A pilot study of ultra-deep targeted sequencing of plasma DNA identifies driver mutations in hepatocellular carcinoma
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A pilot study of ultra-deep targeted sequencing of plasma DNA identifies driver mutations in hepatocellular carcinoma. / Labgaa, Ismail; Villacorta-Martin, Carlos; D'Avola, Delia; Craig, Amanda J; von Felden, Johann; Martins-Filho, Sebastiao N; Sia, Daniela; Stueck, Ashley; Ward, Stephen C; Fiel, M Isabel; Mahajan, Milind; Tabrizian, Parissa; Thung, Swan N; Ang, Celina; Friedman, Scott L; Llovet, Josep M; Schwartz, Myron; Villanueva, Augusto.
In: ONCOGENE, Vol. 37, No. 27, 07.2018, p. 3740-3752.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - A pilot study of ultra-deep targeted sequencing of plasma DNA identifies driver mutations in hepatocellular carcinoma
AU - Labgaa, Ismail
AU - Villacorta-Martin, Carlos
AU - D'Avola, Delia
AU - Craig, Amanda J
AU - von Felden, Johann
AU - Martins-Filho, Sebastiao N
AU - Sia, Daniela
AU - Stueck, Ashley
AU - Ward, Stephen C
AU - Fiel, M Isabel
AU - Mahajan, Milind
AU - Tabrizian, Parissa
AU - Thung, Swan N
AU - Ang, Celina
AU - Friedman, Scott L
AU - Llovet, Josep M
AU - Schwartz, Myron
AU - Villanueva, Augusto
PY - 2018/7
Y1 - 2018/7
N2 - Cellular components of solid tumors including DNA are released into the bloodstream, but data on circulating-free DNA (cfDNA) in hepatocellular carcinoma (HCC) are still scarce. This study aimed at analyzing mutations in cfDNA and their correlation with tissue mutations in patients with HCC. We included 8 HCC patients treated with surgical resection for whom we collected paired tissue and plasma/serum samples. We analyzed 45 specimens, including multiregional tumor tissue sampling (n = 24), peripheral blood mononuclear cells (PMBC, n = 8), plasma (n = 8) and serum (n = 5). Ultra-deep sequencing (5500× coverage) of all exons was performed in a targeted panel of 58 genes, including frequent HCC driver genes and druggable mutations. Mutations detected in plasma included known HCC oncogenes and tumor suppressors (e.g., TERT promoter, TP53, and NTRK3) as well as a candidate druggable mutation (JAK1). This approach increased the detection rates previously reported for mutations in plasma of HCC patients. A thorough characterization of cis mutations found in plasma confirmed their tumoral origin, which provides definitive evidence of the release of HCC-derived DNA fragments into the bloodstream. This study demonstrates that ultra-deep sequencing of cfDNA is feasible and can confidently detect somatic mutations found in tissue; these data reinforce the role of plasma DNA as a promising minimally invasive tool to interrogate HCC genetics.
AB - Cellular components of solid tumors including DNA are released into the bloodstream, but data on circulating-free DNA (cfDNA) in hepatocellular carcinoma (HCC) are still scarce. This study aimed at analyzing mutations in cfDNA and their correlation with tissue mutations in patients with HCC. We included 8 HCC patients treated with surgical resection for whom we collected paired tissue and plasma/serum samples. We analyzed 45 specimens, including multiregional tumor tissue sampling (n = 24), peripheral blood mononuclear cells (PMBC, n = 8), plasma (n = 8) and serum (n = 5). Ultra-deep sequencing (5500× coverage) of all exons was performed in a targeted panel of 58 genes, including frequent HCC driver genes and druggable mutations. Mutations detected in plasma included known HCC oncogenes and tumor suppressors (e.g., TERT promoter, TP53, and NTRK3) as well as a candidate druggable mutation (JAK1). This approach increased the detection rates previously reported for mutations in plasma of HCC patients. A thorough characterization of cis mutations found in plasma confirmed their tumoral origin, which provides definitive evidence of the release of HCC-derived DNA fragments into the bloodstream. This study demonstrates that ultra-deep sequencing of cfDNA is feasible and can confidently detect somatic mutations found in tissue; these data reinforce the role of plasma DNA as a promising minimally invasive tool to interrogate HCC genetics.
KW - Journal Article
U2 - 10.1038/s41388-018-0206-3
DO - 10.1038/s41388-018-0206-3
M3 - SCORING: Journal article
C2 - 29628508
VL - 37
SP - 3740
EP - 3752
JO - ONCOGENE
JF - ONCOGENE
SN - 0950-9232
IS - 27
ER -