Cargando…

Whole Genome Sequencing of Familial Non-Medullary Thyroid Cancer Identifies Germline Alterations in MAPK/ERK and PI3K/AKT Signaling Pathways

Evidence of familial inheritance in non-medullary thyroid cancer (NMTC) has accumulated over the last few decades. However, known variants account for a very small percentage of the genetic burden. Here, we focused on the identification of common pathways and networks enriched in NMTC families to be...

Descripción completa

Detalles Bibliográficos
Autores principales: Srivastava, Aayushi, Kumar, Abhishek, Giangiobbe, Sara, Bonora, Elena, Hemminki, Kari, Försti, Asta, Bandapalli, Obul Reddy
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6843654/
https://www.ncbi.nlm.nih.gov/pubmed/31614935
http://dx.doi.org/10.3390/biom9100605
_version_ 1783468267037261824
author Srivastava, Aayushi
Kumar, Abhishek
Giangiobbe, Sara
Bonora, Elena
Hemminki, Kari
Försti, Asta
Bandapalli, Obul Reddy
author_facet Srivastava, Aayushi
Kumar, Abhishek
Giangiobbe, Sara
Bonora, Elena
Hemminki, Kari
Försti, Asta
Bandapalli, Obul Reddy
author_sort Srivastava, Aayushi
collection PubMed
description Evidence of familial inheritance in non-medullary thyroid cancer (NMTC) has accumulated over the last few decades. However, known variants account for a very small percentage of the genetic burden. Here, we focused on the identification of common pathways and networks enriched in NMTC families to better understand its pathogenesis with the final aim of identifying one novel high/moderate-penetrance germline predisposition variant segregating with the disease in each studied family. We performed whole genome sequencing on 23 affected and 3 unaffected family members from five NMTC-prone families and prioritized the identified variants using our Familial Cancer Variant Prioritization Pipeline (FCVPPv2). In total, 31 coding variants and 39 variants located in upstream, downstream, 5′ or 3′ untranslated regions passed FCVPPv2 filtering. Altogether, 210 genes affected by variants that passed the first three steps of the FCVPPv2 were analyzed using Ingenuity Pathway Analysis software. These genes were enriched in tumorigenic signaling pathways mediated by receptor tyrosine kinases and G-protein coupled receptors, implicating a central role of PI3K/AKT and MAPK/ERK signaling in familial NMTC. Our approach can facilitate the identification and functional validation of causal variants in each family as well as the screening and genetic counseling of other individuals at risk of developing NMTC.
format Online
Article
Text
id pubmed-6843654
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-68436542019-11-25 Whole Genome Sequencing of Familial Non-Medullary Thyroid Cancer Identifies Germline Alterations in MAPK/ERK and PI3K/AKT Signaling Pathways Srivastava, Aayushi Kumar, Abhishek Giangiobbe, Sara Bonora, Elena Hemminki, Kari Försti, Asta Bandapalli, Obul Reddy Biomolecules Article Evidence of familial inheritance in non-medullary thyroid cancer (NMTC) has accumulated over the last few decades. However, known variants account for a very small percentage of the genetic burden. Here, we focused on the identification of common pathways and networks enriched in NMTC families to better understand its pathogenesis with the final aim of identifying one novel high/moderate-penetrance germline predisposition variant segregating with the disease in each studied family. We performed whole genome sequencing on 23 affected and 3 unaffected family members from five NMTC-prone families and prioritized the identified variants using our Familial Cancer Variant Prioritization Pipeline (FCVPPv2). In total, 31 coding variants and 39 variants located in upstream, downstream, 5′ or 3′ untranslated regions passed FCVPPv2 filtering. Altogether, 210 genes affected by variants that passed the first three steps of the FCVPPv2 were analyzed using Ingenuity Pathway Analysis software. These genes were enriched in tumorigenic signaling pathways mediated by receptor tyrosine kinases and G-protein coupled receptors, implicating a central role of PI3K/AKT and MAPK/ERK signaling in familial NMTC. Our approach can facilitate the identification and functional validation of causal variants in each family as well as the screening and genetic counseling of other individuals at risk of developing NMTC. MDPI 2019-10-13 /pmc/articles/PMC6843654/ /pubmed/31614935 http://dx.doi.org/10.3390/biom9100605 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Srivastava, Aayushi
Kumar, Abhishek
Giangiobbe, Sara
Bonora, Elena
Hemminki, Kari
Försti, Asta
Bandapalli, Obul Reddy
Whole Genome Sequencing of Familial Non-Medullary Thyroid Cancer Identifies Germline Alterations in MAPK/ERK and PI3K/AKT Signaling Pathways
title Whole Genome Sequencing of Familial Non-Medullary Thyroid Cancer Identifies Germline Alterations in MAPK/ERK and PI3K/AKT Signaling Pathways
title_full Whole Genome Sequencing of Familial Non-Medullary Thyroid Cancer Identifies Germline Alterations in MAPK/ERK and PI3K/AKT Signaling Pathways
title_fullStr Whole Genome Sequencing of Familial Non-Medullary Thyroid Cancer Identifies Germline Alterations in MAPK/ERK and PI3K/AKT Signaling Pathways
title_full_unstemmed Whole Genome Sequencing of Familial Non-Medullary Thyroid Cancer Identifies Germline Alterations in MAPK/ERK and PI3K/AKT Signaling Pathways
title_short Whole Genome Sequencing of Familial Non-Medullary Thyroid Cancer Identifies Germline Alterations in MAPK/ERK and PI3K/AKT Signaling Pathways
title_sort whole genome sequencing of familial non-medullary thyroid cancer identifies germline alterations in mapk/erk and pi3k/akt signaling pathways
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6843654/
https://www.ncbi.nlm.nih.gov/pubmed/31614935
http://dx.doi.org/10.3390/biom9100605
work_keys_str_mv AT srivastavaaayushi wholegenomesequencingoffamilialnonmedullarythyroidcanceridentifiesgermlinealterationsinmapkerkandpi3kaktsignalingpathways
AT kumarabhishek wholegenomesequencingoffamilialnonmedullarythyroidcanceridentifiesgermlinealterationsinmapkerkandpi3kaktsignalingpathways
AT giangiobbesara wholegenomesequencingoffamilialnonmedullarythyroidcanceridentifiesgermlinealterationsinmapkerkandpi3kaktsignalingpathways
AT bonoraelena wholegenomesequencingoffamilialnonmedullarythyroidcanceridentifiesgermlinealterationsinmapkerkandpi3kaktsignalingpathways
AT hemminkikari wholegenomesequencingoffamilialnonmedullarythyroidcanceridentifiesgermlinealterationsinmapkerkandpi3kaktsignalingpathways
AT forstiasta wholegenomesequencingoffamilialnonmedullarythyroidcanceridentifiesgermlinealterationsinmapkerkandpi3kaktsignalingpathways
AT bandapalliobulreddy wholegenomesequencingoffamilialnonmedullarythyroidcanceridentifiesgermlinealterationsinmapkerkandpi3kaktsignalingpathways