Testicular Germ Cell Cancer Research Articles

Risk of germ cell testicular cancer according to origin: A migrant cohort study in 1,100,000 Israeli men

Testicular cancer incidence is highest among men of northern European ancestry and lowest among men of Asian/African descent. We conducted a large-scale migrant cohort study to assess origin and migrant generation as predictors of testicular germ cell tumors (TGCTs), controlling for possible confounders. Data on 1,092,373 Jewish Israeli males, who underwent a general health examination prior to compulsory military service at ages 16-19 between the years 1967-2005, were linked to Israel National Cancer Registry to obtain incident TGCTs up to 2006. Cox proportional hazards was used to model time to event. Overall, 1,001 incident cases (534 seminoma and 467 nonseminoma) were detected during 19.2 million person-years of follow-up. Origin was a strong independent predictor of TGCTs with remarkably low incidence for North African-born (HR = 0.10, 95% CI: 0.04-0.21) and Asian-born (HR = 0.35, 0.20-0.62), while intermediate for Israeli-born of North African origin (HR = 0.48, 0.40-0.58) and Asian origin (HR = 0.56, 0.47-0.66), compared to European origin. A comparison of Israeli born of North African and Asian origin with North African and Asian-born yielded a HR of 2.31 (1.36-3.93). Significant risk factors controlled for were year of birth, years of education and height. Findings persisted when analyses were stratified by histologic subtypes of TGCTs. The findings of lower rates of TGCTs among men born in North Africa and Asia compared to European ancestry, but a steep increase in next generation migrants, particularly among the Israeli-born migrants from North Africa, provide clues to direct further research on the role of modern lifestyle and environment in the etiology of TGCTs.

Pathological findings after primary chemotherapy in patients undergoing simultaneous orchidectomy and retroperitoneal lymph node dissection for advanced germ cell tumours

To determine the differential response to systemic chemotherapy in patients undergoing simultaneous orchidectomy and retroperitoneal lymph node dissection (RPLND) after chemotherapy for metastatic testicular cancer. Patients who underwent simultaneous RPLND and orchidectomy after chemotherapy were identified from our clinical databases. Postoperative pathological findings and patient characteristics were reviewed. In all, 42 patients were identified. After chemotherapy, necrosis, teratoma and cancer were identified in 25 (59.5%), 14 (33.3%) and three (7.1%) RPLN specimens and 15 (35.7%), 15 (35.7%) and 12 (28.6%) orchidectomy specimens respectively. Of the 25 patients with necrotic RPLN specimens 12 (48.0%) had active disease within the orchidectomy specimen (eight invasive cancer and four mature teratoma). The overall histological discordance rate was 38.1%. Findings in the orchidectomy specimens were more aggressive than those in the RPLN specimens (i.e. cancer worse than teratoma, which is worse than necrosis) in 33.3%. There is significant disparity between orchidectomy and RPLND findings with viable tumour appearing frequently in the testis despite tumour-free RPLNs. These findings support completion orchidectomy as part of advanced testicular germ cell treatment.

Frequency of the Male Infertility Evaluation: Data from the National Survey of Family Growth

An estimated 7 million American couples per year seek infertility care in the United States. A male factor contributes to 50% of cases but it is unclear what proportion of infertile couples undergoes male evaluation. We analyzed data from cycles 5 to 7 of the National Survey of Family Growth performed by the Centers for Disease Control to determine the frequency of a male infertility evaluation, and associated reproductive and demographic factors. A total of 25,846 women and 11,067 men were surveyed. Male evaluation was not completed in 18% of couples when the male partner was asked vs 27% when female partners were asked. This corresponds to approximately 370,000 to 860,000 men in the population who were not evaluated at the time of infertility evaluation. Longer infertility duration and white race were associated with increased odds of male infertility evaluation. The male and female samples showed no change in the receipt of male examination with time. Many men from infertile couples do not undergo male evaluation in the United States. Given the potential implications to reproductive goals and male health, further examination of this pattern is warranted.

866P - High-Dose Chemotherapy and Autologous Blood Stem Cell Transplantation in Refractory/Metastatic Non-Seminomatous Germ Cell Tumors: Gata Single Center Results

ABSTRACT Introduction Some patients with testis cancers do not respond to standard combination chemotherapy and high-dose chemotherapy (HDC) with autologous stem cell transplantation (OSCT) as salvage therapy can achieve a complete remission in these patients. Materials and methods 62 patients that received HDC and OSCT between February 1993 – December 2011 were retrospectively evaluated. Results Median age was 24 (22-32 years). 56 patients (90.3%) had stage III, 6 (9.6%) had stage II disease. Histopathologically, embryonal carcinoma (64%), yolk-sac (24%) and choriocarcinoma (23%) were present. The primary tumor location was testis in 51 patients (82.2%), and 11 patients (17.7%) had extragonadal region origin [6 patients retroperitoneal (9.6%), 5 patients (8.1%) mediastinal]. Evaluation of metastatic focuses was as follows: liver (n = 20, 32.2%), extrahepatic (bone, lung) involvement (n = 34, 54.8%) and central nervous system involvement (n = 5, 8.1%). Six patients with stage II had refractory-high tumor markers and were treated with at least two different lines of chemotherapy, underwent later HDC and OSCT. Two patients with stage II and 16 patients with stage III disease underwent further RPLND. HDC included ifosfamide, carboplatin, etoposide. Median follow-up was 39 (6-54) months. Pre-OSCT median AFP, β-HCG and LDH were 176 IU / ml (4.9-624), 1090 IU / ml (0.6-72000), 346 IU / ml (126–764), respectively; while on 3rd month of OSCT median AFP, β-hCG and LDH were 20 IU / ml (4–54), 4 IU / ml (0.2-20), 124 IU / ml (102-240), respectively. After HDC, 16 patients (25.8%) achieved CR, 21 patients (33.8%) had PR, 8 patients (12.9%) had SD and 17 patients (27.4%) had PD. Three-year OS rate was 41%. The median neutrophil and platelet engraftment time was 14 days (12–17) and 15 days (13–17). The most important treatment toxicity was nephrotoxicity (grade 1/2) (11.2%). Conclusions OSCT with HDC is an effective and curative treatment option in 26% of cases of refractory/metastatic germ cell testicular cancers. Disclosure All authors have declared no conflicts of interest.

Semiparametric regression in testicular germ cell data

It is possible to approach regression analysis with random covariates from a semiparametric perspective where information is combined from multiple multivariate sources. The approach assumes a semiparametric density ratio model where multivariate distributions are "regressed" on a reference distribution. A kernel density estimator can be constructed from many data sources in conjunction with the semiparametric model. The estimator is shown to be more efficient than the traditional single-sample kernel density estimator, and its optimal bandwidth is discussed in some detail. Each multivariate distribution and the corresponding conditional expectation (regression) of interest are estimated from the combined data using all sources. Graphical and quantitative diagnostic tools are suggested to assess model validity. The method is applied in quantifying the effect of height and age on weight of germ cell testicular cancer patients. Comparisons are made with multiple regression, generalized additive models (GAM) and nonparametric kernel regression.

Accuracy of Cryptorchidism Diagnoses and Corrective Surgical Treatment Registration in the Danish National Patient Registry

In recent years several Danish studies of the etiology, time trends and long-term health consequences of cryptorchidism have relied on diagnoses and surgical treatments registered in the National Patient Registry. We evaluated the diagnostic accuracy of these registry data. According to the Danish National Patient Registry, 16,168 males were diagnosed with cryptorchidism and 9,244 surgical treatments for cryptorchidism were performed between January 1, 1995 and October 10, 2009. We randomly selected 500 diagnosed cases, of which 284 had been managed surgically. We requested the medical records from the departments making the diagnoses and performing the surgery. We successfully retrieved medical records for 452 diagnosed cases (90%) and 249 operations (88%). Overall positive predictive value of a registry diagnosis of cryptorchidism was 80% (95% CI 77-84) using the testicular position described by the physician performing the clinical examination as the gold standard. Similarly the positive predictive value of the surgical treatment registration was 99% (95% CI 98-100) using the type of procedure performed. The data on cryptorchidism in the Danish National Patient Registry are quite accurate. In etiological research the limited misclassification will in most cases only slightly attenuate estimates of the true relative association. Thus, the registry has the potential to serve as a valuable research tool, although caution should be exercised when studying time trends or geographical differences.

Replication of genetic susceptibility loci for testicular germ cell cancer in the Croatian population

Genome-wide association studies in patients with testicular germ-cell tumors (TGCT) from Great Britain and the United States have identified six susceptibility loci in or near biologically plausible candidate genes. However, these loci have not been replicated in an independent European sample. We performed a genetic replication study of previously identified TGCT susceptibility loci in a Croatian case-control sample and performed additional analyses as concerning histological subtypes or tumor staging. We analyzed six single-nucleotide polymorphisms [rs2900333 (ATF7IP), rs210138 (BAK1), rs755383 (DMRT1), rs995030 (KITLG), rs4624820 (SPRY4), and rs4635969 (TERT/CLPTM1L)], each representing one of the published susceptibility loci/genes. Five susceptibility loci were found to be also associated in the Croatian population with P-values between 2.1e-10 (rs995030; odds ratio [OR] 3.08) and 0.01739 (rs4635969; OR 1.37), which remained statistically significant after correction for multiple testing. Although rs2900333 near ATF7IP just showed borderline association with all-TGCT (OR 1.24, P = 0.062), it showed significant association with the more aggressive forms of the tumor (OR 1.51, P = 0.0067)-a clinically interesting finding, which however has to be replicated in an independent sample. Assessment of cumulative risks revealed that men with at least seven risk alleles have a more than 2.5-fold increased disease risk (OR = 2.73, 95% confidence interval = 1.98-3.79). In summary, we independently replicated the majority of TGCT susceptibility loci identified previously in a Croatian sample and suggested a possible role of genetic variation near ATF7IP in regulating disease progression.

Prenatal exposure to smoking and male reproductive health

To assess whether prenatal exposure to smoking is associated with impaired reproductive health in exposed men. Men who have been exposed to maternal smoking in utero have smaller testes and impaired semen quality as compared to nonexposed men, suggesting toxic effects on Sertoli and/or germ cells. According to meta-analyses there is only a weak or no association with fetal exposure to smoking and the incidence of testicular germ cell cancer, cryptorchidism, or hypospadias. Adverse effect of maternal smoking on sperm production capacity of their son is yet another good reason for women to quit smoking before pregnancy.

Paracetamol (acetaminophen), aspirin (acetylsalicylic acid) and indomethacin are anti‐androgenic in the rat foetal testis

More than half the pregnant women in the Western world report taking mild analgesics. These pharmaceutical compounds have been associated with congenital cryptorchidism in humans, the best-known risk factor for low semen quality and testicular germ cell cancer. Furthermore, some of these mild analgesics exert potent anti-androgenic effects in the male rat and several endocrine-disrupting compounds, known to alter masculinization, have also been shown to be potent inhibitors of prostaglandin (PG) synthesis similar to mild analgesics. Using a 3-day ex vivo organotypic model system based on gestational day 14.5 rat testes, we herein show that testosterone production was inhibited by paracetamol, at doses of 0.1 μm to 100 μm. Similar results were obtained for aspirin (1-100 μm) and indomethacin (10 μm). The production of the other Leydig cell hormone, Insl3, was not disrupted by exposure to paracetamol. Investigations of the gross anatomy of the testis as well as Leydig cells number and rate of gonocyte apoptosis after the 3 days of ex vivo differentiation showed no significant effect of the analgesics tested compared with controls. These data indicate therefore that mild analgesics specifically inhibit testosterone production in rat foetal testes in vitro and that these compounds had no effect on gonocyte survival. Parallel determinations of prostaglandin D2 (PGD2) production indicated that the effects of paracetamol and aspirin on PGD2 and testosterone were not connected, whereas the effects of indomethacin were correlated. We conclude that mild analgesics exert direct and specific anti-androgenic effects in rat foetal testis in our experimental setup and that the mechanism of action is probably uncoupled from the inhibition of PG synthesis.

Induction and Persistence of Abnormal Testicular Germ Cells Following Gestational Exposure to Di‐(n‐Butyl) Phthalate in p53‐Null Mice

Phthalate esters are commonly used plasticizers found in many household items, personal care products, and medical devices. Animal studies have shown that in utero exposure to di-(n-butyl) phthalate (DBP) within a critical window during gestation causes male reproductive tract abnormalities resembling testicular dysgenesis syndrome. Our studies utilized p53-deficient mice for their ability to display greater resistance to apoptosis during development. This model was chosen to determine whether multinucleated germ cells (MNG) induced by gestational DBP exposure could survive postnatally and evolve into testicular germ cell cancer. Pregnant dams were exposed to DBP (500 mg/kg/day) by oral gavage from gestational day 12 until birth. Perinatal effects were assessed on gestational day 19 and postnatal days 1, 4, 7, and 10 for the number of MNGs present in control and DBP-treated p53-heterozygous and null animals. As expected, DBP exposure induced MNGs, with greater numbers found in p53-null mice. Additionally, there was a time-dependent decrease in the incidence of MNGs during the early postnatal period. Histologic examination of adult mice exposed in utero to DBP revealed persistence of abnormal germ cells only in DBP-treated p53-null mice, not in p53-heterozygous or wild-type mice. Immunohistochemical staining of perinatal MNGs and adult abnormal germ cells was negative for both octamer-binding protein 3/4 and placental alkaline phosphatase. This unique model identified a role for p53 in the perinatal apoptosis of DBP-induced MNGs and provided insight into the long-term effects of gestational DBP exposure within a p53-null environment.

Glial cell line–derived neurotrophic factor promotes invasive behaviour in testicular seminoma cells

The glial cell line-derived neurotrophic factor (GDNF) has multiple functions that promote cell survival, proliferation and migration in different cell types. The experimental over-expression of GDNF in mouse testis leads to infertility and promotes seminomatous germ cell tumours in older animals, which suggests that deregulation of the GDNF pathway may be implicated in germ cell carcinogenesis. GDNF activates downstream pathways upon binding to its specific co-receptor GDNF family receptor-a 1 (GFRA1). This complex then interacts with Ret and other co-receptors to activate several intracellular signalling cascades. To explore the involvement of the GDNF pathway in the onset and progression of testicular germ cell tumours, we analysed GFRA1 and Ret expression patterns in seminoma samples. We demonstrated, via immunohistochemistry, that GFRA1, but not Ret, is over-expressed in in situ carcinoma (CIS) and in intratubular and invasive seminoma cells compared with normal human germ cells. Functional analysis of the GDNF biological activity was performed on TCam-2 seminoma cell line. Reverse transcription-PCR (RT-PCR) and immunohistochemical analyses demonstrate that TCam-2 cells express both GFRA1 and Ret mRNA, but only GFRA1 was detected at the protein level. In TCam-2 cells, although GDNF is not mitogenic, it is able to induce migration, as demonstrated by a Boyden chamber assay, possibly through the Src and MEK pathways. Moreover, GDNF promotes invasive behaviour, an effect dependent on pericellular protease activity, possibly through the activity of matrix metalloproteinases. GFRA1 over-expression in CIS and seminoma cells, along with the functional analyses in TCam-2 cells, suggests an involvement of the GDNF pathway in the progression of testicular germ cell cancer.

GPR30, the non-classical membrane G protein related estrogen receptor, is overexpressed in human seminoma and promotes seminoma cell proliferation.

BackgroundTesticular germ cell tumours are the most frequent cancer of young men with an increasing incidence all over the world. Pathogenesis and reasons of this increase remain unknown but epidemiological and clinical data have suggested that fetal exposure to environmental endocrine disruptors (EEDs) with estrogenic effects, could participate to testicular germ cell carcinogenesis. However, these EEDs (like bisphenol A) are often weak ligands for classical nuclear estrogen receptors. Several research groups recently showed that the non classical membrane G-protein coupled estrogen receptor (GPER/GPR30) mediates the effects of estrogens and several xenoestrogens through rapid non genomic activation of signal transduction pathways in various human estrogen dependent cancer cells (breast, ovary, endometrium). The aim of this study was to demonstrate that GPER was overexpressed in testicular tumours and was able to trigger JKT-1 seminoma cell proliferation.ResultsWe report here for the first time a complete morphological and functional characterization of GPER in normal and malignant human testicular germ cells. In normal adult human testes, GPER was expressed by somatic (Sertoli cells) and germ cells (spermatogonia and spermatocytes). GPER was exclusively overexpressed in seminomas, the most frequent testicular germ cell cancer, localized at the cell membrane and triggered a proliferative effect on JKT-1 cells in vitro, which was completely abolished by G15 (a GPER selective antagonist) and by siRNA invalidation.ConclusionThese results demonstrate that GPER is expressed by human normal adult testicular germ cells, specifically overexpressed in seminoma tumours and able to trigger seminoma cell proliferation in vitro. It should therefore be considered rather than classical ERs when xeno-estrogens or other endocrine disruptors are assessed in testicular germ cell cancers. It may also represent a prognosis marker and/or a therapeutic target for seminomas.

Therapeutic Potential of SOX2 Inhibition for Embryonal Carcinoma

Some nonseminomatous germ cell tumors are resistant to any type of chemotherapy. Control of embryonal carcinoma cells is crucial to manage nonseminomatous germ cell tumors. We established SOX2 targeting therapy in an embryonal carcinoma model. SOX2 expression was evaluated in a series of testicular germ cell tumor tissue samples. The antitumor effect of SOX2 knockdown was analyzed in vitro and in vivo using an embryonal carcinoma model. In testicular germ cell tumor tissue SOX2 was expressed in the foci of embryonal carcinoma but negative in seminoma and yolk sac tumors. In an embryonal carcinoma model SOX2-siRNA induced apoptotic cell death in vitro and significant growth suppression in vivo. This study shows the therapeutic potential of SOX2 silencing for embryonal carcinoma. However, further improvements are needed in SOX2-siRNA delivery to the tumor.

Impact of age on clinicopathological outcomes and recurrence‐free survival after the surgical management of nonseminomatous germ cell tumour

Study Type - Therapy (case series) Level of Evidence 4. What's known on the subject? and What does the study add? The effect of advancing age on the clinicopathological outcomes of men with germ cell testicular cancers remains uncertain. Through the review and comparison of the present large cohort of men with testis cancer, we report on our experience in men aged ≥50 years. Our results showed similar clinical and pathological characteristics, and survival outcomes that compare favourably with those of men aged <50 years. To determine the impact of age on clinicopathological findings and disease recurrence in men with nonseminomatous germ cell tumour (NSGCT) undergoing retroperitoneal lymph node dissection (RPLND). We identified 1246 patients with NSGCT who underwent either primary or post-chemotherapy-RPLND (PC-RPLND) between 1989 and 2006 from our prospective testis cancer database. • Perioperative characteristics were compared among men aged < or ≥50 years. • Multivariable models were used to evaluate the association of age with disease-free survival, controlling for established clinical and pathological features. Of 514 men undergoing primary and 732 men undergoing PC-RPLND, 12 (2.3%) and 23 (3.1%) were aged ≥50 years, respectively. • There were no significant differences between men aged < or ≥50 years for perioperative clinicopathological characteristics, with the exception of pre-RPLND CT nodal size. • The pathological distributions at primary RPLND were similar in men aged < or ≥50 years. After PC-RPLND, there were no differences in RPLND histology, number of lymph nodes resected, estimated blood loss, hospital stay, or perioperative complication rate. • Age at surgery was not a significant predictor of disease recurrence when subjected to a multivariable analysis. Our data suggests that age at RPLND does not predict for disease recurrence and men aged ≥50 years had similar pre- and postoperative characteristics to those aged <50 years. • We conclude that RPLND can be safely performed in men aged ≥50 years and these patients should be offered optimal treatment regimens for NSGCT as directed according to established guidelines.

Testicular cancer risk according to county of birth and county of diagnosis in Norway, 1958–2007

Background. The etiology of testicular germ cell cancer (TGCC) is still poorly understood, but biological and epidemiological evidence suggest that TGCC originates early in life. The aim of the present study was to analyze heterogeneity in TGCC risk within Norway, comparing county of birth to county of diagnosis, in order to assess the relative contribution of risk factors acting early and later in life. A further aim was to present the Norwegian TGCC incidence rates (1958–2007). Material and methods. All TGCC cases (n = 7130) reported to the Cancer Registry of Norway, 1958–2007, were analyzed by county of diagnosis in 10-year intervals. The relative risk of TGCC based on county of birth, was estimated by Poisson regression analysis of all new TGCC cases (n = 1943), based on the mother's county of residence at the time of the son's birth, 1967–2007, obtained by linkage between the Cancer Registry and the Medical Birth Registry of Norway. Results. Between the first (1958–67) and last (1998–2007) 10-year period, the average incidence rate more than tripled from 3.3 to 10.5 per 100 000 person-years (world adjusted), respectively. The average incidence rate during 1968–2007 was highest in the county of Rogaland (8.6) and lowest in Hedmark (5.3), the ratio between them being 1.6. The relative risk of TGCC based on county of birth (1967–2007) varied between 1.43 (Møre og Romsdal) and 0.95 (Buskerud), giving a ratio of 1.5. Conclusions. The ratio between the relative risk in the highest and lowest county was basically similar when comparing counties of birth with counties of diagnosis. Thus, our data do not shed light on the relative contribution of risk factors acting early versus later in life. The incidence rate of TGCC in Norway is among the highest in the world, and the increase in incidence rate does not seem to level off.

Association of polymorphisms in genes encoding hormone receptors ESR1, ESR2 and LHCGR with the risk and clinical features of testicular germ cell cancer

Testicular germ cell cancer (TGCC) is the most common malignancy in young men. Genetic variants known to be associated with risk of TGCC only partially account for the observed familial risks. We aimed to identify additional polymorphisms associated with risk as well as histological and clinical features of TGCC in 367 patients and 214 controls. Polymorphisms in ESR2 (rs1256063; OR=0.53, 95% CI: 0.35–0.79) and LHCGR (rs4597581; OR=0.68, 95% CI: 0.51–0.89, and rs4953617; OR=1.88, 95% CI: 1.21–2.94) associated with risk of TGCC. Polymorphisms in ESR1 (rs9397080; OR=1.85, 95% CI: 1.18–2.91) and LHCGR (rs7371084; OR=2.37, 95% CI: 1.26–4.49) associated with risk of seminoma and metastasis, respectively. SNPs in ESR1 (rs9397080) and LHCGR (rs7371084) were predictors of higher LH levels and higher androgen sensitivity index in healthy subjects. The results suggest that polymorphisms in ESR1, ESR2 and LHCGR contribute to the risk of developing TGCC, histological subtype, and risk to metastasis.

Small Cell Lung Cancer Doubling Time and its Effect on Clinical Presentation: A Concise Review

Small cell lung cancer (SCLC) is one of many types rapidly growing malignant diseases, such as Burkitt’s lymphoma and testicular germ cell cancers. At present, there is no reliable way to screen for SCLC, and imaging modalities tend to be delayed in detecting this type of cancer. The clinical presentation of acutely and rapidly growing SCLC can mimic those of pulmonary inflammatory or infectious disorders, and in some instances, this delays appropriate management and negatively affects patient outcome.

Commentary on “Survival after resection for metastatic testicular nonseminomatous germ cell cancer to the lung or mediastinum.” Kenneth A. Kesler, a Laura E. Kruter, a Susan M. Perkins, b Karen M. Rieger, a Katherine J. Sullivan, a Matthew L. Runyan, a John W. Brown, a Lawrence H. Einhorn, caDepartment of Surgery, Cardiothoracic Division and Medicine, Indiana University Melvin and Bren

Commentary on “Survival after resection for metastatic testicular nonseminomatous germ cell cancer to the lung or mediastinum.” Kenneth A. Kesler, a Laura E. Kruter, a Susan M. Perkins, b Karen M. Rieger, a Katherine J. Sullivan, a Matthew L. Runyan, a John W. Brown, a Lawrence H. Einhorn, caDepartment of Surgery, Cardiothoracic Division and Medicine, Indiana University Melvin and Bren

Telomerase-Independent Paths to Immortality in Predictable Cancer Subtypes

The vast majority of cancers commandeer the activity of telomerase - the remarkable enzyme responsible for prolonging cellular lifespan by maintaining the length of telomeres at the ends of chromosomes. Telomerase is only normally active in embryonic and highly proliferative somatic cells. Thus, targeting telomerase is an attractive anti-cancer therapeutic rationale currently under investigation in various phases of clinical development. However, previous reports suggest that an average of 10-15% of all cancers lose the functional activity of telomerase and most of these turn to an Alternative Lengthening of Telomeres pathway (ALT). ALT-positive tumours will therefore not respond to anti-telomerase therapies and there is a real possibility that such drugs would be toxic to normal telomerase-utilising cells and ultimately select for resistant cells that activate an ALT mechanism. ALT exploits certain DNA damage response (DDR) components to counteract telomere shortening and rapid trimming. ALT has been reported in many cancer subtypes including sarcoma, gastric carcinoma, central nervous system malignancies, subtypes of kidney (Wilm's Tumour) and bladder carcinoma, mesothelioma, malignant melanoma and germ cell testicular cancers to name but a few. A recent heroic study that analysed ALT in over six thousand tumour samples supports this historical spread, although only reporting an approximate 4% prevalence. This review highlights the various methods of ALT detection, unravels several molecular ALT models thought to promote telomere maintenance and elongation, spotlights the DDR components known to facilitate these and explores why certain tissues are more likely to subvert DDR away from its usually protective functions, resulting in a predictive pattern of prevalence in specific cancer subsets.

Epigenetic: a molecular link between testicular cancer and environmental exposures

In the last decades, studies in rodents have highlighted links between in utero and/or neonatal exposures to molecules that alter endocrine functions and the development of genital tract abnormalities, such as cryptorchidism, hypospadias, and impaired spermatogenesis. Most of these molecules, called endocrine disrupters exert estrogenic and/or antiandrogenic activities. These data led to the hypothesis of the testicular dysgenesis syndrome which postulates that these disorders are one clinical entity and are linked by epidemiological and pathophysiological relations. Furthermore, infertility has been stated as a risk factor for testicular cancer (TC). The incidence of TC has been increasing over the past decade. Most of testicular germ cell cancers develop through a pre-invasive carcinoma in situ from fetal germ cells (primordial germ cell or gonocyte). During their development, fetal germ cells undergo epigenetic modifications. Interestingly, several lines of evidence have shown that gene regulation through epigenetic mechanisms (DNA and histone modifications) plays an important role in normal development as well as in various diseases, including TC. Here we will review chromatin modifications which can affect testicular physiology leading to the development of TC; and highlight potential molecular pathways involved in these alterations in the context of environmental exposures.