Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma

Adrian Ally; Miruna Balasundaram; Rebecca Carlsen; Eric Chuah; Amanda Clarke; Noreen Dhalla; Robert A. Holt; Steven J.M. Jones; Darlene Lee; Yussanne Ma; Marco A. Marra; Michael Mayo; Richard A. Moore; Andrew J. Mungall; Jacqueline E. Schein; Payal Sipahimalani; Angela Tam; Nina Thiessen; Dorothy Cheung; Tina Wong; Denise Brooks; A. Gordon Robertson; Reanne Bowlby; Karen Mungall; Sara Sadeghi; Liu Xi; Kyle Covington; Eve Shinbrot; David A. Wheeler; Richard A. Gibbs; Lawrence A. Donehower; Linghua Wang; Jay Bowen; Julie M. Gastier-Foster; Mark Gerken; Carmen Helsel; Kristen M. Leraas; Tara M. Lichtenberg; Nilsa C. Ramirez; Lisa Wise; Erik Zmuda; Stacey B. Gabriel; Matthew Meyerson; Carrie Cibulskis; Bradley A. Murray; Juliann Shih; Rameen Beroukhim; Andrew D. Cherniack; Steven E. Schumacher; Nasra H. Giama; The Cancer Genome Atlas Research Network

doi:10.1016/j.cell.2017.05.046

Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma

Adrian Ally, Miruna Balasundaram, Rebecca Carlsen, Eric Chuah, Amanda Clarke, Noreen Dhalla, Robert A. Holt, Steven J.M. Jones, Darlene Lee, Yussanne Ma, Marco A. Marra, Michael Mayo, Richard A. Moore, Andrew J. Mungall, Jacqueline E. Schein, Payal Sipahimalani, Angela Tam, Nina Thiessen, Dorothy Cheung, Tina WongDenise Brooks, A. Gordon Robertson, Reanne Bowlby, Karen Mungall, Sara Sadeghi, Liu Xi, Kyle Covington, Eve Shinbrot, David A. Wheeler, Richard A. Gibbs, Lawrence A. Donehower, Linghua Wang, Jay Bowen, Julie M. Gastier-Foster, Mark Gerken, Carmen Helsel, Kristen M. Leraas, Tara M. Lichtenberg, Nilsa C. Ramirez, Lisa Wise, Erik Zmuda, Stacey B. Gabriel, Matthew Meyerson, Carrie Cibulskis, Bradley A. Murray, Juliann Shih, Rameen Beroukhim, Andrew D. Cherniack, Steven E. Schumacher, Nasra H. Giama, The Cancer Genome Atlas Research Network

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Abstract

Liver cancer has the second highest worldwide cancer mortality rate and has limited therapeutic options. We analyzed 363 hepatocellular carcinoma (HCC) cases by whole-exome sequencing and DNA copy number analyses, and we analyzed 196 HCC cases by DNA methylation, RNA, miRNA, and proteomic expression also. DNA sequencing and mutation analysis identified significantly mutated genes, including LZTR1, EEF1A1, SF3B1, and SMARCA4. Significant alterations by mutation or downregulation by hypermethylation in genes likely to result in HCC metabolic reprogramming (ALB, APOB, and CPS1) were observed. Integrative molecular HCC subtyping incorporating unsupervised clustering of five data platforms identified three subtypes, one of which was associated with poorer prognosis in three HCC cohorts. Integrated analyses enabled development of a p53 target gene expression signature correlating with poor survival. Potential therapeutic targets for which inhibitors exist include WNT signaling, MDM4, MET, VEGFA, MCL1, IDH1, TERT, and immune checkpoint proteins CTLA-4, PD-1, and PD-L1.

Original language	English (US)
Pages (from-to)	1327-1341.e23
Journal	Cell
Volume	169
Issue number	7
DOIs	https://doi.org/10.1016/j.cell.2017.05.046
State	Published - Jun 15 2017

Bibliographical note

Publisher Copyright:
© 2017 Elsevier Inc.

Keywords

IDH1/2
TP53
cancer subtyping
expression profile
hepatocellular carcinoma
metabolic reprogramming
promoter hypermethylation
significantly mutated genes
sonic hedgehog signaling
stem cell phenotype

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cell.2017.05.046

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5680778

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Ally, A., Balasundaram, M., Carlsen, R., Chuah, E., Clarke, A., Dhalla, N., Holt, R. A., Jones, S. J. M., Lee, D., Ma, Y., Marra, M. A., Mayo, M., Moore, R. A., Mungall, A. J., Schein, J. E., Sipahimalani, P., Tam, A., Thiessen, N., Cheung, D., ... The Cancer Genome Atlas Research Network (2017). Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma. Cell, 169(7), 1327-1341.e23. https://doi.org/10.1016/j.cell.2017.05.046

Ally, A, Balasundaram, M, Carlsen, R, Chuah, E, Clarke, A, Dhalla, N, Holt, RA, Jones, SJM, Lee, D, Ma, Y, Marra, MA, Mayo, M, Moore, RA, Mungall, AJ, Schein, JE, Sipahimalani, P, Tam, A, Thiessen, N, Cheung, D, Wong, T, Brooks, D, Robertson, AG, Bowlby, R, Mungall, K, Sadeghi, S, Xi, L, Covington, K, Shinbrot, E, Wheeler, DA, Gibbs, RA, Donehower, LA, Wang, L, Bowen, J, Gastier-Foster, JM, Gerken, M, Helsel, C, Leraas, KM, Lichtenberg, TM, Ramirez, NC, Wise, L, Zmuda, E, Gabriel, SB, Meyerson, M, Cibulskis, C, Murray, BA, Shih, J, Beroukhim, R, Cherniack, AD, Schumacher, SE, Giama, NH & The Cancer Genome Atlas Research Network 2017, 'Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma', Cell, vol. 169, no. 7, pp. 1327-1341.e23. https://doi.org/10.1016/j.cell.2017.05.046

@article{8e67dd9e38374892a2d920a608b914b8,

title = "Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma",

abstract = "Liver cancer has the second highest worldwide cancer mortality rate and has limited therapeutic options. We analyzed 363 hepatocellular carcinoma (HCC) cases by whole-exome sequencing and DNA copy number analyses, and we analyzed 196 HCC cases by DNA methylation, RNA, miRNA, and proteomic expression also. DNA sequencing and mutation analysis identified significantly mutated genes, including LZTR1, EEF1A1, SF3B1, and SMARCA4. Significant alterations by mutation or downregulation by hypermethylation in genes likely to result in HCC metabolic reprogramming (ALB, APOB, and CPS1) were observed. Integrative molecular HCC subtyping incorporating unsupervised clustering of five data platforms identified three subtypes, one of which was associated with poorer prognosis in three HCC cohorts. Integrated analyses enabled development of a p53 target gene expression signature correlating with poor survival. Potential therapeutic targets for which inhibitors exist include WNT signaling, MDM4, MET, VEGFA, MCL1, IDH1, TERT, and immune checkpoint proteins CTLA-4, PD-1, and PD-L1.",

keywords = "IDH1/2, TP53, cancer subtyping, expression profile, hepatocellular carcinoma, metabolic reprogramming, promoter hypermethylation, significantly mutated genes, sonic hedgehog signaling, stem cell phenotype",

author = "Adrian Ally and Miruna Balasundaram and Rebecca Carlsen and Eric Chuah and Amanda Clarke and Noreen Dhalla and Holt, {Robert A.} and Jones, {Steven J.M.} and Darlene Lee and Yussanne Ma and Marra, {Marco A.} and Michael Mayo and Moore, {Richard A.} and Mungall, {Andrew J.} and Schein, {Jacqueline E.} and Payal Sipahimalani and Angela Tam and Nina Thiessen and Dorothy Cheung and Tina Wong and Denise Brooks and Robertson, {A. Gordon} and Reanne Bowlby and Karen Mungall and Sara Sadeghi and Liu Xi and Kyle Covington and Eve Shinbrot and Wheeler, {David A.} and Gibbs, {Richard A.} and Donehower, {Lawrence A.} and Linghua Wang and Jay Bowen and Gastier-Foster, {Julie M.} and Mark Gerken and Carmen Helsel and Leraas, {Kristen M.} and Lichtenberg, {Tara M.} and Ramirez, {Nilsa C.} and Lisa Wise and Erik Zmuda and Gabriel, {Stacey B.} and Matthew Meyerson and Carrie Cibulskis and Murray, {Bradley A.} and Juliann Shih and Rameen Beroukhim and Cherniack, {Andrew D.} and Schumacher, {Steven E.} and Giama, {Nasra H.} and {The Cancer Genome Atlas Research Network}",

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month = jun,

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doi = "10.1016/j.cell.2017.05.046",

language = "English (US)",

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T1 - Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma

AU - Ally, Adrian

AU - Balasundaram, Miruna

AU - Carlsen, Rebecca

AU - Chuah, Eric

AU - Clarke, Amanda

AU - Dhalla, Noreen

AU - Holt, Robert A.

AU - Jones, Steven J.M.

AU - Lee, Darlene

AU - Ma, Yussanne

AU - Marra, Marco A.

AU - Mayo, Michael

AU - Moore, Richard A.

AU - Mungall, Andrew J.

AU - Schein, Jacqueline E.

AU - Sipahimalani, Payal

AU - Tam, Angela

AU - Thiessen, Nina

AU - Cheung, Dorothy

AU - Wong, Tina

AU - Brooks, Denise

AU - Robertson, A. Gordon

AU - Bowlby, Reanne

AU - Mungall, Karen

AU - Sadeghi, Sara

AU - Xi, Liu

AU - Covington, Kyle

AU - Shinbrot, Eve

AU - Wheeler, David A.

AU - Gibbs, Richard A.

AU - Donehower, Lawrence A.

AU - Wang, Linghua

AU - Bowen, Jay

AU - Gastier-Foster, Julie M.

AU - Gerken, Mark

AU - Helsel, Carmen

AU - Leraas, Kristen M.

AU - Lichtenberg, Tara M.

AU - Ramirez, Nilsa C.

AU - Wise, Lisa

AU - Zmuda, Erik

AU - Gabriel, Stacey B.

AU - Meyerson, Matthew

AU - Cibulskis, Carrie

AU - Murray, Bradley A.

AU - Shih, Juliann

AU - Beroukhim, Rameen

AU - Cherniack, Andrew D.

AU - Schumacher, Steven E.

AU - Giama, Nasra H.

AU - The Cancer Genome Atlas Research Network

PY - 2017/6/15

Y1 - 2017/6/15

N2 - Liver cancer has the second highest worldwide cancer mortality rate and has limited therapeutic options. We analyzed 363 hepatocellular carcinoma (HCC) cases by whole-exome sequencing and DNA copy number analyses, and we analyzed 196 HCC cases by DNA methylation, RNA, miRNA, and proteomic expression also. DNA sequencing and mutation analysis identified significantly mutated genes, including LZTR1, EEF1A1, SF3B1, and SMARCA4. Significant alterations by mutation or downregulation by hypermethylation in genes likely to result in HCC metabolic reprogramming (ALB, APOB, and CPS1) were observed. Integrative molecular HCC subtyping incorporating unsupervised clustering of five data platforms identified three subtypes, one of which was associated with poorer prognosis in three HCC cohorts. Integrated analyses enabled development of a p53 target gene expression signature correlating with poor survival. Potential therapeutic targets for which inhibitors exist include WNT signaling, MDM4, MET, VEGFA, MCL1, IDH1, TERT, and immune checkpoint proteins CTLA-4, PD-1, and PD-L1.

AB - Liver cancer has the second highest worldwide cancer mortality rate and has limited therapeutic options. We analyzed 363 hepatocellular carcinoma (HCC) cases by whole-exome sequencing and DNA copy number analyses, and we analyzed 196 HCC cases by DNA methylation, RNA, miRNA, and proteomic expression also. DNA sequencing and mutation analysis identified significantly mutated genes, including LZTR1, EEF1A1, SF3B1, and SMARCA4. Significant alterations by mutation or downregulation by hypermethylation in genes likely to result in HCC metabolic reprogramming (ALB, APOB, and CPS1) were observed. Integrative molecular HCC subtyping incorporating unsupervised clustering of five data platforms identified three subtypes, one of which was associated with poorer prognosis in three HCC cohorts. Integrated analyses enabled development of a p53 target gene expression signature correlating with poor survival. Potential therapeutic targets for which inhibitors exist include WNT signaling, MDM4, MET, VEGFA, MCL1, IDH1, TERT, and immune checkpoint proteins CTLA-4, PD-1, and PD-L1.

KW - IDH1/2

KW - TP53

KW - cancer subtyping

KW - expression profile

KW - hepatocellular carcinoma

KW - metabolic reprogramming

KW - promoter hypermethylation

KW - significantly mutated genes

KW - sonic hedgehog signaling

KW - stem cell phenotype

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AN - SCOPUS:85020833799

SN - 0092-8674

VL - 169

SP - 1327-1341.e23

JO - Cell

JF - Cell

IS - 7

ER -

Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma

Abstract

Bibliographical note

Keywords

UN SDGs

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