TY  - JOUR
AU  - Srivastava, Aayushi
AU  - Kumar, Abhishek
AU  - Giangiobbe, Sara
AU  - Bonora, Elena
AU  - Hemminki, Kari
AU  - Försti, Asta
AU  - Bandapalli, Obul Reddy
TI  - Whole Genome Sequencing of Familial Non-Medullary Thyroid Cancer Identifies Germline Alterations in MAPK/ERK and PI3K/AKT Signaling Pathways.
JO  - Biomolecules
VL  - 9
IS  - 10
SN  - 2218-273X
CY  - Basel
PB  - MDPI
M1  - DKFZ-2019-02467
SP  - 605
PY  - 2019
N1  - 2019, 9(10), 605
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:31614935
DO  - DOI:10.3390/biom9100605
UR  - https://inrepo02.dkfz.de/record/147346
ER  -