Fatemeh Fardi Golyan1, Morteza Moghaddassian2, Mohammad Mahdi Forghanifard3, Samaneh Talebi1, Moein Farshchian4, Reihaneh Alsadat Mahmoudian1, Mohammad Reza Abbaszadegan5. 1. Immunology research center, Mashhad university of Medical Sciences, Mashhad, Iran. 2. Division of Human Genetics, Immunology Research Center, Avicenna Research Institute, Mashhad university of Medical Sciences, Mashhad, Iran. 3. Department of Biology, Damghan Branch, Islamic Azad University, Damghan, Iran. 4. Molecular Medicine Research Department, ACECR, Khorasan Razavi Branch, Mashhad, Iran. 5. Immunology research center, Mashhad university of Medical Sciences, Mashhad, Iran. Abbaszadeganmr@mums.ac.ir.
Abstract
PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
PURPOSE: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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Authors: Brenna Osborne; Tsun-Wen Yao; Xin Maggie Wang; Yiqian Chen; L Damla Kotan; Naveed A Nadvi; Mustafa Herdem; Geoffrey W McCaughan; John D Allen; Denise M T Yu; A Kemal Topaloglu; Mark D Gorrell Journal: Biochim Biophys Acta Date: 2014-04-06
Authors: Margit A Huber; Norbert Kraut; John E Park; Roland D Schubert; Wolfgang J Rettig; Ralf U Peter; Pilar Garin-Chesa Journal: J Invest Dermatol Date: 2003-02 Impact factor: 8.551
Authors: Martin R Higgs; John J Reynolds; Alicja Winczura; Andrew N Blackford; Valérie Borel; Edward S Miller; Anastasia Zlatanou; Jadwiga Nieminuszczy; Ellis L Ryan; Nicholas J Davies; Tatjana Stankovic; Simon J Boulton; Wojciech Niedzwiedz; Grant S Stewart Journal: Mol Cell Date: 2015-07-09 Impact factor: 17.970