TY - JOUR
T1 - Clinically actionable mutation profiles in patients with cancer identified by whole-genome sequencing
AU - Schuh, Anna
AU - Dreau, Helene
AU - Knight, Samantha J.L.
AU - Ridout, Kate
AU - Mizani, Tuba
AU - Vavoulis, Dimitris
AU - Colling, Richard
AU - Antoniou, Pavlos
AU - Kvikstad, Erika M.
AU - Pentony, Melissa M.
AU - Hamblin, Angela
AU - Protheroe, Andrew
AU - Parton, Marina
AU - Shah, Ketan A.
AU - Orosz, Zsolt
AU - Athanasou, Nick
AU - Hassan, Bass
AU - Flanagan, Adrienne M.
AU - Ahmed, Ahmed
AU - Winter, Stuart
AU - Harris, Adrian
AU - Tomlinson, Ian
AU - Popitsch, Niko
AU - Church, David
AU - Taylor, Jenny C.
N1 - Publisher Copyright:
© 2018 Schuh et al.
PY - 2018/4
Y1 - 2018/4
N2 - Next-generation sequencing (NGS) efforts have established catalogs of mutations relevant to cancer development. However, the clinical utility of this information remains largely unexplored. Here, we present the results of the first eight patients recruited into a clinical whole-genome sequencing (WGS) program in the United Kingdom. We performed PCR-freeWGSof fresh frozen tumors and germline DNA at 75× and 30×, respectively, using the HiSeq2500 HTv4. Subtracted tumor VCFs and paired germlines were subjected to comprehensive analysis of coding and noncoding regions, integration of germline with somatically acquired variants, and global mutation signatures and pathway analyses. Results were classified into tiers and presented to a multidisciplinary tumor board. WGS results helped to clarify an uncertain histopathological diagnosis in one case, led to informed or supported prognosis in two cases, leading to de-escalation of therapy in one, and indicated potential treatments in all eight. Overall 26 different tier 1 potentially clinically actionable findings were identified using WGS compared with six SNVs/indels using routine targeted NGS. These initial results demonstrate the potential ofWGSto inform future diagnosis, prognosis, and treatment choice in cancer and justify the systematic evaluation of the clinical utility of WGS in larger cohorts of patients with cancer.
AB - Next-generation sequencing (NGS) efforts have established catalogs of mutations relevant to cancer development. However, the clinical utility of this information remains largely unexplored. Here, we present the results of the first eight patients recruited into a clinical whole-genome sequencing (WGS) program in the United Kingdom. We performed PCR-freeWGSof fresh frozen tumors and germline DNA at 75× and 30×, respectively, using the HiSeq2500 HTv4. Subtracted tumor VCFs and paired germlines were subjected to comprehensive analysis of coding and noncoding regions, integration of germline with somatically acquired variants, and global mutation signatures and pathway analyses. Results were classified into tiers and presented to a multidisciplinary tumor board. WGS results helped to clarify an uncertain histopathological diagnosis in one case, led to informed or supported prognosis in two cases, leading to de-escalation of therapy in one, and indicated potential treatments in all eight. Overall 26 different tier 1 potentially clinically actionable findings were identified using WGS compared with six SNVs/indels using routine targeted NGS. These initial results demonstrate the potential ofWGSto inform future diagnosis, prognosis, and treatment choice in cancer and justify the systematic evaluation of the clinical utility of WGS in larger cohorts of patients with cancer.
UR - http://www.scopus.com/inward/record.url?scp=85061388510&partnerID=8YFLogxK
U2 - 10.1101/mcs.a002279
DO - 10.1101/mcs.a002279
M3 - Article
C2 - 29610388
AN - SCOPUS:85061388510
SN - 2373-2873
VL - 4
JO - Cold Spring Harbor molecular case studies
JF - Cold Spring Harbor molecular case studies
IS - 2
M1 - a002279
ER -
