Deep sequencing of human papillomavirus positive loco-regionally advanced oropharyngeal squamous cell carcinomas reveals novel mutational signature

Christian Grønhøj; David H Jensen; Tina Agander; Katalin Kiss; Estrid Høgdall; Lena Specht; Frederik Otzen Bagger; Finn Cilius Nielsen; Christian von Buchwald

doi:10.1186/s12885-018-4567-3

Deep sequencing of human papillomavirus positive loco-regionally advanced oropharyngeal squamous cell carcinomas reveals novel mutational signature

Christian Grønhøj, David H Jensen, Tina Agander, Katalin Kiss, Estrid Høgdall, Lena Specht, Frederik Otzen Bagger, Finn Cilius Nielsen, Christian von Buchwald

Institut for Klinisk Medicin

7 Citationer (Scopus)

28 Downloads (Pure)

Abstract

BACKGROUND: The genetic profile for human papilloma virus positive (HPV+) oropharyngeal squamous cell carcinomas (OPSCC) remains largely unknown. The purpose of this study was to sequence tissue material from a large cohort of locoregionally-advanced HPV+ OPSCCs.

METHODS: We performed targeted deep sequencing of 395 cancer-associated genes in 114 matched tumor/normal loco-regionally advanced HPV+ OPSCCs. Mutations and copy number aberrations were determined.

RESULTS: We identified a total of 3459 mutations with an average of 10 mutations per megabase and a median of 28 variants per sample. The most frequently mutated genes were KALRN (28%), SPTBN1 (32%), KMT2A (31%), ZNRF3 (9%), BNC2 (12%), NOTCH2 (25%), FGFR2 (12%), SMAD2 (6%), and AR (13%). Our findings were dominated by COSMIC signature 5 and 12, represented in other head and neck cancers and in hepatocellular carcinomas, respectively.

CONCLUSIONS: We have identified multiple genetic aberrations in HPV+ OPSCCs, and the COSMIC signature 12 as most prevalent. The mutations harbour both therapeutic and prognostic potential.

Originalsprog	Engelsk
Artikelnummer	640
Tidsskrift	BMC Cancer
Vol/bind	18
Udgave nummer	1
Sider (fra-til)	1-10
Antal sider	10
ISSN	1471-2407
DOI	https://doi.org/10.1186/s12885-018-4567-3
Status	Udgivet - 7 jun. 2018

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Deep sequencing of human papillomavirus positive loco-regionally advanced oropharyngeal squamous cell carcinomas reveals novel mutational signatureForlagets udgivne version, 1,63 MBLicens: CC BY

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abstract = "BACKGROUND: The genetic profile for human papilloma virus positive (HPV+) oropharyngeal squamous cell carcinomas (OPSCC) remains largely unknown. The purpose of this study was to sequence tissue material from a large cohort of locoregionally-advanced HPV+ OPSCCs.METHODS: We performed targeted deep sequencing of 395 cancer-associated genes in 114 matched tumor/normal loco-regionally advanced HPV+ OPSCCs. Mutations and copy number aberrations were determined.RESULTS: We identified a total of 3459 mutations with an average of 10 mutations per megabase and a median of 28 variants per sample. The most frequently mutated genes were KALRN (28%), SPTBN1 (32%), KMT2A (31%), ZNRF3 (9%), BNC2 (12%), NOTCH2 (25%), FGFR2 (12%), SMAD2 (6%), and AR (13%). Our findings were dominated by COSMIC signature 5 and 12, represented in other head and neck cancers and in hepatocellular carcinomas, respectively.CONCLUSIONS: We have identified multiple genetic aberrations in HPV+ OPSCCs, and the COSMIC signature 12 as most prevalent. The mutations harbour both therapeutic and prognostic potential.",

keywords = "Biomarkers, Tumor/genetics, DNA Mutational Analysis, High-Throughput Nucleotide Sequencing, Humans, Oropharyngeal Neoplasms/genetics, Papillomavirus Infections/complications, Squamous Cell Carcinoma of Head and Neck/genetics, Transcriptome",

author = "Christian Gr{\o}nh{\o}j and Jensen, {David H} and Tina Agander and Katalin Kiss and Estrid H{\o}gdall and Lena Specht and Bagger, {Frederik Otzen} and Nielsen, {Finn Cilius} and {von Buchwald}, Christian",

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T1 - Deep sequencing of human papillomavirus positive loco-regionally advanced oropharyngeal squamous cell carcinomas reveals novel mutational signature

AU - Grønhøj, Christian

AU - Jensen, David H

AU - Agander, Tina

AU - Kiss, Katalin

AU - Høgdall, Estrid

AU - Specht, Lena

AU - Bagger, Frederik Otzen

AU - Nielsen, Finn Cilius

AU - von Buchwald, Christian

PY - 2018/6/7

Y1 - 2018/6/7

N2 - BACKGROUND: The genetic profile for human papilloma virus positive (HPV+) oropharyngeal squamous cell carcinomas (OPSCC) remains largely unknown. The purpose of this study was to sequence tissue material from a large cohort of locoregionally-advanced HPV+ OPSCCs.METHODS: We performed targeted deep sequencing of 395 cancer-associated genes in 114 matched tumor/normal loco-regionally advanced HPV+ OPSCCs. Mutations and copy number aberrations were determined.RESULTS: We identified a total of 3459 mutations with an average of 10 mutations per megabase and a median of 28 variants per sample. The most frequently mutated genes were KALRN (28%), SPTBN1 (32%), KMT2A (31%), ZNRF3 (9%), BNC2 (12%), NOTCH2 (25%), FGFR2 (12%), SMAD2 (6%), and AR (13%). Our findings were dominated by COSMIC signature 5 and 12, represented in other head and neck cancers and in hepatocellular carcinomas, respectively.CONCLUSIONS: We have identified multiple genetic aberrations in HPV+ OPSCCs, and the COSMIC signature 12 as most prevalent. The mutations harbour both therapeutic and prognostic potential.

AB - BACKGROUND: The genetic profile for human papilloma virus positive (HPV+) oropharyngeal squamous cell carcinomas (OPSCC) remains largely unknown. The purpose of this study was to sequence tissue material from a large cohort of locoregionally-advanced HPV+ OPSCCs.METHODS: We performed targeted deep sequencing of 395 cancer-associated genes in 114 matched tumor/normal loco-regionally advanced HPV+ OPSCCs. Mutations and copy number aberrations were determined.RESULTS: We identified a total of 3459 mutations with an average of 10 mutations per megabase and a median of 28 variants per sample. The most frequently mutated genes were KALRN (28%), SPTBN1 (32%), KMT2A (31%), ZNRF3 (9%), BNC2 (12%), NOTCH2 (25%), FGFR2 (12%), SMAD2 (6%), and AR (13%). Our findings were dominated by COSMIC signature 5 and 12, represented in other head and neck cancers and in hepatocellular carcinomas, respectively.CONCLUSIONS: We have identified multiple genetic aberrations in HPV+ OPSCCs, and the COSMIC signature 12 as most prevalent. The mutations harbour both therapeutic and prognostic potential.

KW - Biomarkers, Tumor/genetics

KW - DNA Mutational Analysis

KW - High-Throughput Nucleotide Sequencing

KW - Humans

KW - Oropharyngeal Neoplasms/genetics

KW - Papillomavirus Infections/complications

KW - Squamous Cell Carcinoma of Head and Neck/genetics

KW - Transcriptome

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DO - 10.1186/s12885-018-4567-3

M3 - Journal article

C2 - 29879932

SN - 1471-2407

VL - 18

SP - 1

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JO - BMC Cancer

JF - BMC Cancer

IS - 1

M1 - 640

ER -

Deep sequencing of human papillomavirus positive loco-regionally advanced oropharyngeal squamous cell carcinomas reveals novel mutational signature

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