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Germline PTPRT mutation potentially involved in cancer predisposition
  • +9
  • Lorena Martin,
  • Victor Lorca,
  • Pedro Pérez-Segura,
  • Patricia Llovet,
  • Vanesa García-Barberán,
  • Maria Luisa Gonzalez-Morales,
  • Sami Belhad,
  • Gabriel Capellá,
  • Laura Valle,
  • Miguel de la Hoya,
  • Pilar Garre,
  • Trinidad Caldes
Lorena Martin
Hospital Clinico San Carlos. IdISCC

Corresponding Author:[email protected]

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Victor Lorca
Hospital Clinico San Carlos. IdISSC
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Pedro Pérez-Segura
Hospital Clinico San Carlos. IdISSC
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Patricia Llovet
Hospital Clinico San Carlos. IdISCC
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Vanesa García-Barberán
Hospital Clínico San Carlos, IdISCC, CIBERONC
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Maria Luisa Gonzalez-Morales
Hospital Clinico San Carlos. IdISSC
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Sami Belhad
IDIBELL
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Gabriel Capellá
ICO-IDIBELL
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Laura Valle
IDIBELL
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Miguel de la Hoya
Hospital Clinico San Carlos. IdISSC
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Pilar Garre
Hospital clinico San Carlos. IdISSC
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Trinidad Caldes
Hospital Clinico San Carlos. IdISSC
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Abstract

Familial Colorectal Cancer Type X (FCCTX) is a term used to describe a group of families with an increased predisposition to colorectal and other related cancers, but an unknown genetic basis. Whole-exome sequencing in two cancer-affected and one healthy members of a FCCTX family revealed a truncating germline mutation in PTPRT [c.4090dup, p.(Asp1364GlyfsTer24)]. PTPRT encodes a receptor phosphatase and is a tumor suppressor gene found to be frequently mutated at somatic level in many cancers, having been proven that these mutations act as drivers that promote tumor development. This germline variant shows a compatible cosegregation with cancer in the family and results in the loss of a significant fraction of the second phosphatase domain of the protein, which is essential for PTPRT’s activity. In addition, the tumors of the carriers exhibit epigenetic inactivation of the wild-type allele and an altered expression of PTPRT downstream target genes, consistent with a causal role of this germline mutation in the cancer predisposition of the family. Although PTPRT’s role cancer initiation and progression has been well studied, this is the first time that a germline PTPRT mutation is linked with cancer susceptibility and hereditary cancer, which highlights the relevance of the present study.