Clinically actionable mutation profiles in patients with cancer identified by whole-genome sequencing. - PubMed - NCBI
Clinically actionable mutation profiles in patients with cancer identified by whole-genome sequencing.
Schuh A1,2,
Dreau H1,3,
Knight SJL2,4,
Ridout K2,3,
Mizani T1,2,
Vavoulis D2,3,
Colling R1,3,
Antoniou P5,
Kvikstad EM2,4,
Pentony MM2,4,
Hamblin A6,
Protheroe A7,
Parton M8,
Shah KA9,
Orosz Z8,9,
Athanasou N10,
Hassan B11,
Flanagan AM12,
Ahmed A13,
Winter S14,
Harris A15,
Tomlinson I4,
Popitsch N16,
Church D4,
Taylor JC2,4.
Abstract
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-free WGS of 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 of WGS to 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. KEYWORDS:
colon cancer; cutaneous leiomyosarcoma; endometrial carcinoma; neoplasm of the breast; pharyngeal neoplasm; prostate cancer
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