Generic placeholder image

Current Topics in Medicinal Chemistry


ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

Review Article

Current Insights into Interethnic Variability in Testicular Cancers: Population Pharmacogenetics, Clinical Trials, Genetic Basis of Chemotherapy- Induced Toxicities and Molecular Signal Transduction

Author(s): Aman Vasistha, Rishi Kothari, Adarsh Mishra, Fernando De Andrés, Adrián LLerena and Sujit Nair*

Volume 20, Issue 20, 2020

Page: [1824 - 1838] Pages: 15

DOI: 10.2174/1568026620666200618112205

Price: $65


Testicular cancer is an aggressive malignancy with a rising incidence rate across the globe. Testicular germ cell tumors are the most commonly diagnosed cancers, and surgical removal of the testes is often a radical necessity along with chemotherapy and radiotherapy. While seminomas are receptive to radiotherapy as well as chemotherapy, non-seminomatous germ cell tumors respond to chemotherapy only. Due to the singular nature of testicular cancers with associated orchiectomy and mortality, it is important to study the molecular basis and genetic underpinnings of this group of cancers across male populations globally. In this review, we shed light on the population pharmacogenetics of testicular cancer, pediatric and adult tumors, current clinical trials, genetic determinants of chemotherapy-induced toxicity in testicular cancer, as well as the molecular signal transduction pathways operating in this malignancy. Taken together, our discussions will help in enhancing our understanding of genetic factors in testicular carcinogenesis and chemotherapy-induced toxicity, augment our knowledge of this aggressive cancer at the cellular and molecular level, as well as improve precision medicine approaches to combat this disease.

Keywords: Variant polymorphism, Pharmacogenetics, Population pharmacogenetics, Precision medicine, Testicular seminoma, Testicular cancer, Ethnicity, Pharmacogenomics, Toxicity, Clinical trials, Molecular aspects, Signal transduction.

Graphical Abstract
National Cancer Institute. Cancer stat facts: Testicular cancer. Available from: (Accessed 5 December 2018)
Horner, M.; Ries, L.; Krapcho, M.; Neyman, N.; Aminou, R.; Howlader, N.; Altekruse, S.; Feuer, E.; Huang, L.; Mariotto, A. SEER Cancer statistics review, 1975-2006. Available from (Accessed 2009)
Yuvaraja, T.; Waigankar, S.; Bakshi, G.; Prakash, G. Genitourinary cancers: Summary of Indian data. South Asian J. Cancer, 2016, 5(3), 122.
Smith, S.; Janitz, A.; Campbell, J. Epidemiology of testicular cancer in Oklahoma and the United States. J. Okla. State Med. Assoc., 2016, 109(7-8), 385-390.
[PMID: 27885307]
Ghazarian, A.A.; Rusner, C.; Trabert, B.; Braunlin, M.; McGlynn, K.A.; Stang, A. Testicular cancer among US men aged 50 years and older. Cancer Epidemiol., 2018, 55, 68-72.
[ PMID: 29807233]
Ehrlich, Y.; Margel, D.; Lubin, M.A.; Baniel, J. Advances in the treatment of testicular cancer. Transl. Androl. Urol., 2015, 4(3), 381-390.
[PMID: 26816836]
Saltzman, A.F.; Cost, N.G. Adolescent and young adult testicular germ cell tumors: Special considerations. Adv. Urol., 2018, 20182375176
[ PMID: 29662516]
Miller, K.D.; Siegel, R.L.; Lin, C.C.; Mariotto, A.B.; Kramer, J.L.; Rowland, J.H.; Stein, K.D.; Alteri, R.; Jemal, A. Cancer treatment and survivorship statistics 2016. CA Cancer J. Clin., 2016, 66(4), 271-289.
Moch, H.; Cubilla, A.L.; Humphrey, P.A.; Reuter, V.E.; Ulbright, T.M. The 2016 WHO classification of tumours of the urinary system and male genital organs-part A: renal, penile, and testicular tumours. Eur. Urol., 2016, 70(1), 93-105.
[ PMID: 26935559]
Looijenga, L.H.; Stoop, H.; Biermann, K.J.V.A. Testicular cancer: biology and biomarkers. Virchows Arch., 2014, 464(3), 301-313.
Çalışkan, S.; Kaba, S.; Özsoy, E.; Koca, O.; Akyüz, M.; Öztürk, M.İ. The hematological parameters in testicular cancer. Journal of Oncological Sciences, 2017, 3(3), 117-119.
Jimenez, R.E.; Gupta, S.; Herrera-Hernandez, L.P.; Sebo, T.J. Pathology and Biology of Human Germ Cell Tumors; Springer, 2017, pp. 267-325.
Sharma, P.; Dhillon, J.; Sexton, W.J. Intratubular germ cell neoplasia of the testis, bilateral testicular cancer, and aberrant histologies. Urol. Clin. North Am., 2015, 42(3), 277-285.
[ PMID: 26216815]
Vigneswaran, H.T.; Abern, M. Encyclopedia of Reproduction, 2nd ed; Skinner, M.K., Ed.; Academic Press: Oxford, 2018, pp. 479-483.
Djureinovic, D.; Hallström, B.M.; Horie, M.; Mattsson, J.S.M.; La Fleur, L.; Fagerberg, L.; Brunnström, H.; Lindskog, C.; Madjar, K.; Rahnenführer, J.; Ekman, S.; Ståhle, E.; Koyi, H.; Brandén, E.; Edlund, K.; Hengstler, J.G.; Lambe, M.; Saito, A.; Botling, J.; Pontén, F.; Uhlén, M.; Micke, P. Profiling cancer testis antigens in non-small-cell lung cancer. JCI Insight, 2016, 1(10), e86837-e86837.
[] [PMID: 27699219]
Andreassen, K.E.; Kristiansen, W.; Karlsson, R.; Aschim, E.L.; Dahl, O.; Fosså, S.D.; Adami, H.O.; Wiklund, F.; Haugen, T.B.; Grotmol, T. Genetic variation in AKT1, PTEN and the 8q24 locus, and the risk of testicular germ cell tumor. Hum. Reprod., 2013, 28(7), 1995-2002.
[] [PMID: 23639623]
Jia, Y.; Xie, X.; Shi, X.; Li, S. Associations of common IL-4 gene polymorphisms with cancer risk: A meta-analysis. Mol. Med. Rep., 2017, 16(2), 1927-1945.
[] [PMID: 28656227]
Relling, M.V.; Dervieux, T. Pharmacogenetics and cancer therapy. Nat. Rev. Cancer, 2001, 1(2), 99-108.
[] [PMID: 11905809]
Pirmohamed, M. Pharmacogenetics and pharmacogenomics. Br. J. Clin. Pharmacol., 2001, 52(4), 345-347.
[] [PMID: 11678777]
Del Re, M.; Latiano, T.; Fidilio, L.; Restante, G.; Morelli, F.; Maiello, E.; Danesi, R. Unusual gastrointestinal and cutaneous toxicities by bleomycin, etoposide, and cisplatin: a case report with pharmacogenetic analysis to personalize treatment. EPMA J., 2017, 8(1), 69-73.
[ PMID: 28620445]
Rabbani, B.; Nakaoka, H.; Akhondzadeh, S.; Tekin, M.; Mahdieh, N. Next generation sequencing: implications in personalized medicine and pharmacogenomics. Mol. Biosyst., 2016, 12(6), 1818-1830.
[] [PMID: 27066891]
Ewis, A.A.; Lee, J.; Naroda, T.; Kagawa, S.; Baba, Y.; Nakahori, Y. Lack of association between the incidence of testicular germ cell tumors and Y‐chromosome haplogroups in the Japanese population. Int. J. Urol., 2006, 13(9), 1212-1217.
Boer, H.; Westerink, N.L.; Altena, R.; Nuver, J.; Dijck-Brouwer, D.A.J.; van Faassen, M.; Klont, F.; Kema, I.P.; Lefrandt, J.D.; Zwart, N.; Boezen, H.M.; Smit, A.J.; Meijer, C.; Gietema, J.A. Single-nucleotide polymorphism in the 5-α-reductase gene (SRD5A2) is associated with increased prevalence of metabolic syndrome in chemotherapy-treated testicular cancer survivors. Eur. J. Cancer, 2016, 54, 104-111.
[] [PMID: 26751392]
O’Donnell, P.H.; Gamazon, E.; Zhang, W.; Stark, A.L.; Kistner-Griffin, E.O.; Stephanie Huang, R.; Eileen Dolan, M. Population differences in platinum toxicity as a means to identify novel genetic susceptibility variants. Pharmacogenet. Genomics, 2010, 20(5), 327-337.
[] [PMID: 20393316]
Brunham, L.R.; Chan, S.L.; Li, R.; Aminkeng, F.; Liu, X.; Saw, W.Y.; Ong, R.T.; Pillai, E.N.; Carleton, B.C.; Toh, D.; Tan, S.H.; Koo, S.H.; Lee, E.J.; Chia, K.S.; Ross, C.J.; Hayden, M.R.; Sung, C.; Teo, Y.Y. Pharmacogenomic diversity in Singaporean populations and Europeans. Pharmacogenomics J., 2014, 14(6), 555-563.
[] [PMID: 24861855]
Dai, Q.; Luo, H.; Li, X.P.; Huang, J.; Zhou, T.J.; Yang, Z.H. XRCC1 and ERCC1 polymorphisms are related to susceptibility and survival of colorectal cancer in the Chinese population. Mutagenesis, 2015, 30(3), 441-449.
[] [PMID: 25690281]
Zhang, H.; Ge, J.; Hong, H.; Bi, L.; Sun, Z. Genetic polymorphisms in ERCC1 and ERCC2 genes are associated with response to chemotherapy in osteosarcoma patients among Chinese population: a meta-analysis. World J. Surg. Oncol., 2017, 15(1), 75.
[] [PMID: 28388903]
Yu, D.; Shi, J.; Sun, T.; Du, X.; Liu, L.; Zhang, X.; Lu, C.; Tang, X.; Li, M.; Xiao, L.; Zhang, Z.; Yuan, Q.; Yang, M. Pharmacogenetic role of ERCC1 genetic variants in treatment response of platinum-based chemotherapy among advanced non-small cell lung cancer patients. Tumour Biol., 2012, 33(3), 877-884.
[] [PMID: 22249976]
Xu, X.; Ren, H.; Zhou, B.; Zhao, Y.; Yuan, R.; Ma, R.; Zhou, H.; Liu, Z. Prediction of copper transport protein 1 (CTR1) genotype on severe cisplatin induced toxicity in non-small cell lung cancer (NSCLC) patients. Lung Cancer, 2012, 77(2), 438-442.
[] [PMID: 22516052]
Zhang, J.; Zhou, W. Ameliorative effects of SLC22A2 gene polymorphism 808 G/T and cimetidine on cisplatin-induced nephrotoxicity in Chinese cancer patients. FFood and chemical toxicol., 2012, 50(7), 2289-2293.
Xu, Z.; Cai, H.; Li, X.; Xu, W.; Xu, T.; Yu, B.; Zou, Q.; Xu, L. ERCC1 C118T polymorphism has predictive value for platinum-based chemotherapy in patients with late-stage bladder cancer. Genet. Mol. Res., 2016, 15(2)
Cheng, H.; Sun, N.; Sun, X.; Chen, B.; Li, F.; Feng, J.; Cheng, L.; Cao, Y. Polymorphisms in hMSH2 and hMLH1 and response to platinum-based chemotherapy in advanced non-small-cell lung cancer patients. Acta Biochim. Biophys. Sin. (Shanghai), 2010, 42(5), 311-317.
Price, B.; Peters, N. Treatment of metastatic testicular tumours with bleomycin, etoposide, cisplatin and vincristine. JRSM, 1992, 28(2), 615.
Yin, J.Y.; Huang, Q.; Yang, Y.; Zhang, J.T.; Zhong, M.Z.; Zhou, H.H.; Liu, Z.Q. Characterization and analyses of multidrug resistance-associated protein 1 (MRP1/ABCC1) polymorphisms in Chinese population. Pharmacogenet. Genomics, 2009, 19(3), 206-216.
[] [PMID: 19214144]
Kume, H.; Kakutani, S.; Tomita, K.; Kitamura, T. Salvage combination chemotherapy with docetaxel, ifosfamide and cisplatin (DIP): successful treatment of a case with metastatic testicular immature teratoma. Jpn. J. Clin. Oncol., 2008, 38(2), 143-145.
[] [PMID: 18250203]
Chan, S.L.; Samaranayake, N.; Ross, C.J.D.; Toh, M.T.; Carleton, B.; Hayden, M.R.; Teo, Y.Y.; Dissanayake, V.H.W.; Brunham, L.R. Genetic diversity of variants involved in drug response and metabolism in Sri Lankan populations: implications for clinical implementation of pharmacogenomics. Pharmacogenet. Genomics, 2016, 26(1), 28-39.
[] [PMID: 26444257]
Yang, G.; Shu, X.O.; Ruan, Z.X.; Cai, Q.Y.; Jin, F.; Gao, Y.T.; Zheng, W. Genetic polymorphisms in glutathione‐S‐transferase genes (GSTM1, GSTT1, GSTP1) and survival after chemotherapy for invasive breast carcinoma. Cancer, 2005, 103(1), 52-58.
Du, Y.; Su, T.; Zhao, L.; Tan, X.; Chang, W.; Zhang, H.; Cao, G. Associations of polymorphisms in DNA repair genes and MDR1 gene with chemotherapy response and survival of non-small cell lung cancer. PLoS One, 2014, 9(6)e99843
Usanova, S.; Piée-Staffa, A.; Sied, U.; Thomale, J.; Schneider, A.; Kaina, B.; Köberle, B. Cisplatin sensitivity of testis tumour cells is due to deficiency in interstrand-crosslink repair and low ERCC1-XPF expression. Mol. Cancer, 2010, 9, 248-248.
[] [PMID: 20846399]
Li, J.; Zuo, X.; Lv, X.; Kong, F.; Xu, W.; Yang, S. Association of DNA repair gene polymorphisms with response to chemotherapy and prognosis of gastric cancer in a Chinese population. Tumour Biol., 2014, 35(8), 7569-7574.
[] [PMID: 24793015]
Cui, L-H.; Yu, Z.; Zhang, T-T.; Shin, M-H.; Kim, H-N.; Choi, J-S. Influence of polymorphisms in MTHFR 677 C→ T, TYMS 3R→ 2R and MTR 2756 A→ G on NSCLC risk and response to platinum-based chemotherapy in advanced NSCLC. Pharmacogenomics, 2011, 12(6), 797-808.
Mizukami, H.; Hamamatsu, A.; Mori, S.; Hara, S.; Kuroda, M.; Nagai, T.; Fukunaga, T. Autopsy and genetic diagnosis of 21-hydroxylase deficiency with bilateral testicular tumors in a case under no medication for over one year. Forensic Sci. Int., 2011, 206(1-3), e71-e75.
[] [PMID: 20951518]
Lee, S.S.; Kim, S-Y.; Kim, W-Y.; Thi-Le, H.; Yoon, Y-R.; Yea, S.S.; Shin, J-G. MDR1 genetic polymorphisms and comparison of MDR1 haplotype profiles in Korean and Vietnamese populations. Ther. Drug Monit., 2005, 27(4), 531-535.
O’Donnell, P.H.; Dolan, M.E. Cancer pharmacoethnicity: ethnic differences in susceptibility to the effects of chemotherapy. Clin. Cancer Res., 2009, 15(15), 4806-4814.
[] [PMID: 19622575]
Zeron-Medina, J.; Wang, X.; Repapi, E.; Campbell, M.R.; Su, D.; Castro-Giner, F.; Davies, B.; Peterse, E.F.; Sacilotto, N.; Walker, G.J.; Terzian, T.; Tomlinson, I.P.; Box, N.F.; Meinshausen, N.; De Val, S.; Bell, D.A.; Bond, G.L. A polymorphic p53 response element in KIT ligand influences cancer risk and has undergone natural selection. Cell, 2013, 155(2), 410-422.
[] [PMID: 24120139]
Bertholee, D.; Maring, J.G.; van Kuilenburg, A.B. Genotypes affecting the pharmacokinetics of anticancer drugs. Clin. Pharmacokinet., 2017, 56(4), 317-337.
[] [PMID: 27641154]
Chen, X.; Jiang, M.; Zhao, R-K.; Gu, G-H. Quantitative assessment of the association between ABC polymorphisms and osteosarcoma response: a meta-analysis. Asian Pac. J. Cancer Prev., 2015, 16(11), 4659-4664.
Dessilly, G.; Elens, L.; Panin, N.; Karmani, L.; Demoulin, J-B.; Haufroid, V.J.P. ABCB1 1199G> A polymorphism (rs2229109) affects the transport of imatinib, nilotinib and dasatinib. Pharmacogenomics, 2016, 17(8), 883-890.
Tsuchiya, N.; Inoue, T.; Narita, S.; Kumazawa, T.; Saito, M.; Obara, T.; Tsuruta, H.; Horikawa, Y.; Yuasa, T. Drug related genetic polymorphisms affecting adverse reactions to methotrexate, vinblastine, doxorubicin and cisplatin in patients with urothelial cancer. J. Urol., 2008, 180(6), 2389-2395.
Wheeler, H.E.; Gamazon, E.R.; Frisina, R.D.; Perez-Cervantes, C.; El Charif, O.; Mapes, B.; Fossa, S.D.; Feldman, D.R.; Hamilton, R.J.; Vaughn, D. Variants in WFS1 and other Mendelian deafness genes are associated with cisplatin-associated ototoxicity. Clin. Cancer Res., 2017, 23(13), 3325-3333.
Qin, Q.; Zhang, C.; Yang, X.; Zhu, H.; Yang, B.; Cai, J.; Cheng, H.; Ma, J.; Lu, J.; Zhan, L. Polymorphisms in XPD gene could predict clinical outcome of platinum-based chemotherapy for non-small cell lung cancer patients: a meta-analysis of 24 studies. PLoS One, 2013, 8(11)e79864
Cárcano, F.M.; Vidal, D.O.; van Helvoort Lengert, A.; Neto, C.S.; Queiroz, L.; Marques, H.; Baltazar, F.; da Silva Martinelli, C.M.; Soares, P.; da Silva, E. Hotspot TERT promoter mutations are rare events in testicular germ cell tumors. Tumor Bio., 2016, 37(4), 4901-4907.
Biggar, R.J.; Baade, P.D.; Sun, J.; Brandon, L.E.; Kimlin, M. Germ cell testicular cancer incidence, latitude and sunlight associations in the United States and australia. Germ cell testicular cancer incidence, latitude and sunlight associations in the United States and Australia. Photochem. Photobiol., 2016, 92(5), 735-741.
[] [PMID: 27400420]
Drögemöller, B.I.; Monzon, J.G.; Bhavsar, A.P.; Borrie, A.E.; Brooks, B.; Wright, G.E.; Liu, G.; Renouf, D.J.; Kollmannsberger, C.K.; Bedard, P.L. Association between SLC16A5 genetic variation and cisplatin-induced ototoxic effects in adult patients with testicular cancer. JAMA Oncol., 2017, 3(11), 1558-1562.
Spracklen, T.; Vorster, A.; Ramma, L.; Dalvie, S.; Ramesar, R.J. Promoter region variation in NFE2L2 influences susceptibility to ototoxicity in patients exposed to high cumulative doses of cisplatin. Pharmacogenomics J., 2017, 17(6), 515.
Jennis, M.; Kung, C-P.; Basu, S.; Budina-Kolomets, A.; Julia, I.; Leu, J.; Khaku, S.; Scott, J.P.; Cai, K.Q.; Campbell, M. African-specific polymorphism in the TP53 gene impairs p53 tumor suppressor function in a mouse model. Genes Dev., 2016, 30(8), 918-930.
Bagrodia, A.; Lee, B.H.; Lee, W.; Cha, E.K.; Sfakianos, J.P.; Iyer, G.; Pietzak, E.J.; Gao, S.P.; Zabor, E.C.; Ostrovnaya, I.J. Genetic determinants of cisplatin resistance in patients with advanced germ cell tumors. J. Clin. Col., 2016, 34(33), 4000.
Zhai, X-H.; Huang, J.; Wu, F-X.; Zhu, D-Y.; Wang, A-C. treatment, Impact of XRCC1, GSTP1, and GSTM1 polymorphisms on the survival of ovarian carcinoma patients treated with chemotherapy. Oncol. Res. Treat., 2016, 39(7-8), 440-446.
Mutlu, P.; Elçi, M.P.; Yıldırım, M.; Nevruz, O.; Çetin, A.T.; Avcu, F.J.I.J.O.H.; Transfusion, B. Identification of XRCC1 Arg399Gln and XRCC3 Thr241Met polymorphisms in a Turkish population and their association with the risk of chronic lymphocytic leukemia. Sci. Rep., 2015, 31(3), 332-338.
Yi, L.; Xiao-Feng, H.; Yun-Tao, L.; Hao, L.; Ye, S.; Song-Tao, Q. Association between the XRCC1 Arg399Gln polymorphism and risk of cancer: evidence from 297 case-control studies. PLoS One, 2013, 8(10)e78071
[] [PMID: 24205095]
Yan, J.; Wang, X.; Tao, H.; Deng, Z.; Yang, W.; Lin, F.J. Meta-analysis of the relationship between XRCC1-Arg399Gln and Arg280His polymorphisms and the risk of prostate cancer. Sci. Rep., 2015, 5, 9905.
Huang, Y.; Li, L.; Yu, L.J.M. XRCC1 Arg399Gln, Arg194Trp and Arg280His polymorphisms in breast cancer risk: a meta-analysis. Mutagenesis, 2009, 24(4), 331-339.
American Society of Clinical Oncology. Testicular cancer: about clinical trials., Available from:
[64] Genetics of Familial Testicular Cancer Available 305 from:,
Clinical Identification of predictive markers for testis cancer in a population of men with high risk. Available from:,
[66] Germ cell tumor and testicular tumor DNA Registry. Available from:,
[67] Toxicity attributed to genetic polymorphisms in testicular germ cell tumor survivors. Available from:,
Frazier, A.L.; Stoneham, S.; Rodriguez-Galindo, C.; Dang, H.; Xia, C.; Olson, T.A.; Murray, M.J.; Amatruda, J.F.; Shaikh, F.; Pashankar, F.; Billmire, D.; Krailo, M.; Stark, D.; Brougham, M.F.H.; Nicholson, J.C.; Hale, J.P. Comparison of carboplatin versus cisplatin in the treatment of paediatric extracranial malignant germ cell tumours: A report of the Malignant Germ Cell International Consortium. Eur. J. Cancer, 2018, 98, 30-37.
[] [PMID: 29859339]
Choeyprasert, W.; Sawangpanich, R.; Lertsukprasert, K.; Udomsubpayakul, U.; Songdej, D.; Unurathapan, U.; Pakakasama, S.; Hongeng, S.J. Cisplatin-induced ototoxicity in pediatric solid tumors: the role of glutathione S-transferases and megalin genetic polymorphisms. J. Pediatr. Hematol. Oncol., 2013, 35(4), e138-e143.
[70] Studying biomarkers in samples from younger patients with malignant germ cell tumor progression. Available from:, Cancer&draw=10&rank=87
Williams, L.A.; Mills, L.; Hooten, A.J.; Langer, E.; Roesler, M.; Frazier, A.L.; Krailo, M.; Nelson, H.H.; Bestrashniy, J.; Amatruda, J.F.; Poynter, J.N. Differences in DNA methylation profiles by histologic subtype of paediatric germ cell tumours: a report from the Children’s Oncology Group. Br. J. Cancer, 2018, 119(7), 864-872.
[] [PMID: 30287918]
Huang, D.; Wang, C.; Duan, Y.; Meng, Q.; Liu, Z.; Huo, X.; Sun, H.; Ma, X.; Liu, K. Targeting Oct2 and P53: Formononetin prevents cisplatin-induced acute kidney injury. Toxicol. Appl. Pharmacol., 2017, 326, 15-24.
[] [PMID: 28414026]
Filipski, K.K.; Mathijssen, R.H.; Mikkelsen, T.S.; Schinkel, A.H.; Sparreboom, A. Contribution of organic cation transporter 2 (OCT2) to cisplatin-induced nephrotoxicity. Clin. Pharmacol. Ther., 2009, 86(4), 396-402.
[] [PMID: 19625999]
Iwata, K.; Aizawa, K.; Kamitsu, S.; Jingami, S.; Fukunaga, E.; Yoshida, M.; Yoshimura, M.; Hamada, A.; Saito, H. Effects of genetic variants in SLC22A2 organic cation transporter 2 and SLC47A1 multidrug and toxin extrusion 1 transporter on cisplatin-induced adverse events. Clin. Exp. Nephrol., 2012, 16(6), 843-851.
[] [PMID: 22569819]
Harrach, S.; Ciarimboli, G.J. Role of transporters in the distribution of platinum-based drugs. Front. Pharmacol., 2015, 6, 85.
Rybak, L.P.; Mukherjea, D.; Jajoo, S.; Ramkumar, V. Cisplatin ototoxicity and protection: clinical and experimental studies. Tohoku J. Exp. Med., 2009, 219(3), 177-186.
[] [PMID: 19851045]
Bogefors, K.; Giwercman, Y.L.; Eberhard, J.; Stahl, O.; Cavallin-Stahl, E.; Cohn-Cedermark, G.; Arver, S.; Giwercman, A. Androgen receptor gene CAG and GGN repeat lengths as predictors of recovery of spermatogenesis following testicular germ cell cancer treatment. Asian J. Androl., 2017, 19(5), 538.
de Haas, E.C.; Zwart, N.; Meijer, C.; Nuver, J.; Boezen, H.M.; Suurmeijer, A.J.; Hoekstra, H.J.; van der Steege, G.; Sleijfer, D.T.; Gietema, J.A. Variation in bleomycin hydrolase gene is associated with reduced survival after chemotherapy for testicular germ cell cancer. J. Clin. Oncol., 2008, 26(11), 1817-1823.
van der Schoot, G.G.; Westerink, N-D.L.; Lubberts, S.; Nuver, J.; Zwart, N.; Walenkamp, A.M.; Wempe, J.B.; Meijer, C.; Gietema, J.A. Variation in the HFE gene is associated with the development of bleomycin-induced pulmonary toxicity in testicular cancer patients. Eur. J. Cancer, 2016, 59, 134-141.
Sharma, D.K.; Bressler, K.; Patel, H.; Balasingam, N.; Thakor, N. Role of eukaryotic initiation factors during cellular stress and cancer progression. J. Nucleic Acids, 2016, 2016, 8235121-8235121.
[] [PMID: 28083147]
Bag, A.; Jeena, L.; Bag, N. Genetic polymorphisms and cisplatin-related nephrotoxicity., Global J. Canc. Therapy, 2015, 4, 001.
Tzvetkov, M.V.; Behrens, G.; O’Brien, V.P.; Hohloch, K.; Brockmöller, J.; Benöhr, P.J.P. Pharmacogenetic analyses of cisplatin-induced nephrotoxicity indicate a renoprotective effect of ERCC1 polymorphisms. Pharmacogenomics, 2011, 12(10), 1417-1427.
Zhang, G.; Guan, Y.; Zhao, Y.; van der Straaten, T.; Xiao, S.; Xue, P.; Zhu, G.; Liu, Q.; Cai, Y.; Jin, C.J. ERCC2/XPD Lys751Gln alter DNA repair efficiency of platinum-induced DNA damage through P53 pathway. Chem. Biol. Interact., 2017, 263, 55-65.
Rao, K.S.; Paul, A.; Kumar, A.S.A.; Umamaheswaran, G.; Dubashi, B.; Gunaseelan, K.; Dkhar, S.A.J.B.c. Allele and genotype distributions of DNA repair gene polymorphisms in South Indian healthy population. Biomark. Cancer, 2014, 263, 55-65.
[85] Health status and burden of late effects in very long-term testicular cancer survivors (STANDBY-study). Available from: (4 December 2018)
[86] Cardiovascular morbidity in testicular cancer survivors: study of risk factors and assessment of pharmacogenomic determinants of toxicity. Available from:,
Abraham, J.E.; Guo, Q.; Dorling, L.; Tyrer, J.; Ingle, S.; Hardy, R.; Vallier, A.L.; Hiller, L.; Burns, R.; Jones, L.J. Replication of genetic polymorphisms reported to be associated with taxane-related sensory neuropathy in patients with early breast cancer treated with paclitaxel-letter. Clin. Cancer Res., 2015, 21(18), 4244.
Tsai, S-M.; Lin, C-Y.; Wu, S-H.; Hou, L.A.; Ma, H.; Tsai, L-Y.; Hou, M-F. Side effects after docetaxel treatment in Taiwanese breast cancer patients with CYP3A4, CYP3A5, and ABCB1 gene polymorphisms. Clin. Chim. Acta, 2009, 404(2), 160-165.
Kim, H.J. Im, S.A.; Keam, B. Ham, H.S.; Lee, K.H.; Kim, T.Y.; Kim, Y.J.; Oh, D.Y.; Kim, J.H.; Han, W. ABCB 1 polymorphism as prognostic factor in breast cancer patients treated with docetaxel and doxorubicin neoadjuvant chemotherapy. Cancer Sci., 2015, 106, p. (1)86-93.
Changal, K.H.; Raina, H.; Changal, Q.H.; Raina, M. Bleomycin-induced flagellate erythema: a rare and unique drug rash. West Indian Med. J., 2014, 63(7), 807-809.
[PMID: 25867573]
Vogelzang, N.J.; Bosl, G.J.; Johnson, K.; Kennedy, B.J. Raynaud’s phenomenon: a common toxicity after combination chemotherapy for testicular cancer. Ann. Intern. Med., 1981, 95(3), 288-292.
Oldenburg, J.; Kraggerud, S.M.; Brydøy, M.; Cvancarova, M.; Lothe, R.A.; Fossa, S.D.J.J.o.t. Association between long-term neuro-toxicities in testicular cancer survivors and polymorphisms in glutathione-s-transferase-P1 and-M1, a retrospective cross sectional study J. Trad. Med., 2007, 5(1), 1.
Grzybowska, E.; Butkiewicz, D.; Motykiewicz, G.; Chora̧ży, M.J.M.R.G.T.; Mutagenesis, E. The effect of the genetic polymorphisms of CYP1A1, CYP2D6, GSTM1 and GSTP1 on aromatic DNA adduct levels in the population of healthy women. Mutat. Res., 2000, 469(2), 271-277.
Reddy, P.; Naidoo, R.N.; Robins, T.G.; Mentz, G.; London, S.J.; Li, H.; Naidoo, R.J.L. GSTM1, GSTP1, and NQO1 polymorphisms and susceptibility to atopy and airway hyperresponsiveness among South African schoolchildren. Lung, 2010, 188(5), 409-414.
Tran, A.; Jullien, V.; Alexandre, J.; Rey, E.; Rabillon, F.; Girre, V.; Dieras, V.; Pons, G.; Goldwasser, F.; Tréluyer, J.J.C.P. Pharmacokinetics and toxicity of docetaxel: role of CYP3A, MDR1, and GST polymorphisms. Clin. Pharmacol. Ther., 2006, 79(6), 570-580.
Khrunin, A. Moisseev, A.; Gorbunova, V.; Limborska, S. In Ovarian Cancer-From Pathogenesis to Treatment; IntechOpen: London, , 2018.
Trendowski, M.R.; El Charif, O.; Dinh, P.C., Jr; Travis, L.B.; Dolan, M.E. Genetic and modifiable risk factors contributing to cisplatin-induced toxicities. Clin. Cancer Res., 2019, 25(4), 1147-1155.
[] [PMID: 30305294]
Kolch, W.; Halasz, M.; Granovskaya, M.; Kholodenko, B.N. The dynamic control of signal transduction networks in cancer cells. Nat. Rev. Cancer, 2015, 15(9), 515-527.
[] [PMID: 26289315]
Ferguson, L.; Agoulnik, A.I. Testicular cancer and cryptorchidism. Front. Endocrinol. (Lausanne), 2013, 4, 32.
[] [PMID: 23519268]
Nakai, Y.; Nonomura, N.; Oka, D.; Shiba, M.; Arai, Y.; Nakayama, M.; Inoue, H.; Nishimura, K.; Aozasa, K.; Mizutani, Y.; Miki, T.; Okuyama, A. KIT (c-kit oncogene product) pathway is constitutively activated in human testicular germ cell tumors. Biochem. Biophys. Res. Commun., 2005, 337(1), 289-296.
[] [PMID: 16188233]
Reuter, V.E. Origins and molecular biology of testicular germ cell tumors. Mod. Pathol., 2005, 18(Suppl. 2), S51-S60.
[] [PMID: 15761466]
Cardoso, H.J.; Figueira, M.I.; Socorro, S. The stem cell factor (SCF)/c-KIT signalling in testis and prostate cancer. J. Cell Commun. Signal., 2017, 11(4), 297-307.
[] [PMID: 28656507]
McIntyre, A.; Gilbert, D.; Goddard, N.; Looijenga, L.; Shipley, J. Genes, chromosomes and the development of testicular germ cell tumors of adolescents and adults. Genes Chromosomes Cancer, 2008, 47(7), 547-557.
[] [PMID: 18381640]
Virtanen, H.E.; Rajpert-De Meyts, E.; Main, K.M.; Skakkebaek, N.E.; Toppari, J. Testicular dysgenesis syndrome and the development and occurrence of male reproductive disorders. Toxicol. Appl. Pharmacol., 2005, 207(2)(Suppl.), 501-505.
[] [PMID: 16005920]
Skakkebaek, N.E.; Rajpert-De Meyts, E.; Main, K.M. Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects. Hum. Reprod., 2001, 16(5), 972-978.
[] [PMID: 11331648]
Peltomäki, P.; Lothe, R.A.; Børresen, A.L.; Fosså, S.D.; Brøgger, A.; de la Chapelle, A. Chromosome 12 in human testicular cancer: dosage changes and their parental origin. Cancer Genet. Cytogenet., 1992, 64(1), 21-26.
[] [PMID: 1458445]
Kemmer, K.; Corless, C.L.; Fletcher, J.A.; McGreevey, L.; Haley, A.; Griffith, D.; Cummings, O.W.; Wait, C.; Town, A.; Heinrich, M.C. KIT mutations are common in testicular seminomas. Am. J. Pathol., 2004, 164(1), 305-313.
[] [PMID: 14695343]
Mulder, M.P.; Keijzer, W.; Verkerk, A.; Boot, A.J.; Prins, M.E.; Splinter, T.A.; Bos, J.L. Activated ras genes in human seminoma: evidence for tumor heterogeneity. Oncogene, 1989, 4(11), 1345-1351.
[PMID: 2682461]
Ganguly, S.; Murty, V.V.; Samaniego, F.; Reuter, V.E.; Bosl, G.J.; Chaganti, R.S. Detection of preferential NRAS mutations in human male germ cell tumors by the polymerase chain reaction. Genes Chromosomes Cancer, 1990, 1(3), 228-232.
[] [PMID: 1964583]
Ridanpää, M.; Lothe, R.A.; Onfelt, A.; Fosså, S.; Børresen, A.L.; Husgafvel-Pursiainen, K. K-ras oncogene codon 12 point mutations in testicular cancer. Environ. Health Perspect., 1993, 101(Suppl. 3), 185-187.
[PMID: 8143614]
Hacioglu, B.M. Kodaz, H.; Erdogan, B.; Cinkaya, A.; Tastekin, E.; Hacibekiroglu, I.; Turkmen, E.; Kostek, O.; Genc, E.; Uzunoglu, S.; Cicin, I. K-RAS and N-RAS mutations in testicular germ cell tumors. Bosn. J. Basic Med. Sci., 2017, 17(2), 159-163.
[] [PMID: 28426398]
Boublikova, L.; Bakardjieva-Mihaylova, V.; Skvarova Kramarzova, K.; Kuzilkova, D.; Dobiasova, A.; Fiser, K.; Stuchly, J.; Kotrova, M.; Buchler, T.; Dusek, P.; Grega, M.; Rosova, B.; Vernerova, Z.; Klezl, P.; Pesl, M.; Zachoval, R.; Krolupper, M.; Kubecova, M.; Stahalova, V.; Abrahamova, J.; Babjuk, M.; Kodet, R.; Trka, J. Wilms tumor gene 1 (WT1), TP53, RAS/BRAF and KIT aberrations in testicular germ cell tumors. Cancer Lett., 2016, 376(2), 367-376.
[] [PMID: 27085458]
Peltomäki, P.; Alfthan, O.; de la Chapelle, A. Oncogenes in human testicular cancer: DNA and RNA studies. Br. J. Cancer, 1991, 63(6), 851-858.
[] [PMID: 1829952]
Chieffi, P. An Overview on Predictive Biomarkers of Testicular Germ Cell Tumors. J. Cell. Physiol., 2017, 232(2), 276-280.
[] [PMID: 27405110]
Chieffi, P.; Chieffi, S. Molecular biomarkers as potential targets for therapeutic strategies in human testicular germ cell tumors: an overview. J. Cell. Physiol., 2013, 228(8), 1641-1646.
[] [PMID: 23359388]
Markulin, D.; Vojta, A.; Samaržija, I.; Gamulin, M.; Bečeheli, I.; Jukić, I.; Maglov, Č.; Zoldoš, V.; Fučić, A. Association between RASSF1A promoter methylation and testicular germ cell tumor: a meta-analysis and a cohort study. Cancer Genomics Proteomics, 2017, 14(5), 363-372.
[PMID: 28871003]
Yi, M.; Yang, J.; Li, W.; Li, X.; Xiong, W.; McCarthy, J.B.; Li, G.; Xiang, B. The NOR1/OSCP1 proteins in cancer: from epigenetic silencing to functional characterization of a novel tumor suppressor. J. Cancer, 2017, 8(4), 626-635.
[] [PMID: 28367242]
Sheikine, Y.; Genega, E.; Melamed, J.; Lee, P.; Reuter, V.E.; Ye, H. Molecular genetics of testicular germ cell tumors. Am. J. Cancer Res., 2012, 2(2), 153-167.
[PMID: 22432056]
Landero-Huerta, D.A.; Vigueras-Villasenor, R.M.; Yokoyama-Rebollar, E.; Arechaga-Ocampo, E.; Rojas-Castaneda, J.C.; Jimenez-Trejo, F.; Chavez-Saldana, M. Epigenetic and risk factors of testicular germ cell tumors: a brief review. Front. Biosci., 2017, 22, 1073-1098.
[] [PMID: 28199193]
Shi, Z.; Chen, J.; Zhang, X.; Chu, J.; Han, Z.; Xu, D.; Gan, S.; Pan, X.; Ye, J.; Cui, X. Ataxin-3 promotes testicular cancer cell proliferation by inhibiting anti-oncogene PTEN. Biochem. Biophys. Res. Commun., 2018, 503(1), 391-396.
[] [PMID: 29902454]
Sacco, J.J.; Yau, T.Y.; Darling, S.; Patel, V.; Liu, H.; Urbé, S.; Clague, M.J.; Coulson, J.M. The deubiquitylase Ataxin-3 restricts PTEN transcription in lung cancer cells. Oncogene, 2014, 33(33), 4265-4272.
[] [PMID: 24292675]
Yamada, Y.; Takayama, K.i.; Fujimura, T.; Ashikari, D.; Obinata, D.; Takahashi, S.; Ikeda, K.; Kakutani, S.; Urano, T.; Fukuhara, H.J.C.s. A novel prognostic factor TRIM44 promotes cell proliferation and migration, and inhibits apoptosis in testicular germ cell tumor. Cancer Sci., 2017, 108(1), 32-41.
Wang, C.; Fok, K.L.; Cai, Z.; Chen, H.; Chan, H.C. CD147 regulates extrinsic apoptosis in spermatocytes by modulating NFκB signaling pathways. Oncotarget, 2017, 8(2), 3132-3143.
[] [PMID: 27902973]
de Jong, J.; Stoop, H.; Gillis, A.J.; Hersmus, R.; van Gurp, R.J.; van de Geijn, G.J.; van Drunen, E.; Beverloo, H.B.; Schneider, D.T.; Sherlock, J.K.; Baeten, J.; Kitazawa, S.; van Zoelen, E.J.; van Roozendaal, K.; Oosterhuis, J.W.; Looijenga, L.H. Further characterization of the first seminoma cell line TCam-2. Genes Chromosomes Cancer, 2008, 47(3), 185-196.
[] [PMID: 18050305]
Wu, D.; Wu, J.; Liu, H.; Yu, M.; Tao, L.; Dong, S.; Tong, X.J.B. Pharmacotherapy, Role of Pannexin1 channels in the resistance of I-10 testicular cancer cells to cisplatin mediated by ATP/IP3 pathway. Biomed. Pharmacother., 2017, 94, 514-522.
Boccellino, M.; Vanacore, D.; Zappavigna, S.; Cavaliere, C.; Rossetti, S.; D’Aniello, C.; Chieffi, P.; Amler, E.; Buonerba, C.; Di Lorenzo, G.; Di Franco, R.; Izzo, A.; Piscitelli, R.; Iovane, G.; Muto, P.; Botti, G.; Perdonà, S.; Caraglia, M.; Facchini, G. Testicular cancer from diagnosis to epigenetic factors. Oncotarget, 2017, 8(61), 104654-104663.
[] [PMID: 29262668]
Nair, S. LLerena, A. New perspectives in personalised medicine for ethnicity in cancer: population pharmacogenomics and pharmacometrics. Drug Metab. Pers. Ther., 2018, 33(2), 61-64.
[] [PMID: 29688886]
Nair, S.; Kong, A.T. Emerging roles for clinical pharmacometrics in cancer precision medicine. Curr. Pharmacol. Rep., 2018, 4(3), 276-283.
[] [PMID: 30345221]
Pan, J.H.; Han, J.X.; Wu, J.M.; Huang, H.N.; Yu, Q.Z.; Sheng, L.J. MDR1 single nucleotide polymorphism G2677T/A and haplotype are correlated with response to docetaxel-cisplatin chemotherapy in patients with non-small-cell lung cancer. Respiration, 2009, 78(1), 49-55.
[130] Testosterone, cognition, ageing, and cancer. Available from:
[131] International ovarian & testicular stromal tumor registry (OTST) Available from:
[132] Paclitaxel albumin-stabilized nanoparticle formulation in treating patients with advanced or refractory solid tumors. Available from:,,
[133] Dasatinib, ifosfamide, carboplatin, and etoposide in treating young patients with metastatic or recurrent malignant solid tumors. Available from:,
[134] Studying genes in samples from younger patients with ovarian or testicular sex cord stromal tumors. Available from:
[135] Health status and burden of late effects in very long-term testicular cancer survivors (STANDBY-study) (STANDBY). Available from:.
[136] Study of cisplatin-induced peripheral neuropathy in patients with germ cell tumor. Available from:,
[137] Studying biomarkers in samples from younger patients with malignant germ cell tumor progression Available from:,
[138] Establishing of neuronal-like cells from patients with cisplatin-induced peripheral neuropathy Available from:,
[139] Studying a tumor marker for testicular cancer, skin cancer, small intestine cancer, and pancreatic cancer. Available from:,
[140] DNA analysis in samples from younger patients with germ cell tumors and their parents or siblings. Available from:,
[141] A case-control study to assess the association between environmental, domestic and occupational exposures and the Risk of Testicular Germ Cell Tumor (TESTIS) Available from:.
[142] Cardiovascular morbidity in testicular cancer survivors: study of risk factors and assessment of pharmacogenomic determinants of toxicity Available from:,
[143] Toxicity attributed to genetic polymorphisms in testicular germ cell tumor survivors. Available from:,
[144] Genetics of familial testicular cancer. Available from:.

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy