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Constitutional cytogenetic analysis in men with familial testicular germ cell tumor: no evidence of disease-related abnormalities

Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Department of Health and Human Services, 6120 Executive Boulevard, EPS 7101, Rockville, MD 20852-7231, USA.
Cancer Epidemiology Biomarkers & Prevention (Impact Factor: 4.32). 01/2008; 16(12):2791-4. DOI: 10.1158/1055-9965.EPI-07-0521
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    • "An autosomal recessive model has provided the best data fit in the two segregation analyses performed to date, and several genomic regions of interest have been identified in linkage analyses, but no high-penetrance susceptibility genes have yet been identified [7-11]. We reported no disease-associated germline cytogenetic abnormalities in either the 28 FTGCT men we studied by high-resolution chromosome analysis and spectral karyotyping, or 17 previously-reported FTGCT men [12]. A Y-chromosome deletion (gr/gr) has been identified as conferring 2- and 3-fold increases in risk of sporadic and familial testicular cancers, respectively, in a small percentage of men, and reports have identified germline variants in PDE11A and DND1 as candidate modifiers of familial testicular cancer risk [13-15]. "
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    ABSTRACT: Testicular germ cell tumor (TGCT) is the most common malignancy in young men. Familial clustering, epidemiologic evidence of increased risk with family or personal history, and the association of TGCT with genitourinary (GU) tract anomalies have suggested an underlying genetic predisposition. Linkage data have not identified a rare, highly-penetrant, single gene in familial TGCT (FTGCT) cases. Based on its association with congenital GU tract anomalies and suggestions that there is an intrauterine origin to TGCT, we hypothesized the existence of unrecognized dysmorphic features in FTGCT. We evaluated 38 FTGCT individuals and 41 first-degree relatives from 22 multiple-case families with detailed dysmorphology examinations, physician-based medical history and physical examination, laboratory testing, and genitourinary imaging studies. The prevalence of major abnormalities and minor variants did not significantly differ between either FTGCT individuals or their first-degree relatives when compared with normal population controls, except for tall stature, macrocephaly, flat midface, and retro-/micrognathia. However, these four traits were not manifest as a constellation of features in any one individual or family. We did detect an excess prevalence of the genitourinary anomalies cryptorchidism and congenital inguinal hernia in our population, as previously described in sporadic TGCT, but no congenital renal, retroperitoneal or mediastinal anomalies were detected. Overall, our study did not identify a constellation of dysmorphic features in FTGCT individuals, which is consistent with results of genetic studies suggesting that multiple low-penetrance genes are likely responsible for FTGCT susceptibility.
    Hereditary Cancer in Clinical Practice 02/2014; 12(1):3. DOI:10.1186/1897-4287-12-3 · 2.10 Impact Factor
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    • "In this modern era of 'big genomic science', in which the primary research focus has shifted to large, international multi-institution analyses of pooled data sets comprising tens of thousands of study participants and literally millions of data elements, it is easy to lose sight of the fact that a great deal of important work can still be accomplished on a smaller scale, even by a single institution, in which study subjects are seen face to face, and evaluated in a comprehensive, systematic, multidisciplinary fashion. The NCI CGB Familial Testicular Cancer project is an excellent illustration of this research strategy (Peters et al. 2006, 2008, Mai et al. 2007, Mueller et al. 2007, Cook et al. 2008, Korde et al. 2008, Giambartolomei et al. 2009, Horvath et al. 2009, Vadaparampil et al. 2009), having yielded both novel, highimpact positive findings and definitive negative results, both of which are helping to shape ongoing and future research efforts into the etiology, clinical phenotype, and management of familial testicular cancer. "
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    ABSTRACT: Familial aggregations of testicular germ cell tumor (FTGCT) have been well described, suggesting the existence of a hereditary TGCT subset. Approximately 1.4% of newly diagnosed TGCT patients report a positive family history of TGCT. Sons and siblings of TGCT patients have four- to sixfold and eight- to tenfold increases in TGCT risk respectively. Segregation analyses suggest an autosomal recessive mode of inheritance. Linkage analyses have identified several genomic regions of modest interest, although no high-penetrance cancer susceptibility gene has been mapped yet. These data suggest that the combined effects of multiple common alleles, each conferring modest risk, might underlie familial testicular cancer. Families display a mild phenotype: the most common number of affected families is 2. Age at diagnosis is 2-3 years younger for familial versus sporadic cases. The ratio of familial seminoma to nonseminoma is 1.0. FTGCT is more likely to be bilateral than sporadic TGCT. This syndrome is cancer site specific. Testicular microlithiasis is a newly recognized FTGCT component. Candidate gene-association studies have implicated the Y chromosome gr/gr deletion and PDE11A gene mutations as genetic modifiers of FTGCT risk. Two genomewide association studies of predominantly sporadic but also familial cases of TGCT have implicated the KIT-ligand, SPRY4, and BAK1 genes as TGCT risk modifiers. All five loci are involved in normal testicular development and/or male infertility. These genetic data provide a novel insight into the genetic basis of FTGCT, and an invaluable guide to future TGCT research.
    Endocrine Related Cancer 03/2010; 17(2):R109-21. DOI:10.1677/ERC-09-0254 · 4.91 Impact Factor
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    • "The National Cancer Institute's Clinical Genetics Branch (CGB) is conducting a multidisciplinary aetiologic study of familial testicular cancer aimed at ascertaining and studying families with TGCT. The study objectives are to (1) characterise the clinical phenotype of familial TGCT (Mai et al, 2007); (2) determine the underlying genetic mechanism(s) for susceptibility to TGCT in families (Rapley et al, 2000; Nathanson et al, 2005; Crockford et al, 2006; Coffey et al, 2007; Mueller et al, 2007); (3) evaluate psychosocial and behavioural issues resulting from being a member of a family at increased risk of TGCT (Peters et al, 2006, 2008) and (4) create a repository of annotated biospecimens to permit translational research investigations. In this analysis, we present the results of testicular ultrasound (TUS) examinations performed during a comprehensive clinical evaluation in a subset of families enrolled on the CGB FTGCT study. "
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    ABSTRACT: Testicular germ cell tumours (TGCT) cluster in families, but responsible genes remain unidentified. The association between testicular microlithiasis (TM) and testicular carcinoma in situ (CIS) suggests that TM may be a TC risk factor. We report testicular ultrasound findings in men with familial TGCT (FTGCT) and their unaffected relatives. A total of 81 men (48 affected and 33 unaffected) from 31 families with > or =2 TC cases underwent testicular ultrasound. Testicular microlithiasis was defined as either 'classic' (> or =5 microliths) or 'limited' (<5 microliths). Statistical analyses used Fisher's exact test and permutation testing. Testicular microlithiasis was more frequent in the contralateral testicles of men with a history of TGCT (affected men) than in unaffected men (48 vs 24%, P=0.04). The association appeared stronger for classic TM (21 vs 9%) than for limited TM (27 vs 15%). Testicular microlithiases were bilateral in six out of seven (87%) unaffected men. Among affected men, TM was not associated with histology, age at diagnosis or cancer treatment. Of the 31 families, 10 accounted for a majority (61%) of the TM cases identified (P=0.11). Testicular microlithiasis was more prevalent among FTGCT family members than described previously in the general population, and was more common among FTGCT cases vs unaffected blood relatives. Testicular microlithiasis appeared to cluster in certain families. These findings suggest both a familial predisposition to TM and an association between TM and FTGCT. If proven, this could be clinically important to men in FTGCT families, and may be useful in identifying specific genes involved in FTGCT.
    British Journal of Cancer 10/2008; 99(10):1748-53. DOI:10.1038/sj.bjc.6604704 · 4.82 Impact Factor
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