Exome-wide sequencing shows low mutation rates and identifies novel mutated genes in seminomas

Ioana Cutcutache, Yuka Suzuki, Iain Beehuat Tan, Subhashini Ramgopal, Shenli Zhang, Kalpana Ramnarayanan, Anna Gan, Heng Hong Lee, Su Ting Tay, Aikseng Ooi, Choon Kiat Ong, Jonathan T. Bolthouse, Brian R. Lane, John G. Anema, Richard J. Kahnoski, Patrick Tan, Bin Tean Teh, Steven G. Rozen

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Background: Testicular germ cell tumors are the most common cancer diagnosed in young men, and seminomas are the most common type of these cancers. There have been no exome-wide examinations of genes mutated in seminomas or of overall rates of nonsilent somatic mutations in these tumors. Objective: The objective was to analyze somatic mutations in seminomas to determine which genes are affected and to determine rates of nonsilent mutations. Design, setting, and participants: Eight seminomas and matched normal samples were surgically obtained from eight patients. Intervention: DNA was extracted from tissue samples and exome sequenced on massively parallel Illumina DNA sequencers. Single-nucleotide polymorphism chip-based copy number analysis was also performed to assess copy number alterations. Outcome measurements and statistical analysis: The DNA sequencing read data were analyzed to detect somatic mutations including single-nucleotide substitutions and short insertions and deletions. The detected mutations were validated by independent sequencing and further checked for subclonality. Results and limitations: The rate of nonsynonymous somatic mutations averaged 0.31 mutations/Mb. We detected nonsilent somatic mutations in 96 genes that were not previously known to be mutated in seminomas, of which some may be driver mutations. Many of the mutations appear to have been present in subclonal populations. In addition, two genes, KIT and KRAS, were affected in two tumors each with mutations that were previously observed in other cancers and are presumably oncogenic. Conclusions: Our study, the first report on exome sequencing of seminomas, detected somatic mutations in 96 new genes, several of which may be targetable drivers. Furthermore, our results show that seminoma mutation rates are five times higher than previously thought, but are nevertheless low compared to other common cancers. Similar low rates are seen in other cancers that also have excellent rates of remission achieved with chemotherapy. Patient summary: We examined the DNA sequences of seminomas, the most common type of testicular germ cell cancer. Our study identified 96 new genes in which mutations occurred during seminoma development, some of which might contribute to cancer development or progression. The study also showed that the rates of DNA mutations during seminoma development are higher than previously thought, but still lower than for other common solid-organ cancers. Such low rates are also observed among other cancers that, like seminomas, show excellent rates of disease remission after chemotherapy.

Original languageEnglish (US)
Pages (from-to)77-83
Number of pages7
JournalEuropean Urology
Volume68
Issue number1
DOIs
StatePublished - 2015
Externally publishedYes

Fingerprint

Exome
Seminoma
Mutation Rate
Mutation
Genes
Neoplasms
DNA
Drug Therapy
Germ Cell and Embryonal Neoplasms
Testicular Neoplasms
DNA Sequence Analysis
Single Nucleotide Polymorphism

Keywords

  • Copy number
  • Exome sequencing
  • Germ cell tumor
  • KIT
  • KRAS
  • Somatic mutation
  • Testicular cancer

ASJC Scopus subject areas

  • Urology

Cite this

Cutcutache, I., Suzuki, Y., Tan, I. B., Ramgopal, S., Zhang, S., Ramnarayanan, K., ... Rozen, S. G. (2015). Exome-wide sequencing shows low mutation rates and identifies novel mutated genes in seminomas. European Urology, 68(1), 77-83. https://doi.org/10.1016/j.eururo.2014.12.040

Exome-wide sequencing shows low mutation rates and identifies novel mutated genes in seminomas. / Cutcutache, Ioana; Suzuki, Yuka; Tan, Iain Beehuat; Ramgopal, Subhashini; Zhang, Shenli; Ramnarayanan, Kalpana; Gan, Anna; Lee, Heng Hong; Tay, Su Ting; Ooi, Aikseng; Ong, Choon Kiat; Bolthouse, Jonathan T.; Lane, Brian R.; Anema, John G.; Kahnoski, Richard J.; Tan, Patrick; Teh, Bin Tean; Rozen, Steven G.

In: European Urology, Vol. 68, No. 1, 2015, p. 77-83.

Research output: Contribution to journalArticle

Cutcutache, I, Suzuki, Y, Tan, IB, Ramgopal, S, Zhang, S, Ramnarayanan, K, Gan, A, Lee, HH, Tay, ST, Ooi, A, Ong, CK, Bolthouse, JT, Lane, BR, Anema, JG, Kahnoski, RJ, Tan, P, Teh, BT & Rozen, SG 2015, 'Exome-wide sequencing shows low mutation rates and identifies novel mutated genes in seminomas', European Urology, vol. 68, no. 1, pp. 77-83. https://doi.org/10.1016/j.eururo.2014.12.040
Cutcutache, Ioana ; Suzuki, Yuka ; Tan, Iain Beehuat ; Ramgopal, Subhashini ; Zhang, Shenli ; Ramnarayanan, Kalpana ; Gan, Anna ; Lee, Heng Hong ; Tay, Su Ting ; Ooi, Aikseng ; Ong, Choon Kiat ; Bolthouse, Jonathan T. ; Lane, Brian R. ; Anema, John G. ; Kahnoski, Richard J. ; Tan, Patrick ; Teh, Bin Tean ; Rozen, Steven G. / Exome-wide sequencing shows low mutation rates and identifies novel mutated genes in seminomas. In: European Urology. 2015 ; Vol. 68, No. 1. pp. 77-83.
@article{96f7ce13eb984e28bb4285bfecee96ac,
title = "Exome-wide sequencing shows low mutation rates and identifies novel mutated genes in seminomas",
abstract = "Background: Testicular germ cell tumors are the most common cancer diagnosed in young men, and seminomas are the most common type of these cancers. There have been no exome-wide examinations of genes mutated in seminomas or of overall rates of nonsilent somatic mutations in these tumors. Objective: The objective was to analyze somatic mutations in seminomas to determine which genes are affected and to determine rates of nonsilent mutations. Design, setting, and participants: Eight seminomas and matched normal samples were surgically obtained from eight patients. Intervention: DNA was extracted from tissue samples and exome sequenced on massively parallel Illumina DNA sequencers. Single-nucleotide polymorphism chip-based copy number analysis was also performed to assess copy number alterations. Outcome measurements and statistical analysis: The DNA sequencing read data were analyzed to detect somatic mutations including single-nucleotide substitutions and short insertions and deletions. The detected mutations were validated by independent sequencing and further checked for subclonality. Results and limitations: The rate of nonsynonymous somatic mutations averaged 0.31 mutations/Mb. We detected nonsilent somatic mutations in 96 genes that were not previously known to be mutated in seminomas, of which some may be driver mutations. Many of the mutations appear to have been present in subclonal populations. In addition, two genes, KIT and KRAS, were affected in two tumors each with mutations that were previously observed in other cancers and are presumably oncogenic. Conclusions: Our study, the first report on exome sequencing of seminomas, detected somatic mutations in 96 new genes, several of which may be targetable drivers. Furthermore, our results show that seminoma mutation rates are five times higher than previously thought, but are nevertheless low compared to other common cancers. Similar low rates are seen in other cancers that also have excellent rates of remission achieved with chemotherapy. Patient summary: We examined the DNA sequences of seminomas, the most common type of testicular germ cell cancer. Our study identified 96 new genes in which mutations occurred during seminoma development, some of which might contribute to cancer development or progression. The study also showed that the rates of DNA mutations during seminoma development are higher than previously thought, but still lower than for other common solid-organ cancers. Such low rates are also observed among other cancers that, like seminomas, show excellent rates of disease remission after chemotherapy.",
keywords = "Copy number, Exome sequencing, Germ cell tumor, KIT, KRAS, Somatic mutation, Testicular cancer",
author = "Ioana Cutcutache and Yuka Suzuki and Tan, {Iain Beehuat} and Subhashini Ramgopal and Shenli Zhang and Kalpana Ramnarayanan and Anna Gan and Lee, {Heng Hong} and Tay, {Su Ting} and Aikseng Ooi and Ong, {Choon Kiat} and Bolthouse, {Jonathan T.} and Lane, {Brian R.} and Anema, {John G.} and Kahnoski, {Richard J.} and Patrick Tan and Teh, {Bin Tean} and Rozen, {Steven G.}",
year = "2015",
doi = "10.1016/j.eururo.2014.12.040",
language = "English (US)",
volume = "68",
pages = "77--83",
journal = "European Urology",
issn = "0302-2838",
publisher = "Elsevier",
number = "1",

}

TY - JOUR

T1 - Exome-wide sequencing shows low mutation rates and identifies novel mutated genes in seminomas

AU - Cutcutache, Ioana

AU - Suzuki, Yuka

AU - Tan, Iain Beehuat

AU - Ramgopal, Subhashini

AU - Zhang, Shenli

AU - Ramnarayanan, Kalpana

AU - Gan, Anna

AU - Lee, Heng Hong

AU - Tay, Su Ting

AU - Ooi, Aikseng

AU - Ong, Choon Kiat

AU - Bolthouse, Jonathan T.

AU - Lane, Brian R.

AU - Anema, John G.

AU - Kahnoski, Richard J.

AU - Tan, Patrick

AU - Teh, Bin Tean

AU - Rozen, Steven G.

PY - 2015

Y1 - 2015

N2 - Background: Testicular germ cell tumors are the most common cancer diagnosed in young men, and seminomas are the most common type of these cancers. There have been no exome-wide examinations of genes mutated in seminomas or of overall rates of nonsilent somatic mutations in these tumors. Objective: The objective was to analyze somatic mutations in seminomas to determine which genes are affected and to determine rates of nonsilent mutations. Design, setting, and participants: Eight seminomas and matched normal samples were surgically obtained from eight patients. Intervention: DNA was extracted from tissue samples and exome sequenced on massively parallel Illumina DNA sequencers. Single-nucleotide polymorphism chip-based copy number analysis was also performed to assess copy number alterations. Outcome measurements and statistical analysis: The DNA sequencing read data were analyzed to detect somatic mutations including single-nucleotide substitutions and short insertions and deletions. The detected mutations were validated by independent sequencing and further checked for subclonality. Results and limitations: The rate of nonsynonymous somatic mutations averaged 0.31 mutations/Mb. We detected nonsilent somatic mutations in 96 genes that were not previously known to be mutated in seminomas, of which some may be driver mutations. Many of the mutations appear to have been present in subclonal populations. In addition, two genes, KIT and KRAS, were affected in two tumors each with mutations that were previously observed in other cancers and are presumably oncogenic. Conclusions: Our study, the first report on exome sequencing of seminomas, detected somatic mutations in 96 new genes, several of which may be targetable drivers. Furthermore, our results show that seminoma mutation rates are five times higher than previously thought, but are nevertheless low compared to other common cancers. Similar low rates are seen in other cancers that also have excellent rates of remission achieved with chemotherapy. Patient summary: We examined the DNA sequences of seminomas, the most common type of testicular germ cell cancer. Our study identified 96 new genes in which mutations occurred during seminoma development, some of which might contribute to cancer development or progression. The study also showed that the rates of DNA mutations during seminoma development are higher than previously thought, but still lower than for other common solid-organ cancers. Such low rates are also observed among other cancers that, like seminomas, show excellent rates of disease remission after chemotherapy.

AB - Background: Testicular germ cell tumors are the most common cancer diagnosed in young men, and seminomas are the most common type of these cancers. There have been no exome-wide examinations of genes mutated in seminomas or of overall rates of nonsilent somatic mutations in these tumors. Objective: The objective was to analyze somatic mutations in seminomas to determine which genes are affected and to determine rates of nonsilent mutations. Design, setting, and participants: Eight seminomas and matched normal samples were surgically obtained from eight patients. Intervention: DNA was extracted from tissue samples and exome sequenced on massively parallel Illumina DNA sequencers. Single-nucleotide polymorphism chip-based copy number analysis was also performed to assess copy number alterations. Outcome measurements and statistical analysis: The DNA sequencing read data were analyzed to detect somatic mutations including single-nucleotide substitutions and short insertions and deletions. The detected mutations were validated by independent sequencing and further checked for subclonality. Results and limitations: The rate of nonsynonymous somatic mutations averaged 0.31 mutations/Mb. We detected nonsilent somatic mutations in 96 genes that were not previously known to be mutated in seminomas, of which some may be driver mutations. Many of the mutations appear to have been present in subclonal populations. In addition, two genes, KIT and KRAS, were affected in two tumors each with mutations that were previously observed in other cancers and are presumably oncogenic. Conclusions: Our study, the first report on exome sequencing of seminomas, detected somatic mutations in 96 new genes, several of which may be targetable drivers. Furthermore, our results show that seminoma mutation rates are five times higher than previously thought, but are nevertheless low compared to other common cancers. Similar low rates are seen in other cancers that also have excellent rates of remission achieved with chemotherapy. Patient summary: We examined the DNA sequences of seminomas, the most common type of testicular germ cell cancer. Our study identified 96 new genes in which mutations occurred during seminoma development, some of which might contribute to cancer development or progression. The study also showed that the rates of DNA mutations during seminoma development are higher than previously thought, but still lower than for other common solid-organ cancers. Such low rates are also observed among other cancers that, like seminomas, show excellent rates of disease remission after chemotherapy.

KW - Copy number

KW - Exome sequencing

KW - Germ cell tumor

KW - KIT

KW - KRAS

KW - Somatic mutation

KW - Testicular cancer

UR - http://www.scopus.com/inward/record.url?scp=84942983991&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84942983991&partnerID=8YFLogxK

U2 - 10.1016/j.eururo.2014.12.040

DO - 10.1016/j.eururo.2014.12.040

M3 - Article

C2 - 25597018

AN - SCOPUS:84942983991

VL - 68

SP - 77

EP - 83

JO - European Urology

JF - European Urology

SN - 0302-2838

IS - 1

ER -