title: Ovarian metastasis from uveal melanoma with MLH1/PMS2 protein loss in a patient with germline MLH1 mutated Lynch syndrome: consequence or coincidence?
abstract: Currently, uveal melanoma is not considered within the Lynch syndrome tumor spectrum. However, there are studies suggesting a contribution of microsatellite instability in sporadic uveal melanoma tumorigenesis. We report a 45-year-old woman who was referred for genetic counseling due to a family history of Lynch syndrome caused by a MLH1 mutation. She originally underwent enucleation of the right eye secondary to a uveal spindle cell melanoma diagnosed at age 25. The tumor recurred 22 years later presenting as an ovarian metastasis and concurrently a microscopic endometrial endometrioid carcinoma, grade 1/3 was diagnosed. Subsequent studies highlighted that the uveal melanoma showed high microsatellite instability and loss of MLH1 and PMS2 protein expression, with no MLH1 promoter methylation or BRAF mutation. Additionally, a GNAQ mutation was found. We conclude that our patient's uveal melanoma is most likely related to MLH1 germline mutation and thus Lynch syndrome related. To the best of our knowledge, this is the first report of uveal melanoma showing MLH1/PMS2 protein loss in the context of Lynch syndrome.
authors.affiliation: Department of Pathology, Portuguese Oncology Institute of Porto, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal.|Cancer Biology and Epigenetics Group, Research Center (CI-IPOP), Portuguese Oncology Institute of Porto, Porto, Portugal.|Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal.
authors.forename: João
authors.initials: J
authors.lastname: Lobo
authors.affiliation: Department of Genetics, Portuguese Oncology Institute of Porto, Porto, Portugal.
authors.forename: Carla
authors.initials: C
authors.lastname: Pinto
authors.affiliation: Cancer Biology and Epigenetics Group, Research Center (CI-IPOP), Portuguese Oncology Institute of Porto, Porto, Portugal.
authors.forename: Micaela
authors.initials: M
authors.lastname: Freitas
authors.affiliation: Department of Genetics, Portuguese Oncology Institute of Porto, Porto, Portugal.
authors.forename: Manuela
authors.initials: M
authors.lastname: Pinheiro
authors.affiliation: Department of Pathology, Centro Hospitalar do Porto, Porto, Portugal.
authors.forename: Rámon
authors.initials: R
authors.lastname: Vizcaino
authors.affiliation: James Homer Wright Pathology Laboratories, Massachusetts General Hospital, Boston, MA, USA.|Department of Pathology, Harvard Medical School, Boston, MA, USA.
authors.forename: Esther
authors.initials: E
authors.lastname: Oliva
authors.affiliation: Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal.|Department of Genetics, Portuguese Oncology Institute of Porto, Porto, Portugal.
authors.forename: Manuel R
authors.initials: MR
authors.lastname: Teixeira
authors.affiliation: Cancer Biology and Epigenetics Group, Research Center (CI-IPOP), Portuguese Oncology Institute of Porto, Porto, Portugal.|Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal.
authors.forename: Carmen
authors.initials: C
authors.lastname: Jerónimo
authors.affiliation: Department of Pathology, Portuguese Oncology Institute of Porto, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal. carlabartosch@med.up.pt.|Cancer Biology and Epigenetics Group, Research Center (CI-IPOP), Portuguese Oncology Institute of Porto, Porto, Portugal. carlabartosch@med.up.pt.|Department of Pathology and Oncology, Medical Faculty, University of Porto, Porto, Portugal. carlabartosch@med.up.pt.
authors.forename: Carla
authors.identifier: http://orcid.org/0000-0003-0646-7667
authors.initials: C
authors.lastname: Bartosch
mesh_terms: D000328:Adult; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics / Q000473:pathology*; D005260:Female; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000556:secondary*; D008875:Middle Aged; D000070976:Mismatch Repair Endonuclease PMS2 / Q000235:genetics*; D000070957:MutL Protein Homolog 1 / Q000235:genetics*; D009154:Mutation; D010051:Ovarian Neoplasms / Q000235:genetics / Q000556:secondary*; D014604:Uveal Neoplasms / Q000235:genetics / Q000556:secondary*; D000098943:Uveal Melanoma
chemical_list: C554061:GNAQ protein, human; C501486:MLH1 protein, human; C094934:PMS2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D043802:GTP-Binding Protein alpha Subunits, Gq-G11
keywords: GNAQ mutation; Lynch syndrome; MLH1 mutation; Ovary; Uveal melanoma