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08.04.2019 | Original Research | Ausgabe 1/2020

Journal of Gastrointestinal Cancer 1/2020

Whole Exome Sequencing Reveals a Novel Damaging Mutation in Human Fibroblast Activation Protein in a Family with Esophageal Squamous Cell Carcinoma

Journal of Gastrointestinal Cancer > Ausgabe 1/2020
Fatemeh Fardi Golyan, Morteza Moghaddassian, Mohammad Mahdi Forghanifard, Samaneh Talebi, Moein Farshchian, Reihaneh Alsadat Mahmoudian, Mohammad Reza Abbaszadegan
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Esophageal squamous cancer cell (ESCC), with late diagnosis and poor rate of survival, is a significant cause of mortality in the developing countries. The hypothesis of rare high penetrance with mutations in new genes may explain the underlying predisposition in some of these familial cases.


Exome sequencing was performed in the patients with ESCC with strong disease aggregation, two sisters with ESCC cancer, and one with breast cancer. Data analysis selected only very rare variants (0–0.1%) located in genes with a role compatible with cancer. In addition, the homology modeling of the novel mutation (A459D) discovered in FAP gene was performed by using the online Swiss-Prot server for automated modeling and the resulted structure has been modified and analyzed by using bioinformatics software to thoroughly study the structural deficiencies caused by the novel mutation.


Ten final candidate variants were selected and six genes validated by Sanger sequencing. Correct family segregation and somatic studies were used to categorize the most interesting variants in FAP, BOD1L, RAD51, Gasdermin D, LGR5, and CERS4. A novel, human mutation C1367A encoding Ala459 Asp (accession number: KT988039), occurring in the blade of the β propeller domain, was identified in two sisters with ESCC.


We identified novel mutations in three drug delivery genes, a tumor suppressor and also a stem cell marker of esophageal that may have a role in cancer treatment and are involved in cellular pathways, which supports their putative involvement in germ-line predisposition to this neoplasm.

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