Ioana Cutcutache1, Yuka Suzuki1, Iain Beehuat Tan2, Subhashini Ramgopal1, Shenli Zhang3, Kalpana Ramnarayanan3, Anna Gan4, Heng Hong Lee4, Su Ting Tay3, Aikseng Ooi5, Choon Kiat Ong6, Jonathan T Bolthouse7, Brian R Lane7, John G Anema7, Richard J Kahnoski7, Patrick Tan8, Bin Tean Teh9, Steven G Rozen10. 1. Centre for Computational Biology, Duke-NUS Graduate Medical School, Singapore; Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore. 2. Department of Medical Oncology, National Cancer Centre Singapore, Singapore; Genome Institute of Singapore, A*STAR, Singapore. 3. Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore. 4. Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore; Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore. 5. Laboratory of Interdisciplinary Renal Oncology, Van Andel Research Institute, Grand Rapids, MI, USA. 6. Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore. 7. Division of Urology, Spectrum Health Hospital System, Grand Rapids, MI, USA. 8. Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore; Genome Institute of Singapore, A*STAR, Singapore; Cancer Science Institute of Singapore, National University of Singapore, Singapore. Electronic address: gmstanp@duke-nus.edu.sg. 9. Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore; Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore; Cancer Science Institute of Singapore, National University of Singapore, Singapore. Electronic address: teh.bin.tean@singhealth.com.sg. 10. Centre for Computational Biology, Duke-NUS Graduate Medical School, Singapore; Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore. Electronic address: steve.rozen@duke-nus.edu.sg.
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.
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.
Authors: Pavlos Msaouel; Mehmet A Bilen; Miao Zhang; Matthew Campbell; Jennifer Wang; Shi-Ming Tu Journal: Curr Opin Oncol Date: 2017-05 Impact factor: 3.645
Authors: Christoph Oing; Winfried H Alsdorf; Gunhild von Amsberg; Karin Oechsle; Carsten Bokemeyer Journal: World J Urol Date: 2016-07-23 Impact factor: 4.226
Authors: Liang Cheng; Peter Albers; Daniel M Berney; Darren R Feldman; Gedske Daugaard; Timothy Gilligan; Leendert H J Looijenga Journal: Nat Rev Dis Primers Date: 2018-10-05 Impact factor: 52.329
Authors: Andreas M Hoff; Sharmini Alagaratnam; Sen Zhao; Jarle Bruun; Peter W Andrews; Ragnhild A Lothe; Rolf I Skotheim Journal: Cancer Res Date: 2015-12-09 Impact factor: 12.701