Increased prevalence of testicular microlithiasis in men with familial testicular cancer and their relatives

Korde, Larissa A.; Premkumar, Ahalya; Mueller, Christine M.; Rosenberg, Philip S.; Soho, C; Bratslavsky, Gennady; Greene, Mark H.

doi:10.1038/sj.bjc.6604704

Cited by 42 publications

(42 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Male infertility also confers a significantly increased risk of testicular cancer (Standardized Incidence Ratio [SIR] 2.8, 95%CI=1.5–4.8) (33). Both our group and British investigators have implicated testicular microlithiasis in TGCT risk (34, 35). There is also evidence that infertility may be increased in males from TGCT families compared with the general population (36).…”

Section: Introductionmentioning

confidence: 86%

Prospectively Identified Incident Testicular Cancer Risk in a Familial Testicular Cancer Cohort

Pathak

Adams

Loud

et al. 2015

Cancer Epidemiology, Biomarkers &Amp; Prevention

View full text Add to dashboard Cite

Background Human testicular germ cell tumors (TGCT) have a strong genetic component and a high familial relative risk. However, linkage analyses have not identified a rare, highly-penetrant familial TGCT (FTGCT) susceptibility locus. Currently, multiple low-penetrance genes are hypothesized to underlie the familial multiple-case phenotype. The observation that two is the most common number of affected individuals per family presents an impediment to FTGCT gene discovery. Clinically, the prospective TGCT risk in the multiple-case family context is unknown. Methods We performed a prospective analysis of TGCT incidence in a cohort of multiple-affected-person families and sporadic-bilateral-case families; 1,260 men from 140 families (10,207 person-years of follow-up) met our inclusion criteria. Age-, gender-, and calendar time-specific standardized incidence ratios (SIR) for TGCT relative to the general population were calculated using SEER*Stat. Results Eight incident TGCTs occurred during prospective FTGCT cohort follow-up (versus 0.67 expected; SIR=11.9; 95% confidence interval [CI]=5.1–23.4; excess absolute risk=7.2/10,000). We demonstrate that the incidence rate of TGCT is greater among bloodline male relatives from multiple-case testicular cancer families than that expected in the general population, a pattern characteristic of adult-onset Mendelian cancer susceptibility disorders. Two of these incident TGCTs occurred in relatives of sporadic-bilateral cases (0.15 expected; SIR=13.4; 95%CI=1.6–48.6). Conclusions Our data are the first indicating that despite relatively low numbers of affected individuals per family, members of both multiple-affected-person FTGCT families and sporadic-bilateral TGCT families comprise high-risk groups for incident testicular cancer. Impact Men at high TGCT risk might benefit from tailored risk stratification and surveillance strategies.

show abstract

Section: Introductionmentioning

confidence: 86%

Prospectively Identified Incident Testicular Cancer Risk in a Familial Testicular Cancer Cohort

Pathak

Adams

Loud

et al. 2015

Cancer Epidemiology, Biomarkers &Amp; Prevention

View full text Add to dashboard Cite

show abstract

“…There are important aetiologic implications if it can be established that single nucleotide polymorphism (SNP) associations are homogenous in familial and sporadic cases. The National Cancer Institute's (NCI) Clinical Genetics Branch is conducting a multidisciplinary aetiologic study of familial and sporadic bilateral TGCT, and those cases are independent of those published in GWAS to date 14. Here, we investigated whether four of the previously identified regions are associated with familial or bilateral TGCT cases in our study cohort.…”

Section: Introductionmentioning

confidence: 99%

Variants in or near KITLG, BAK1, DMRT1, and TERT-CLPTM1L predispose to familial testicular germ cell tumour

Kratz

Han

Rosenberg

et al. 2011

Journal of Medical Genetics

View full text Add to dashboard Cite

Background Familial testicular germ cell tumours (TGCTs) and bilateral TGCTs comprise 1–2% and 5% of all TGCTs, respectively, but their genetic basis remains largely unknown. Aim To investigate the contribution of known testicular cancer risk variants in familial and bilateral TGCTs. Methods and results The study genotyped 106 single nucleotide polymorphisms (SNPs) in four regions (BAK1, DMRT1, KITLG, TERT-CLPTM1L) previously identified from genome-wide association studies of TGCT, including risk single nucleotide polymorphisms (SNPs) rs210138 (BAK1), rs755383 (DMRT1), rs4635969 (TERT-CLPTM1L) in 97 cases with familial TGCT and 22 affected individuals with sporadic bilateral TGCT as well as 871 controls. Using a generalised estimating equations method that takes into account blood relationships among cases, the associations with familial and bilateral TGCT were analysed. Three previously identified risk SNPs were found to be associated with familial and bilateral TGCT (rs210138: OR 1.80, CI 1.35 to 2.41, p = 7.03×10−5; rs755383: OR 1.67, CI 1.23 to 2.22, p=6.70×10−4; rs4635969: OR 1.59, CI 1.16 to 2.19, p=4.07×10−3). Evidence for a second independent association was found for an SNP in TERT (rs4975605: OR 1.68, CI 1.23 to 2.29, p=1.24×10−3). Another association with an SNP was identified in KITLG (rs2046971: OR 2.33, p=1.28×10−3); this SNP is in high linkage disequilibrium (LD) with reported risk variant rs995030. Conclusion This study provides evidence for replication of recent genome-wide association studies results and shows that variants in or near BAK1, DMRT1, TERT-CLPTM1L, and KITLG predispose to familial and bilateral TGCT. These findings imply that familial TGCT and sporadic TGCT share a common genetic basis.

show abstract

“…Indeed, a genetic predisposition has been suggested for human testicular microlithiasis (ie, microcalcification within seminiferous tubules). 45,46 In clinical studies of humans, testicular microlithiasis has been detected in several pathological conditions, including infertility, cryptorchidism, testicular neoplasms, Klinefelter's syndrome, varicocele, and torsion of the testis, 47,48 as well as in normal testes. 45,49 Whether scrotal hyperthermia can induce irreversible calcification in human testes is unclear, but it has been reported that scrotal hyperthermia by exposure to sauna heat could have adverse effects on human spermatogenesis over 3 months.…”

Section: Heat-induced Testicular Calcificationmentioning

confidence: 99%

The Onset of Heat-Induced Testicular Calcification in Mice

Chihara

Nakamura

Sakakibara

et al. 2014

The American Journal of Pathology

View full text Add to dashboard Cite

Spermatocytes of MRL/MpJ mice are more heat resistant than those of C57BL/6 mice in experimental cryptorchidism. This phenotype depends in part on the locus at the 81-cM region of MRL/MpJ-type chromosome 1 (Chr 1). To evaluate the function of this locus, we examined pathological changes in mouse testes resulting from transient scrotal heat stress. Immediately after scrotal heat stress, meiosis progression and blood-testis barrier integrity were preserved in MRL/MpJ but not in C57BL/6 mice, nor in a C57BL/6-based congenic strain carrying the MRL/MpJ-derived Chr 1 locus (B6.MRLc1). Testicular damage was severe in the weeks after scrotal heat stress in all three strains; however, testicular calcification was observed only in C57BL/6 and MRL/MpJ mice (initially as nanocrystals in mitochondria of degenerating germ cells). In testes, expression of gremlin 2, a bone morphogenetic protein antagonist encoded on Chr 1, was markedly higher in B6.MRLc1 than in C57BL/6 or MRL/MpJ mice. Furthermore, gremlin-2 and bone morphogenetic protein 2 mRNA levels in heated testes correlated negatively and positively, respectively, with calcification. Thus, although the MRL/MpJ-derived locus on Chr 1 may play a pivotal role in recovery from heat-induced testicular damage, especially via inhibition of calcification, MRL/MpJ mice have a precipitating factor for testicular calcification and heat shock-resistant factors that reside outside the 81-cM region of Chr 1.

show abstract

Increased prevalence of testicular microlithiasis in men with familial testicular cancer and their relatives

Cited by 42 publications

References 34 publications

Prospectively Identified Incident Testicular Cancer Risk in a Familial Testicular Cancer Cohort

Prospectively Identified Incident Testicular Cancer Risk in a Familial Testicular Cancer Cohort

Variants in or near KITLG, BAK1, DMRT1, and TERT-CLPTM1L predispose to familial testicular germ cell tumour

The Onset of Heat-Induced Testicular Calcification in Mice

Contact Info

Product

Resources

About