Integrated genomic and molecular characterization of cervical cancer

doi:10.1038/nature21386

Integrated genomic and molecular characterization of cervical cancer

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1210 Scopus citations

Abstract

Cervical cancer remains one of the leading causes of cancer-related deaths worldwide. Here we report the extensive molecular characterization of 228 primary cervical cancers, one of the largest comprehensive genomic studies of cervical cancer to date. We observed notable APOBEC mutagenesis patterns and identified SHKBP1, ERBB3, CASP8, HLA-A and TGFBR2 as novel significantly mutated genes in cervical cancer. We also discovered amplifications in immune targets CD274 (also known as PD-L1) and PDCD1LG2 (also known as PD-L2), and the BCAR4 long non-coding RNA, which has been associated with response to lapatinib. Integration of human papilloma virus (HPV) was observed in all HPV18-related samples and 76% of HPV16-related samples, and was associated with structural aberrations and increased target-gene expression. We identified a unique set of endometrial-like cervical cancers, comprised predominantly of HPV-negative tumours with relatively high frequencies of KRAS, ARID1A and PTEN mutations. Integrative clustering of 178 samples identified keratin-low squamous, keratin-high squamous and adenocarcinoma-rich subgroups. These molecular analyses reveal new potential therapeutic targets for cervical cancers.

Original language	English
Pages (from-to)	378-384
Number of pages	7
Journal	Nature
Volume	543
Issue number	7645
DOIs	https://doi.org/10.1038/nature21386
State	Published - Mar 16 2017

Bibliographical note

Publisher Copyright:
© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

Funding

Funders	Funder number
National Childhood Cancer Registry – National Cancer Institute	P30CA016672, U24CA143858, U24CA143848, ZIACP010124, U24CA210949, U24CA210978, U24CA144025, U24CA143882, U24CA211006, U24CA210950, U24CA210974, U24CA143843, U24CA143799, U24CA143866, U24CA143867, U24CA143845, U24CA180951, U24CA143835, U24CA143883, U24CA143840, U24CA199461
National Institute on Deafness and Other Communication Disorders	ZIADC000074
National Human Genome Research Institute	U54HG003273, U54HG003079, U54HG003067
European Commission	322986

ASJC Scopus subject areas

General

UN SDGs

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

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@article{5526915dc7164c5882c1b2fea540a9d4,

title = "Integrated genomic and molecular characterization of cervical cancer",

abstract = "Cervical cancer remains one of the leading causes of cancer-related deaths worldwide. Here we report the extensive molecular characterization of 228 primary cervical cancers, one of the largest comprehensive genomic studies of cervical cancer to date. We observed notable APOBEC mutagenesis patterns and identified SHKBP1, ERBB3, CASP8, HLA-A and TGFBR2 as novel significantly mutated genes in cervical cancer. We also discovered amplifications in immune targets CD274 (also known as PD-L1) and PDCD1LG2 (also known as PD-L2), and the BCAR4 long non-coding RNA, which has been associated with response to lapatinib. Integration of human papilloma virus (HPV) was observed in all HPV18-related samples and 76\% of HPV16-related samples, and was associated with structural aberrations and increased target-gene expression. We identified a unique set of endometrial-like cervical cancers, comprised predominantly of HPV-negative tumours with relatively high frequencies of KRAS, ARID1A and PTEN mutations. Integrative clustering of 178 samples identified keratin-low squamous, keratin-high squamous and adenocarcinoma-rich subgroups. These molecular analyses reveal new potential therapeutic targets for cervical cancers.",

author = "Burk, \{Robert D.\} and Zigui Chen and Charles Saller and Katherine Tarvin and Carvalho, \{Andre L.\} and Cristovam Scapulatempo-Neto and Silveira, \{Henrique C.\} and Fregnani, \{Jos{\'e} H.\} and Creighton, \{Chad J.\} and Anderson, \{Matthew L.\} and Patricia Castro and Wang, \{Sophia S.\} and Christina Yau and Christopher Benz and \{Gordon Robertson\}, A. and Karen Mungall and Lynette Lim and Reanne Bowlby and Sara Sadeghi and Denise Brooks and Payal Sipahimalani and Richard Mar and Adrian Ally and Amanda Clarke and Mungall, \{Andrew J.\} and Angela Tam and Darlene Lee and Eric Chuah and Schein, \{Jacqueline E.\} and Kane Tse and Katayoon Kasaian and Yussanne Ma and Marra, \{Marco A.\} and Michael Mayo and Miruna Balasundaram and Nina Thiessen and Noreen Dhalla and Rebecca Carlsen and Moore, \{Richard A.\} and Holt, \{Robert A.\} and Jones, \{Steven J.M.\} and Tina Wong and Angeliki Pantazi and Michael Parfenov and Raju Kucherlapati and Angela Hadjipanayis and Jonathan Seidman and Melanie Kucherlapati and Xiaojia Ren and Therese Bocklage",

year = "2017",

month = mar,

day = "16",

doi = "10.1038/nature21386",

language = "English",

volume = "543",

pages = "378--384",

number = "7645",

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T1 - Integrated genomic and molecular characterization of cervical cancer

AU - Burk, Robert D.

AU - Chen, Zigui

AU - Saller, Charles

AU - Tarvin, Katherine

AU - Carvalho, Andre L.

AU - Scapulatempo-Neto, Cristovam

AU - Silveira, Henrique C.

AU - Fregnani, José H.

AU - Creighton, Chad J.

AU - Anderson, Matthew L.

AU - Castro, Patricia

AU - Wang, Sophia S.

AU - Yau, Christina

AU - Benz, Christopher

AU - Gordon Robertson, A.

AU - Mungall, Karen

AU - Lim, Lynette

AU - Bowlby, Reanne

AU - Sadeghi, Sara

AU - Brooks, Denise

AU - Sipahimalani, Payal

AU - Mar, Richard

AU - Ally, Adrian

AU - Clarke, Amanda

AU - Mungall, Andrew J.

AU - Tam, Angela

AU - Lee, Darlene

AU - Chuah, Eric

AU - Schein, Jacqueline E.

AU - Tse, Kane

AU - Kasaian, Katayoon

AU - Ma, Yussanne

AU - Marra, Marco A.

AU - Mayo, Michael

AU - Balasundaram, Miruna

AU - Thiessen, Nina

AU - Dhalla, Noreen

AU - Carlsen, Rebecca

AU - Moore, Richard A.

AU - Holt, Robert A.

AU - Jones, Steven J.M.

AU - Wong, Tina

AU - Pantazi, Angeliki

AU - Parfenov, Michael

AU - Kucherlapati, Raju

AU - Hadjipanayis, Angela

AU - Seidman, Jonathan

AU - Kucherlapati, Melanie

AU - Ren, Xiaojia

AU - Bocklage, Therese

PY - 2017/3/16

Y1 - 2017/3/16

N2 - Cervical cancer remains one of the leading causes of cancer-related deaths worldwide. Here we report the extensive molecular characterization of 228 primary cervical cancers, one of the largest comprehensive genomic studies of cervical cancer to date. We observed notable APOBEC mutagenesis patterns and identified SHKBP1, ERBB3, CASP8, HLA-A and TGFBR2 as novel significantly mutated genes in cervical cancer. We also discovered amplifications in immune targets CD274 (also known as PD-L1) and PDCD1LG2 (also known as PD-L2), and the BCAR4 long non-coding RNA, which has been associated with response to lapatinib. Integration of human papilloma virus (HPV) was observed in all HPV18-related samples and 76% of HPV16-related samples, and was associated with structural aberrations and increased target-gene expression. We identified a unique set of endometrial-like cervical cancers, comprised predominantly of HPV-negative tumours with relatively high frequencies of KRAS, ARID1A and PTEN mutations. Integrative clustering of 178 samples identified keratin-low squamous, keratin-high squamous and adenocarcinoma-rich subgroups. These molecular analyses reveal new potential therapeutic targets for cervical cancers.

AB - Cervical cancer remains one of the leading causes of cancer-related deaths worldwide. Here we report the extensive molecular characterization of 228 primary cervical cancers, one of the largest comprehensive genomic studies of cervical cancer to date. We observed notable APOBEC mutagenesis patterns and identified SHKBP1, ERBB3, CASP8, HLA-A and TGFBR2 as novel significantly mutated genes in cervical cancer. We also discovered amplifications in immune targets CD274 (also known as PD-L1) and PDCD1LG2 (also known as PD-L2), and the BCAR4 long non-coding RNA, which has been associated with response to lapatinib. Integration of human papilloma virus (HPV) was observed in all HPV18-related samples and 76% of HPV16-related samples, and was associated with structural aberrations and increased target-gene expression. We identified a unique set of endometrial-like cervical cancers, comprised predominantly of HPV-negative tumours with relatively high frequencies of KRAS, ARID1A and PTEN mutations. Integrative clustering of 178 samples identified keratin-low squamous, keratin-high squamous and adenocarcinoma-rich subgroups. These molecular analyses reveal new potential therapeutic targets for cervical cancers.

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DO - 10.1038/nature21386

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AN - SCOPUS:85016138846

SN - 0028-0836

VL - 543

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EP - 384

JO - Nature

JF - Nature

IS - 7645

ER -

Integrated genomic and molecular characterization of cervical cancer

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

UN SDGs

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