Molecular landmarks of tumor hypoxia across cancer types

Vinayak Bhandari; Christianne Hoey; Lydia Y Liu; Emilie Lalonde; Jessica Ray; Julie Livingstone; Robert Lesurf; Yu-Jia Shiah; Tina Vujcic; Xiaoyong Huang; Shadrielle M G Espiritu; Lawrence E Heisler; Fouad Yousif; Vincent Huang; Takafumi N Yamaguchi; Cindy Q Yao; Veronica Y Sabelnykova; Michael Fraser; Melvin L K Chua; Theodorus van der Kwast; Stanley K Liu; Paul C Boutros; Robert G Bristow

doi:10.1038/s41588-018-0318-2

Molecular landmarks of tumor hypoxia across cancer types

Vinayak Bhandari, Christianne Hoey, Lydia Y Liu, Emilie Lalonde, Jessica Ray, Julie Livingstone, Robert Lesurf, Yu-Jia Shiah, Tina Vujcic, Xiaoyong Huang, Shadrielle M G Espiritu, Lawrence E Heisler, Fouad Yousif, Vincent Huang, Takafumi N Yamaguchi, Cindy Q Yao, Veronica Y Sabelnykova, Michael Fraser, Melvin L K Chua, Theodorus van der KwastStanley K Liu, Paul C Boutros, Robert G Bristow

Division of Cancer Sciences (L5)

Research output: Contribution to journal › Article › peer-review

Abstract

Many primary-tumor subregions have low levels of molecular oxygen, termed hypoxia. Hypoxic tumors are at elevated risk for local failure and distant metastasis, but the molecular hallmarks of tumor hypoxia remain poorly defined. To fill this gap, we quantified hypoxia in 8,006 tumors across 19 tumor types. In ten tumor types, hypoxia was associated with elevated genomic instability. In all 19 tumor types, hypoxic tumors exhibited characteristic driver-mutation signatures. We observed widespread hypoxia-associated dysregulation of microRNAs (miRNAs) across cancers and functionally validated miR-133a-3p as a hypoxia-modulated miRNA. In localized prostate cancer, hypoxia was associated with elevated rates of chromothripsis, allelic loss of PTEN and shorter telomeres. These associations are particularly enriched in polyclonal tumors, representing a constellation of features resembling tumor nimbosus, an aggressive cellular phenotype. Overall, this work establishes that tumor hypoxia may drive aggressive molecular features across cancers and shape the clinical trajectory of individual tumors.

Original language	English
Pages (from-to)	308-318
Number of pages	11
Journal	Nature Genetics
Volume	51
Issue number	2
Early online date	14 Jan 2019
DOIs	https://doi.org/10.1038/s41588-018-0318-2
Publication status	Published - 1 Feb 2019

Keywords

Alleles
Cell Line, Tumor
Chromothripsis
Gene Expression Profiling/methods
Gene Expression Regulation, Neoplastic/genetics
Genomic Instability/genetics
Humans
Hypoxia/genetics
Male
MicroRNAs/genetics
PC-3 Cells
PTEN Phosphohydrolase/genetics
Prostatic Neoplasms/genetics
Telomere/genetics
Tumor Hypoxia/genetics

Research Beacons, Institutes and Platforms

Lydia Becker Institute
Manchester Cancer Research Centre

UN SDGs

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

Access to Document

10.1038/s41588-018-0318-2

Cite this

Bhandari, V., Hoey, C., Liu, L. Y., Lalonde, E., Ray, J., Livingstone, J., Lesurf, R., Shiah, Y.-J., Vujcic, T., Huang, X., Espiritu, S. M. G., Heisler, L. E., Yousif, F., Huang, V., Yamaguchi, T. N., Yao, C. Q., Sabelnykova, V. Y., Fraser, M., Chua, M. L. K., ... Bristow, R. G. (2019). Molecular landmarks of tumor hypoxia across cancer types. Nature Genetics, 51(2), 308-318. https://doi.org/10.1038/s41588-018-0318-2

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title = "Molecular landmarks of tumor hypoxia across cancer types",

abstract = "Many primary-tumor subregions have low levels of molecular oxygen, termed hypoxia. Hypoxic tumors are at elevated risk for local failure and distant metastasis, but the molecular hallmarks of tumor hypoxia remain poorly defined. To fill this gap, we quantified hypoxia in 8,006 tumors across 19 tumor types. In ten tumor types, hypoxia was associated with elevated genomic instability. In all 19 tumor types, hypoxic tumors exhibited characteristic driver-mutation signatures. We observed widespread hypoxia-associated dysregulation of microRNAs (miRNAs) across cancers and functionally validated miR-133a-3p as a hypoxia-modulated miRNA. In localized prostate cancer, hypoxia was associated with elevated rates of chromothripsis, allelic loss of PTEN and shorter telomeres. These associations are particularly enriched in polyclonal tumors, representing a constellation of features resembling tumor nimbosus, an aggressive cellular phenotype. Overall, this work establishes that tumor hypoxia may drive aggressive molecular features across cancers and shape the clinical trajectory of individual tumors.",

keywords = "Alleles, Cell Line, Tumor, Chromothripsis, Gene Expression Profiling/methods, Gene Expression Regulation, Neoplastic/genetics, Genomic Instability/genetics, Humans, Hypoxia/genetics, Male, MicroRNAs/genetics, PC-3 Cells, PTEN Phosphohydrolase/genetics, Prostatic Neoplasms/genetics, Telomere/genetics, Tumor Hypoxia/genetics",

author = "Vinayak Bhandari and Christianne Hoey and Liu, {Lydia Y} and Emilie Lalonde and Jessica Ray and Julie Livingstone and Robert Lesurf and Yu-Jia Shiah and Tina Vujcic and Xiaoyong Huang and Espiritu, {Shadrielle M G} and Heisler, {Lawrence E} and Fouad Yousif and Vincent Huang and Yamaguchi, {Takafumi N} and Yao, {Cindy Q} and Sabelnykova, {Veronica Y} and Michael Fraser and Chua, {Melvin L K} and {van der Kwast}, Theodorus and Liu, {Stanley K} and Boutros, {Paul C} and Bristow, {Robert G}",

year = "2019",

month = feb,

day = "1",

doi = "10.1038/s41588-018-0318-2",

language = "English",

volume = "51",

pages = "308--318",

journal = "Nature Genetics",

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Bhandari, V, Hoey, C, Liu, LY, Lalonde, E, Ray, J, Livingstone, J, Lesurf, R, Shiah, Y-J, Vujcic, T, Huang, X, Espiritu, SMG, Heisler, LE, Yousif, F, Huang, V, Yamaguchi, TN, Yao, CQ, Sabelnykova, VY, Fraser, M, Chua, MLK, van der Kwast, T, Liu, SK, Boutros, PC & Bristow, RG 2019, 'Molecular landmarks of tumor hypoxia across cancer types', Nature Genetics, vol. 51, no. 2, pp. 308-318. https://doi.org/10.1038/s41588-018-0318-2

TY - JOUR

T1 - Molecular landmarks of tumor hypoxia across cancer types

AU - Bhandari, Vinayak

AU - Hoey, Christianne

AU - Liu, Lydia Y

AU - Lalonde, Emilie

AU - Ray, Jessica

AU - Livingstone, Julie

AU - Lesurf, Robert

AU - Shiah, Yu-Jia

AU - Vujcic, Tina

AU - Huang, Xiaoyong

AU - Espiritu, Shadrielle M G

AU - Heisler, Lawrence E

AU - Yousif, Fouad

AU - Huang, Vincent

AU - Yamaguchi, Takafumi N

AU - Yao, Cindy Q

AU - Sabelnykova, Veronica Y

AU - Fraser, Michael

AU - Chua, Melvin L K

AU - van der Kwast, Theodorus

AU - Liu, Stanley K

AU - Boutros, Paul C

AU - Bristow, Robert G

PY - 2019/2/1

Y1 - 2019/2/1

N2 - Many primary-tumor subregions have low levels of molecular oxygen, termed hypoxia. Hypoxic tumors are at elevated risk for local failure and distant metastasis, but the molecular hallmarks of tumor hypoxia remain poorly defined. To fill this gap, we quantified hypoxia in 8,006 tumors across 19 tumor types. In ten tumor types, hypoxia was associated with elevated genomic instability. In all 19 tumor types, hypoxic tumors exhibited characteristic driver-mutation signatures. We observed widespread hypoxia-associated dysregulation of microRNAs (miRNAs) across cancers and functionally validated miR-133a-3p as a hypoxia-modulated miRNA. In localized prostate cancer, hypoxia was associated with elevated rates of chromothripsis, allelic loss of PTEN and shorter telomeres. These associations are particularly enriched in polyclonal tumors, representing a constellation of features resembling tumor nimbosus, an aggressive cellular phenotype. Overall, this work establishes that tumor hypoxia may drive aggressive molecular features across cancers and shape the clinical trajectory of individual tumors.

AB - Many primary-tumor subregions have low levels of molecular oxygen, termed hypoxia. Hypoxic tumors are at elevated risk for local failure and distant metastasis, but the molecular hallmarks of tumor hypoxia remain poorly defined. To fill this gap, we quantified hypoxia in 8,006 tumors across 19 tumor types. In ten tumor types, hypoxia was associated with elevated genomic instability. In all 19 tumor types, hypoxic tumors exhibited characteristic driver-mutation signatures. We observed widespread hypoxia-associated dysregulation of microRNAs (miRNAs) across cancers and functionally validated miR-133a-3p as a hypoxia-modulated miRNA. In localized prostate cancer, hypoxia was associated with elevated rates of chromothripsis, allelic loss of PTEN and shorter telomeres. These associations are particularly enriched in polyclonal tumors, representing a constellation of features resembling tumor nimbosus, an aggressive cellular phenotype. Overall, this work establishes that tumor hypoxia may drive aggressive molecular features across cancers and shape the clinical trajectory of individual tumors.

KW - Alleles

KW - Cell Line, Tumor

KW - Chromothripsis

KW - Gene Expression Profiling/methods

KW - Gene Expression Regulation, Neoplastic/genetics

KW - Genomic Instability/genetics

KW - Humans

KW - Hypoxia/genetics

KW - Male

KW - MicroRNAs/genetics

KW - PC-3 Cells

KW - PTEN Phosphohydrolase/genetics

KW - Prostatic Neoplasms/genetics

KW - Telomere/genetics

KW - Tumor Hypoxia/genetics

UR - http://www.scopus.com/inward/record.url?scp=85059953156&partnerID=8YFLogxK

U2 - 10.1038/s41588-018-0318-2

DO - 10.1038/s41588-018-0318-2

M3 - Article

C2 - 30643250

SN - 1061-4036

VL - 51

SP - 308

EP - 318

JO - Nature Genetics

JF - Nature Genetics

IS - 2

ER -

Molecular landmarks of tumor hypoxia across cancer types

Abstract

Keywords

Research Beacons, Institutes and Platforms

UN SDGs

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