Identification of a novel large EPCAM-MSH2 duplication, concurrently with LOHs in chromosome 20 and X, in a family with Lynch syndrome
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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.
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.
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.
KeywordsLynch syndrome Loss of heterozygosity EPCAM-MSH2 duplication Next-generation sequencing Multiple gene panel
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.
Compliance with ethical standards
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.
The authors declare that they have no competing interest.
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