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Pitfalls of exome sequencing: a case study of the attribution of HABP2 rs7080536 in familial non-medullary thyroid cancer

Next-generation sequencing using exome capture is a common approach used for analysis of familial cancer syndromes. Despite the development of robust computational algorithms, the accrued experience of analyzing exome data sets and published guidelines, the analytical process remains an ad hoc serie...

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Autores principales: Gerhard, Glenn S., Bann, Darrin V., Broach, James, Goldenberg, David
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5584869/
https://www.ncbi.nlm.nih.gov/pubmed/28884020
http://dx.doi.org/10.1038/s41525-017-0011-x
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author Gerhard, Glenn S.
Bann, Darrin V.
Broach, James
Goldenberg, David
author_facet Gerhard, Glenn S.
Bann, Darrin V.
Broach, James
Goldenberg, David
author_sort Gerhard, Glenn S.
collection PubMed
description Next-generation sequencing using exome capture is a common approach used for analysis of familial cancer syndromes. Despite the development of robust computational algorithms, the accrued experience of analyzing exome data sets and published guidelines, the analytical process remains an ad hoc series of important decisions and interpretations that require significant oversight. Processes and tools used for sequence data generation have matured and are standardized to a significant degree. For the remainder of the analytical pipeline, however, the results can be highly dependent on the choices made and careful review of results. We used primary exome sequence data, generously provided by the corresponding author, from a family with highly penetrant familial non-medullary thyroid cancer reported to be caused by HABP2 rs7080536 to review the importance of several key steps in the application of exome sequencing for discovery of new familial cancer genes. Differences in allele frequencies across populations, probabilities of familial segregation, functional impact predictions, corroborating biological support, and inconsistent replication studies can play major roles in influencing interpretation of results. In the case of HABP2 rs7080536 and familial non-medullary thyroid cancer, these factors led to the conclusion of an association that most data and our re-analysis fail to support, although larger studies from diverse populations will be needed to definitively determine its role.
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spelling pubmed-55848692017-09-05 Pitfalls of exome sequencing: a case study of the attribution of HABP2 rs7080536 in familial non-medullary thyroid cancer Gerhard, Glenn S. Bann, Darrin V. Broach, James Goldenberg, David NPJ Genom Med Perspective Next-generation sequencing using exome capture is a common approach used for analysis of familial cancer syndromes. Despite the development of robust computational algorithms, the accrued experience of analyzing exome data sets and published guidelines, the analytical process remains an ad hoc series of important decisions and interpretations that require significant oversight. Processes and tools used for sequence data generation have matured and are standardized to a significant degree. For the remainder of the analytical pipeline, however, the results can be highly dependent on the choices made and careful review of results. We used primary exome sequence data, generously provided by the corresponding author, from a family with highly penetrant familial non-medullary thyroid cancer reported to be caused by HABP2 rs7080536 to review the importance of several key steps in the application of exome sequencing for discovery of new familial cancer genes. Differences in allele frequencies across populations, probabilities of familial segregation, functional impact predictions, corroborating biological support, and inconsistent replication studies can play major roles in influencing interpretation of results. In the case of HABP2 rs7080536 and familial non-medullary thyroid cancer, these factors led to the conclusion of an association that most data and our re-analysis fail to support, although larger studies from diverse populations will be needed to definitively determine its role. Nature Publishing Group UK 2017-03-28 /pmc/articles/PMC5584869/ /pubmed/28884020 http://dx.doi.org/10.1038/s41525-017-0011-x Text en © The Author(s) 2017 This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Perspective
Gerhard, Glenn S.
Bann, Darrin V.
Broach, James
Goldenberg, David
Pitfalls of exome sequencing: a case study of the attribution of HABP2 rs7080536 in familial non-medullary thyroid cancer
title Pitfalls of exome sequencing: a case study of the attribution of HABP2 rs7080536 in familial non-medullary thyroid cancer
title_full Pitfalls of exome sequencing: a case study of the attribution of HABP2 rs7080536 in familial non-medullary thyroid cancer
title_fullStr Pitfalls of exome sequencing: a case study of the attribution of HABP2 rs7080536 in familial non-medullary thyroid cancer
title_full_unstemmed Pitfalls of exome sequencing: a case study of the attribution of HABP2 rs7080536 in familial non-medullary thyroid cancer
title_short Pitfalls of exome sequencing: a case study of the attribution of HABP2 rs7080536 in familial non-medullary thyroid cancer
title_sort pitfalls of exome sequencing: a case study of the attribution of habp2 rs7080536 in familial non-medullary thyroid cancer
topic Perspective
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5584869/
https://www.ncbi.nlm.nih.gov/pubmed/28884020
http://dx.doi.org/10.1038/s41525-017-0011-x
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