Skip to main content
Grant Details

Grant Number: 5R01CA157823-06 Interpret this number
Primary Investigator: Travis, Lois
Organization: Indiana Univ-Purdue Univ At Indianapolis
Project Title: Genetic Susceptibility and Biomarkers of Platinum-Related Toxicities
Fiscal Year: 2017
Back to top


DESCRIPTION (provided by applicant): Platinum compounds comprise one of the most widely used and successful groups of cytotoxic drugs worldwide, given their efficacy in a wide spectrum of tumor types. Each year more than 5.8 million patients are diagnosed with cancers of colon, rectum, cervix, endometrium, bladder, stomach, head and neck, lung, esophagus, pancreas, osteosarcoma, ovary, and testis, for which first-line therapy can potentially include platinating agents. Platinum now also shows promise for triple-negative breast cancer. Despite over 30 years of clinical use, however, there are no means to identify patients at risk for platinum toxicity who might be offered alternative therapies, or reduced-dose regimens. For patients whose management must include platinating agents, there are no preventive measures and no treatment for these debilitating toxicities. Long-term ototoxicity affects 19-77% of patients, with 35-65% developing tinnitus. Long-term sensory neuropathies affect 30-40% patients. The underlying mechanisms of long-term cisplatin toxicity remain largely un- known. GWAS now provides translational tools to begin to characterize the underlying mechanisms associated with these serious toxicities, with a goal of eventually developing preventive and interventional strategies. The objective of this proposal is to evaluate genetic susceptibility to long-term platinum toxicity among a well- characterized clinical cohort of 3,838 testicular cancer survivors (TCS). This population was selected as the optimal group in which to study the genetic underpinnings of platinum toxicity because of their young age at diagnosis, homogeneity of cisplatin-based therapy, high cure rate, and lifelong risk of treatment sequelae. Moreover, the regimens that we study remain the standard of care. We along with experts in the field recently published a JNCI Commentary (2010;102:1-17), which set forth a new platinum-based research strategy, with an emphasis on providing for the first time a comprehensive understanding of genetic susceptibility to long-term toxicity. Our proposal derives from these recommendations. For almost 2 years, study co-investigators (expert oncologists who daily treat and follow TCS) have systematically queried patients, confirming that their populations are highly motivated to participate in the current study. Our major goals are: 1. For the first time, and through a multi-institutional effort, to establish a large clinically well-characterized cohort of platinum-treated TCS available for lifelong follow-up to enable study of the genetic underpinnings of long-term toxicities; 2. To identify SNPs associated with long-term cisplatin ototoxicity and neurotoxicity; and 3. To determine and validate the extent to which candidate SNPs identified through studies of cellular susceptibility to cisplatin are associated with clinical long-term ototoxicity and neurotoxicity. The novelty of our study is that it comprehensively evaluates for the first time genetic susceptibility to long-term cisplatin toxicity in patients known to be at substantial lifelong risk and will include functional studies. Results from our translational research will potentially impact the millions of patients who are diagnosed annually worldwide with cancers for which therapy can include platinum, not limited to TCS. Our results will eventually permit identification of patients at high risk for long-term toxicity, and the development of preventive and interventional strategies. 1

Back to top


Genetic and Modifiable Risk Factors Contributing to Cisplatin-Induced Toxicities.
Authors: Trendowski M.R. , El Charif O. , Dinh P.C. , Travis L.B. , Dolan M.E. .
Source: Clinical Cancer Research : An Official Journal Of The American Association For Cancer Research, 2018-10-10 00:00:00.0; , .
EPub date: 2018-10-10 00:00:00.0.
PMID: 30305294
Related Citations

Predicting Cardiovascular Disease Among Testicular Cancer Survivors After Modern Cisplatin-based Chemotherapy: Application of the Framingham Risk Score.
Authors: Feldman D.R. , Ardeshir-Rouhani-Fard S. , Monahan P. , Sesso H.D. , Fung C. , Williams A.M. , Hamilton R.J. , Vaughn D.J. , Beard C.J. , Cook R. , et al. .
Source: Clinical Genitourinary Cancer, 2018 Aug; 16(4), p. e761-e769.
EPub date: 2018-02-05 00:00:00.0.
PMID: 29534941
Related Citations

Using an atlas of gene regulation across 44 human tissues to inform complex disease- and trait-associated variation.
Authors: Gamazon E.R. , Segrè A.V. , van de Bunt M. , Wen X. , Xi H.S. , Hormozdiari F. , Ongen H. , Konkashbaev A. , Derks E.M. , Aguet F. , et al. .
Source: Nature Genetics, 2018 Jul; 50(7), p. 956-967.
EPub date: 2018-06-28 00:00:00.0.
PMID: 29955180
Related Citations

Cumulative Burden of Morbidity Among Testicular Cancer Survivors After Standard Cisplatin-Based Chemotherapy: A Multi-Institutional Study.
Authors: Kerns S.L. , Fung C. , Monahan P.O. , Ardeshir-Rouhani-Fard S. , Abu Zaid M.I. , Williams A.M. , Stump T.E. , Sesso H.D. , Feldman D.R. , Hamilton R.J. , et al. .
Source: Journal Of Clinical Oncology : Official Journal Of The American Society Of Clinical Oncology, 2018-05-20 00:00:00.0; 36(15), p. 1505-1512.
EPub date: 2018-04-04 00:00:00.0.
PMID: 29617189
Related Citations

Clinical and Genetic Risk Factors for Adverse Metabolic Outcomes in North American Testicular Cancer Survivors.
Authors: Zaid M.A. , Gathirua-Mwangi W.G. , Fung C. , Monahan P.O. , El-Charif O. , Williams A.M. , Feldman D.R. , Hamilton R.J. , Vaughn D.J. , Beard C.J. , et al. .
Source: Journal Of The National Comprehensive Cancer Network : Jnccn, 2018 Mar; 16(3), p. 257-265.
PMID: 29523664
Related Citations

Gene and MicroRNA Perturbations of Cellular Response to Pemetrexed Implicate Biological Networks and Enable Imputation of Response in Lung Adenocarcinoma.
Authors: Gamazon E.R. , Trendowski M.R. , Wen Y. , Wing C. , Delaney S.M. , Huh W. , Wong S. , Cox N.J. , Dolan M.E. .
Source: Scientific Reports, 2018-01-15 00:00:00.0; 8(1), p. 733.
EPub date: 2018-01-15 00:00:00.0.
PMID: 29335598
Related Citations

Application of stem cell derived neuronal cells to evaluate neurotoxic chemotherapy.
Authors: Wing C. , Komatsu M. , Delaney S.M. , Krause M. , Wheeler H.E. , Dolan M.E. .
Source: Stem Cell Research, 2017 Jul; 22, p. 79-88.
EPub date: 2017-06-15 00:00:00.0.
PMID: 28645005
Related Citations

Clinical and Genome-Wide Analysis of Cisplatin-Induced Peripheral Neuropathy in Survivors of Adult-Onset Cancer.
Authors: Dolan M.E. , El Charif O. , Wheeler H.E. , Gamazon E.R. , Ardeshir-Rouhani-Fard S. , Monahan P. , Feldman D.R. , Hamilton R. , Vaughn D.J. , Beard C. , et al. .
Source: Clinical Cancer Research : An Official Journal Of The American Association For Cancer Research, 2017-06-13 00:00:00.0; , .
EPub date: 2017-06-13 00:00:00.0.
PMID: 28611204
Related Citations

Genome-Wide Association Studies of Chemotherapeutic Toxicities: Genomics of Inequality.
Authors: Mapes B. , El Charif O. , Al-Sawwaf S. , Dolan M.E. .
Source: Clinical Cancer Research : An Official Journal Of The American Association For Cancer Research, 2017-04-25 00:00:00.0; , .
EPub date: 2017-04-25 00:00:00.0.
PMID: 28442506
Related Citations

Multi-Institutional Assessment of Adverse Health Outcomes Among North American Testicular Cancer Survivors After Modern Cisplatin-Based Chemotherapy.
Authors: Fung C. , Sesso H.D. , Williams A.M. , Kerns S.L. , Monahan P. , Abu Zaid M. , Feldman D.R. , Hamilton R.J. , Vaughn D.J. , Beard C.J. , et al. .
Source: Journal Of Clinical Oncology : Official Journal Of The American Society Of Clinical Oncology, 2017-04-10 00:00:00.0; 35(11), p. 1211-1222.
EPub date: 2017-02-27 00:00:00.0.
PMID: 28240972
Related Citations

High-Dose Chemotherapy and Autologous Peripheral-Blood Stem-Cell Transplantation for Relapsed Metastatic Germ Cell Tumors: The Indiana University Experience.
Authors: Adra N. , Abonour R. , Althouse S.K. , Albany C. , Hanna N.H. , Einhorn L.H. .
Source: Journal Of Clinical Oncology : Official Journal Of The American Society Of Clinical Oncology, 2017-04-01 00:00:00.0; 35(10), p. 1096-1102.
EPub date: 2016-11-21 00:00:00.0.
PMID: 27870561
Related Citations

Variants In Wfs1 And Other Mendelian Deafness Genes Are Associated With Cisplatin-associated Ototoxicity
Authors: Wheeler H.E. , Gamazon E.R. , Frisina R. , Perez-Cervantes C. , El Charif O. , Mapes B. , Fossa S.D. , Feldman D. , Hamilton R. , Vaughn D.J. , et al. .
Source: Clinical Cancer Research : An Official Journal Of The American Association For Cancer Research, 2016-12-30 00:00:00.0; , .
PMID: 28039263
Related Citations

Increased Pancreatic Cancer Risk Following Radiotherapy For Testicular Cancer
Authors: Hauptmann M. , Børge Johannesen T. , Gilbert E.S. , Stovall M. , van Leeuwen F.E. , Rajaraman P. , Smith S.A. , Weathers R.E. , Aleman B.M. , Andersson M. , et al. .
Source: British Journal Of Cancer, 2016-09-27 00:00:00.0; 115(7), p. 901-8.
PMID: 27599043
Related Citations

Comprehensive Audiometric Analysis Of Hearing Impairment And Tinnitus After Cisplatin-based Chemotherapy In Survivors Of Adult-onset Cancer
Authors: Frisina R.D. , Wheeler H.E. , Fossa S.D. , Kerns S.L. , Fung C. , Sesso H.D. , Monahan P.O. , Feldman D.R. , Hamilton R. , Vaughn D.J. , et al. .
Source: Journal Of Clinical Oncology : Official Journal Of The American Society Of Clinical Oncology, 2016-08-10 00:00:00.0; 34(23), p. 2712-20.
PMID: 27354478
Related Citations

Novel genetic predictors of venous thromboembolism risk in African Americans.
Authors: Hernandez W. , Gamazon E.R. , Smithberger E. , O'Brien T.J. , Harralson A.F. , Tuck M. , Barbour A. , Kittles R.A. , Cavallari L.H. , Perera M.A. .
Source: Blood, 2016-04-14 00:00:00.0; 127(15), p. 1923-9.
EPub date: 2016-04-14 00:00:00.0.
PMID: 26888256
Related Citations

Chemotherapy-Related Chronic Myelogenous Leukemia: A Case Series of Patients With Germ Cell Tumor.
Authors: Adra N. , Sayar H. , Einhorn L.H. .
Source: Jama Oncology, 2016 Mar; 2(3), p. 391-2.
PMID: 26632950
Related Citations

Chemotherapy-induced peripheral neuropathy: Current status and progress.
Authors: Brewer J.R. , Morrison G. , Dolan M.E. , Fleming G.F. .
Source: Gynecologic Oncology, 2016 Jan; 140(1), p. 176-83.
PMID: 26556766
Related Citations

Cardiovascular Disease Mortality After Chemotherapy or Surgery for Testicular Nonseminoma: A Population-Based Study.
Authors: Fung C. , Fossa S.D. , Milano M.T. , Sahasrabudhe D.M. , Peterson D.R. , Travis L.B. .
Source: Journal Of Clinical Oncology : Official Journal Of The American Society Of Clinical Oncology, 2015-10-01 00:00:00.0; 33(28), p. 3105-15.
EPub date: 2015-10-01 00:00:00.0.
PMID: 26240226
Related Citations

Utilization of sperm banking and barriers to its use in testicular cancer patients.
Authors: Sonnenburg D.W. , Brames M.J. , Case-Eads S. , Einhorn L.H. .
Source: Supportive Care In Cancer : Official Journal Of The Multinational Association Of Supportive Care In Cancer, 2015 Sep; 23(9), p. 2763-8.
PMID: 25680764
Related Citations

Increased stomach cancer risk following radiotherapy for testicular cancer.
Authors: Hauptmann M. , Fossa S.D. , Stovall M. , van Leeuwen F.E. , Johannesen T.B. , Rajaraman P. , Gilbert E.S. , Smith S.A. , Weathers R.E. , Aleman B.M. , et al. .
Source: British Journal Of Cancer, 2015-01-06 00:00:00.0; 112(1), p. 44-51.
EPub date: 2015-01-06 00:00:00.0.
PMID: 25349972
Related Citations

Modeling chemotherapeutic neurotoxicity with human induced pluripotent stem cell-derived neuronal cells.
Authors: Wheeler H.E. , Wing C. , Delaney S.M. , Komatsu M. , Dolan M.E. .
Source: Plos One, 2015; 10(2), p. e0118020.
PMID: 25689802
Related Citations

Testicular cancer: a reflection on 50 years of discovery.
Authors: Hanna N. , Einhorn L.H. .
Source: Journal Of Clinical Oncology : Official Journal Of The American Society Of Clinical Oncology, 2014-10-01 00:00:00.0; 32(28), p. 3085-92.
EPub date: 2014-10-01 00:00:00.0.
PMID: 25024068
Related Citations

Chemotherapy-induced peripheral neurotoxicity and ototoxicity: new paradigms for translational genomics.
Authors: Travis L.B. , Fossa S.D. , Sesso H.D. , Frisina R.D. , Herrmann D.N. , Beard C.J. , Feldman D.R. , Pagliaro L.C. , Miller R.C. , Vaughn D.J. , et al. .
Source: Journal Of The National Cancer Institute, 2014-03-12 00:00:00.0; 106(5), .
EPub date: 2014-03-12 00:00:00.0.
PMID: 24623533
Related Citations

Solid tumors after chemotherapy or surgery for testicular nonseminoma: a population-based study.
Authors: Fung C. , Fossa S.D. , Milano M.T. , Oldenburg J. , Travis L.B. .
Source: Journal Of Clinical Oncology : Official Journal Of The American Society Of Clinical Oncology, 2013-10-20 00:00:00.0; 31(30), p. 3807-14.
EPub date: 2013-10-20 00:00:00.0.
PMID: 24043737
Related Citations

Outcomes in stage I testicular seminoma: a population-based study of 9193 patients.
Authors: Beard C.J. , Travis L.B. , Chen M.H. , Arvold N.D. , Nguyen P.L. , Martin N.E. , Kuban D.A. , Ng A.K. , Hoffman K.E. .
Source: Cancer, 2013-08-01 00:00:00.0; 119(15), p. 2771-7.
EPub date: 2013-08-01 00:00:00.0.
PMID: 23633409
Related Citations

Prognostic factors in patients with poor-risk germ-cell tumors: a retrospective analysis of the Indiana University experience from 1990 to 2014.
Authors: Adra N. , Althouse S.K. , Liu H. , Brames M.J. , Hanna N.H. , Einhorn L.H. , Albany C. .
Source: Annals Of Oncology : Official Journal Of The European Society For Medical Oncology, 2016 05; 27(5), p. 875-9.
EPub date: 2016-02-09 00:00:00.0.
PMID: 26861605
Related Citations

Back to Top