Cargando…
Interaction of germline variants in a family with a history of early‐onset clear cell renal cell carcinoma
BACKGROUND: Identification of genetic factors causing predisposition to renal cell carcinoma has helped improve screening, early detection, and patient survival. METHODS: We report the characterization of a proband with renal and thyroid cancers and a family history of renal and other cancers by who...
Autores principales: | , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6418363/ https://www.ncbi.nlm.nih.gov/pubmed/30680959 http://dx.doi.org/10.1002/mgg3.556 |
_version_ | 1783403724005179392 |
---|---|
author | Nicolas, Emmanuelle Demidova, Elena V. Iqbal, Waleed Serebriiskii, Ilya G. Vlasenkova, Ramilia Ghatalia, Pooja Zhou, Yan Rainey, Kim Forman, Andrea F. Dunbrack, Roland L. Golemis, Erica A. Hall, Michael J. Daly, Mary B. Arora, Sanjeevani |
author_facet | Nicolas, Emmanuelle Demidova, Elena V. Iqbal, Waleed Serebriiskii, Ilya G. Vlasenkova, Ramilia Ghatalia, Pooja Zhou, Yan Rainey, Kim Forman, Andrea F. Dunbrack, Roland L. Golemis, Erica A. Hall, Michael J. Daly, Mary B. Arora, Sanjeevani |
author_sort | Nicolas, Emmanuelle |
collection | PubMed |
description | BACKGROUND: Identification of genetic factors causing predisposition to renal cell carcinoma has helped improve screening, early detection, and patient survival. METHODS: We report the characterization of a proband with renal and thyroid cancers and a family history of renal and other cancers by whole‐exome sequencing (WES), coupled with WES analysis of germline DNA from additional affected and unaffected family members. RESULTS: This work identified multiple predicted protein‐damaging variants relevant to the pattern of inherited cancer risk. Among these, the proband and an affected brother each had a heterozygous Ala45Thr variant in SDHA, a component of the succinate dehydrogenase (SDH) complex. SDH defects are associated with mitochondrial disorders and risk for various cancers; immunochemical analysis indicated loss of SDHB protein expression in the patient’s tumor, compatible with SDH deficiency. Integrated analysis of public databases and structural predictions indicated that the two affected individuals also had additional variants in genes including TGFB2, TRAP1, PARP1, and EGF, each potentially relevant to cancer risk alone or in conjunction with the SDHA variant. In addition, allelic imbalances of PARP1 and TGFB2 were detected in the tumor of the proband. CONCLUSION: Together, these data suggest the possibility of risk associated with interaction of two or more variants. |
format | Online Article Text |
id | pubmed-6418363 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-64183632019-03-27 Interaction of germline variants in a family with a history of early‐onset clear cell renal cell carcinoma Nicolas, Emmanuelle Demidova, Elena V. Iqbal, Waleed Serebriiskii, Ilya G. Vlasenkova, Ramilia Ghatalia, Pooja Zhou, Yan Rainey, Kim Forman, Andrea F. Dunbrack, Roland L. Golemis, Erica A. Hall, Michael J. Daly, Mary B. Arora, Sanjeevani Mol Genet Genomic Med Original Articles BACKGROUND: Identification of genetic factors causing predisposition to renal cell carcinoma has helped improve screening, early detection, and patient survival. METHODS: We report the characterization of a proband with renal and thyroid cancers and a family history of renal and other cancers by whole‐exome sequencing (WES), coupled with WES analysis of germline DNA from additional affected and unaffected family members. RESULTS: This work identified multiple predicted protein‐damaging variants relevant to the pattern of inherited cancer risk. Among these, the proband and an affected brother each had a heterozygous Ala45Thr variant in SDHA, a component of the succinate dehydrogenase (SDH) complex. SDH defects are associated with mitochondrial disorders and risk for various cancers; immunochemical analysis indicated loss of SDHB protein expression in the patient’s tumor, compatible with SDH deficiency. Integrated analysis of public databases and structural predictions indicated that the two affected individuals also had additional variants in genes including TGFB2, TRAP1, PARP1, and EGF, each potentially relevant to cancer risk alone or in conjunction with the SDHA variant. In addition, allelic imbalances of PARP1 and TGFB2 were detected in the tumor of the proband. CONCLUSION: Together, these data suggest the possibility of risk associated with interaction of two or more variants. John Wiley and Sons Inc. 2019-01-24 /pmc/articles/PMC6418363/ /pubmed/30680959 http://dx.doi.org/10.1002/mgg3.556 Text en © 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Articles Nicolas, Emmanuelle Demidova, Elena V. Iqbal, Waleed Serebriiskii, Ilya G. Vlasenkova, Ramilia Ghatalia, Pooja Zhou, Yan Rainey, Kim Forman, Andrea F. Dunbrack, Roland L. Golemis, Erica A. Hall, Michael J. Daly, Mary B. Arora, Sanjeevani Interaction of germline variants in a family with a history of early‐onset clear cell renal cell carcinoma |
title | Interaction of germline variants in a family with a history of early‐onset clear cell renal cell carcinoma |
title_full | Interaction of germline variants in a family with a history of early‐onset clear cell renal cell carcinoma |
title_fullStr | Interaction of germline variants in a family with a history of early‐onset clear cell renal cell carcinoma |
title_full_unstemmed | Interaction of germline variants in a family with a history of early‐onset clear cell renal cell carcinoma |
title_short | Interaction of germline variants in a family with a history of early‐onset clear cell renal cell carcinoma |
title_sort | interaction of germline variants in a family with a history of early‐onset clear cell renal cell carcinoma |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6418363/ https://www.ncbi.nlm.nih.gov/pubmed/30680959 http://dx.doi.org/10.1002/mgg3.556 |
work_keys_str_mv | AT nicolasemmanuelle interactionofgermlinevariantsinafamilywithahistoryofearlyonsetclearcellrenalcellcarcinoma AT demidovaelenav interactionofgermlinevariantsinafamilywithahistoryofearlyonsetclearcellrenalcellcarcinoma AT iqbalwaleed interactionofgermlinevariantsinafamilywithahistoryofearlyonsetclearcellrenalcellcarcinoma AT serebriiskiiilyag interactionofgermlinevariantsinafamilywithahistoryofearlyonsetclearcellrenalcellcarcinoma AT vlasenkovaramilia interactionofgermlinevariantsinafamilywithahistoryofearlyonsetclearcellrenalcellcarcinoma AT ghataliapooja interactionofgermlinevariantsinafamilywithahistoryofearlyonsetclearcellrenalcellcarcinoma AT zhouyan interactionofgermlinevariantsinafamilywithahistoryofearlyonsetclearcellrenalcellcarcinoma AT raineykim interactionofgermlinevariantsinafamilywithahistoryofearlyonsetclearcellrenalcellcarcinoma AT formanandreaf interactionofgermlinevariantsinafamilywithahistoryofearlyonsetclearcellrenalcellcarcinoma AT dunbrackrolandl interactionofgermlinevariantsinafamilywithahistoryofearlyonsetclearcellrenalcellcarcinoma AT golemisericaa interactionofgermlinevariantsinafamilywithahistoryofearlyonsetclearcellrenalcellcarcinoma AT hallmichaelj interactionofgermlinevariantsinafamilywithahistoryofearlyonsetclearcellrenalcellcarcinoma AT dalymaryb interactionofgermlinevariantsinafamilywithahistoryofearlyonsetclearcellrenalcellcarcinoma AT arorasanjeevani interactionofgermlinevariantsinafamilywithahistoryofearlyonsetclearcellrenalcellcarcinoma |