa JP, Hinoda Y, Imai K, Tokino T (2005) The ras effector RASSF2 is a novel tumor-suppressor gene in human colorectal cancer. Gastroenterology 129:156–169. https://doi.org/10.1053/j.gastro.2005.03.051
Zhang Y, Chen X, Qiao MIN et al (2014) Bone morphogenetic protein 2 inhibits the proliferation and growth of human colorectal cancer cells:1013–1020. https://doi.org/10.3892/or.2014.3308
Ye G, Sun G, Jiao P et al (2016) OVOL2, an inhibitor of WNT signaling, reduces invasive activities of human and mouse cancer cells and is down-regulated in human colorectal tumors. 2:659–671. https://doi.org/10.1053/j.gastro.2015.11.041
Schatoff EM, Leach BI, Dow LE (2018) HHS Public Access 13:101–110. https://doi.org/10.1007/s11888-017-0354-9.Wnt
Author information
Authors and Affiliations
Contributions
Conception and design of the study: P.F.; supervision: C.D. and M.G.; writing—original draft preparation: P.F.; writing—review and editing: T.G., U.P, and C.D.; collection and analysis of the clinical data,: D.R., R.M., and F.F.; controls collection: D.M. G.; immunohistochemical analysis: M.M.T.; immunohistochemical result interpretation: P.M.; NGS methodology: C. I., Z.V., and F. A.; NGS data analysis: T.M. and V.S.; SNP array analysis: T. C. and S.V. All authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Ethics approval and consent to participate
The study was performed in accordance with the principles of Good Clinical Practice and the ethical standards laid down in the Declaration of Helsinki and approved by the IRST Ethical Committee (CE IRST IRCCS-AVR, protocol 3030/2018)
Consent for publication
Written informed consent was obtained from participants of this case report.
Competing interest
The authors declare that they have no competing interest.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
ESM 1
(DOCX 20.8 kb)
Rights and permissions
About this article
Cite this article
Pirini, F., Tedaldi, G., Danesi, R. et al. Identification of a novel large EPCAM-MSH2 duplication, concurrently with LOHs in chromosome 20 and X, in a family with Lynch syndrome. Int J Colorectal Dis 34, 1999–2002 (2019). https://doi.org/10.1007/s00384-019-03414-y
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00384-019-03414-y