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• W2045087913 abstract "Testicular germ cell tumor (TGCT) is the most common cancer in young men. Despite a considerable familial component to TGCT risk, no genetic change that confers increased risk has been substantiated to date. The human Y chromosome carries a number of genes specifically involved in male germ cell development, and deletion of the AZFc region at Yq11 is the most common known genetic cause of infertility. Recently, a 1.6-Mb deletion of the Y chromosome that removes part of the AZFc region—known as the “gr/gr” deletion—has been associated with infertility. In epidemiological studies, male infertility has shown an association with TGCT that is out of proportion with what can be explained by tumor effects. Thus, we hypothesized that the gr/gr deletion may be associated with TGCT. Using logistic modeling, we analyzed this deletion in a large series of TGCT cases with and without a family history of TGCT. The gr/gr deletion was present in 3.0% (13/431) of TGCT cases with a family history, 2% (28/1,376) of TGCT cases without a family history, and 1.3% (33/2,599) of unaffected males. Presence of the gr/gr deletion was associated with a twofold increased risk of TGCT (adjusted odds ratio [aOR] 2.1; 95% confidence interval [CI] 1.3–3.6; P = .005) and a threefold increased risk of TGCT among patients with a positive family history (aOR 3.2; 95% CI 1.5–6.7; P = .0027). The gr/gr deletion was more strongly associated with seminoma (aOR 3.0; 95% CI 1.6–5.4; P = .0004) than with nonseminoma TGCT (aOR 1.5; 95% CI 0.72–3.0; P = .29). These data indicate that the Y microdeletion gr/gr is a rare, low-penetrance allele that confers susceptibility to TGCT. Testicular germ cell tumor (TGCT) is the most common cancer in young men. Despite a considerable familial component to TGCT risk, no genetic change that confers increased risk has been substantiated to date. The human Y chromosome carries a number of genes specifically involved in male germ cell development, and deletion of the AZFc region at Yq11 is the most common known genetic cause of infertility. Recently, a 1.6-Mb deletion of the Y chromosome that removes part of the AZFc region—known as the “gr/gr” deletion—has been associated with infertility. In epidemiological studies, male infertility has shown an association with TGCT that is out of proportion with what can be explained by tumor effects. Thus, we hypothesized that the gr/gr deletion may be associated with TGCT. Using logistic modeling, we analyzed this deletion in a large series of TGCT cases with and without a family history of TGCT. The gr/gr deletion was present in 3.0% (13/431) of TGCT cases with a family history, 2% (28/1,376) of TGCT cases without a family history, and 1.3% (33/2,599) of unaffected males. Presence of the gr/gr deletion was associated with a twofold increased risk of TGCT (adjusted odds ratio [aOR] 2.1; 95% confidence interval [CI] 1.3–3.6; P = .005) and a threefold increased risk of TGCT among patients with a positive family history (aOR 3.2; 95% CI 1.5–6.7; P = .0027). The gr/gr deletion was more strongly associated with seminoma (aOR 3.0; 95% CI 1.6–5.4; P = .0004) than with nonseminoma TGCT (aOR 1.5; 95% CI 0.72–3.0; P = .29). These data indicate that the Y microdeletion gr/gr is a rare, low-penetrance allele that confers susceptibility to TGCT. Testicular germ cell tumor (TGCT [MIM 273300]) is the most common cancer in men aged 15–40 years. The worldwide incidence is 7.5 per 100,000, but rates vary between countries, with the highest incidence among men of European descent (Huyghe et al. Huyghe et al., 2003Huyghe E Matsuda T Thonneau P Increasing incidence of testicular cancer worldwide: a review.J Urol. 2003; 170: 5-11Abstract Full Text Full Text PDF PubMed Scopus (453) Google Scholar; Jemal et al. Jemal et al., 2004Jemal A Tiwari RC Murray T Ghafoor A Samuels A Ward E Feuer EJ Thun MJ American Cancer Society Cancer statistics, 2004.CA Cancer J Clin. 2004; 54: 8-29Crossref PubMed Scopus (3853) Google Scholar). The incidence of TGCT has more than doubled over the past 50 years; however, the underlying etiology is unknown (Davies Davies, 1981Davies JM Testicular cancer in England and Wales: some epidemiological aspects.Lancet. 1981; 1: 928-932Abstract PubMed Scopus (102) Google Scholar; Adami et al. Adami et al., 1994Adami HO Bergstrom R Mohner M Zatonski W Storm H Ekbom A Tretli S Teppo L Ziegler H Rahu M Gurevicius R Stengrevics A Testicular cancer in nine northern European countries.Int J Cancer. 1994; 59: 33-38Crossref PubMed Scopus (422) Google Scholar; Bergstrom et al. Bergstrom et al., 1996Bergstrom R Adami HO Mohner M Zatonski W Storm H Ekbom A Tretli S Teppo L Akre O Hakulinen T Increase in testicular cancer incidence in six European countries: a birth cohort phenomenon.J Natl Cancer Inst. 1996; 88: 727-733Crossref PubMed Scopus (385) Google Scholar; Bosl et al. Bosl et al., 1997Bosl GJ Sheinfeld J Bajorin DF Motzer RJ Cancer of the testis.in: Devita VT Hellman S Rosenberg SA Cancer: principles & practice of oncology. Lippincott-Raven, Philadelphia1997: 1397-1425Google Scholar). Family history is among the strongest known risk factors for TGCT, with multiple studies documenting that brothers and fathers of patients with TCGT have an 8–12-fold and a 4–6-fold increased risk, respectively (Forman et al. Forman et al., 1992Forman D Oliver RT Brett AR Marsh SG Moses JH Bodmer JG Chilvers CE Pike MC Familial testicular cancer: a report of the UK family register, estimation of risk and an HLA class 1 sib-pair analysis.Br J Cancer. 1992; 65: 255-262Crossref PubMed Scopus (187) Google Scholar; Heimdal et al. Heimdal et al., 1996Heimdal K Olsson H Tretli S Flodgren P Borresen AL Fossa SD Familial testicular cancer in Norway and southern Sweden.Br J Cancer. 1996; 73: 964-969Crossref PubMed Scopus (110) Google Scholar; Westergaard et al. Westergaard et al., 1996Westergaard T Olsen JH Frisch M Kroman N Nielsen JW Melbye M Cancer risk in fathers and brothers of testicular cancer patients in Denmark: a population-based study.Int J Cancer. 1996; 66: 627-631Crossref PubMed Scopus (119) Google Scholar; Sonneveld et al. Sonneveld et al., 1999Sonneveld DJ Sleijfer DT Schrafford Koops H Sijmons RH van der Graaf WT Sluiter WJ Hoekstra HJ Familial testicular cancer in a single-centre population.Eur J Cancer. 1999; 35: 1368-1373Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar; Hemminki and Li Hemminki and Li, 2004Hemminki K Li X Familial risk in testicular cancer as a clue to a heritable and environmental etiology.Br J Cancer. 2004; 90: 1765-1770Crossref PubMed Scopus (158) Google Scholar). These relative risks are stronger than those for most other cancer types (Hemminki and Eng Hemminki and Eng, 2004Hemminki K Eng C Clinical genetic counselling for familial cancers requires reliable data on familial cancer risks and general action plans.J Med Genet. 2004; 41: 801-807Crossref PubMed Scopus (46) Google Scholar), suggesting that there is a substantial genetic contribution to TGCT susceptibility. Additional risk factors for the development of TGCT include previous TGCT, undescended testes (UDT [MIM 219050]), gonadal dysgenesis (MIM 233430), hypospadius (MIM 146450), hernia, and male infertility (Schottenfeld et al. Schottenfeld et al., 1980Schottenfeld D Warshauer ME Sherlock S Zauber AG Leder M Payne R The epidemiology of testicular cancer in young adults.Am J Epidemiol. 1980; 112: 232-246Crossref PubMed Scopus (247) Google Scholar; Moller and Skakkebaek Moller and Skakkebaek, 1996Moller H Skakkebaek NE Risks of testicular cancer and cryptorchidism in relation to socio-economic status and related factors: case-control studies in Denmark.Int J Cancer. 1996; 66: 287-293Crossref PubMed Scopus (124) Google Scholar; Petersen et al. Petersen et al., 1998bPetersen PM Skakkebaek NE Giwercman A Gonadal function in men with testicular cancer: biological and clinical aspects.APMIS. 1998b; 106: 24-34Crossref PubMed Scopus (74) Google Scholar; Akre et al. Akre et al., 1999Akre O Lipworth L Cnattingius S Sparen P Ekbom A Risk factor patterns for cryptorchidism and hypospadias.Epidemiology. 1999; 10: 364-369Crossref PubMed Scopus (195) Google Scholar). Patients with TGCT often present with abnormal semen characteristics beyond those that can be easily explained by localized or systemic effects of the tumor, and TGCT is found at increased frequency among men who showed abnormal results on semen analysis (Petersen et al. Petersen et al., 1998aPetersen PM Giwercman A Skakkebaek NE Rorth M Gonadal function in men with testicular cancer.Semin Oncol. 1998a; 25: 224-233PubMed Google Scholar; Jacobsen et al. Jacobsen et al., 2000Jacobsen R Bostofte E Engholm G Hansen J Olsen JH Skakkebaek NE Moller H Risk of testicular cancer in men with abnormal semen characteristics: cohort study.BMJ. 2000; 321: 789-792Crossref PubMed Scopus (272) Google Scholar). It has been documented that patients with TGCT have lower fecundity than that of healthy controls (Moller and Skakkebaek Moller and Skakkebaek, 1999Moller H Skakkebaek NE Risk of testicular cancer in subfertile men: case-control study.BMJ. 1999; 318: 559-562Crossref PubMed Scopus (222) Google Scholar; Richiardi et al. Richiardi et al., 2004Richiardi L Akre O Montgomery SM Lambe M Kvist U Ekbom A Fecundity and twinning rates as measures of fertility before diagnosis of germ-cell testicular cancer.J Natl Cancer Inst. 2004; 96: 145-147Crossref PubMed Scopus (58) Google Scholar). Given the link between male infertility and TGCT—and the fact that familial aggregation has also been demonstrated for male infertility—genetic factors may exist that contribute to both conditions (Lilford et al. Lilford et al., 1994Lilford R Jones AM Bishop DT Thornton J Mueller R Case-control study of whether subfertility in men is familial.BMJ. 1994; 309: 570-573Crossref PubMed Scopus (149) Google Scholar). Microdeletions of the Y chromosome are the most common known cause of infertility due to spermatogenic failure and account for ∼10% of cases (Vogt et al. Vogt et al., 1996Vogt PH Edelmann A Kirsch S Henegariu O Hirschmann P Kiesewetter F Kohn FM Schill WB Farah S Ramos C Hartmann M Hartschuh W Meschede D Behre HM Castel A Nieschlag E Weidner W Grone HJ Jung A Engel W Haidl G Human Y chromosome azoospermia factors (AZF) mapped to different subregions in Yq11.Hum Mol Genet. 1996; 5: 933-943Crossref PubMed Scopus (1079) Google Scholar; Kuroda-Kawaguchi et al. Kuroda-Kawaguchi et al., 2001Kuroda-Kawaguchi T Skaletsky H Brown LG Minx PJ Cordum HS Waterston RH Wilson RK Silber S Oates R Rozen S Page DC The AZFc region of the Y chromosome features massive palindromes and uniform recurrent deletions in infertile men.Nat Genet. 2001; 29: 279-286Crossref PubMed Scopus (535) Google Scholar). Male infertility has been associated with specific deletions of Yq11: AZFa, -b, and -c (MIM 415000). The AZF deletions are due to recombination between large palindromic sequences that have >99.9% identity and are composed of long, direct and indirect repeats called “amplicons” (Vogt et al. Vogt et al., 1996Vogt PH Edelmann A Kirsch S Henegariu O Hirschmann P Kiesewetter F Kohn FM Schill WB Farah S Ramos C Hartmann M Hartschuh W Meschede D Behre HM Castel A Nieschlag E Weidner W Grone HJ Jung A Engel W Haidl G Human Y chromosome azoospermia factors (AZF) mapped to different subregions in Yq11.Hum Mol Genet. 1996; 5: 933-943Crossref PubMed Scopus (1079) Google Scholar; Kuroda-Kawaguchi et al. Kuroda-Kawaguchi et al., 2001Kuroda-Kawaguchi T Skaletsky H Brown LG Minx PJ Cordum HS Waterston RH Wilson RK Silber S Oates R Rozen S Page DC The AZFc region of the Y chromosome features massive palindromes and uniform recurrent deletions in infertile men.Nat Genet. 2001; 29: 279-286Crossref PubMed Scopus (535) Google Scholar; Skaletsky et al. Skaletsky et al., 2003Skaletsky H Kuroda-Kawaguchi T Minx PJ Cordum HS Hillier L Brown LG Repping S et al.The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes.Nature. 2003; 423: 825-837Crossref PubMed Scopus (1524) Google Scholar). The ampliconic portion of the male-specific Y (MSY) region of the human Y chromosome contains a high density of genes from nine gene families, with each gene existing in multiple (2–35) near-identical copies (Skaletsky et al. Skaletsky et al., 2003Skaletsky H Kuroda-Kawaguchi T Minx PJ Cordum HS Hillier L Brown LG Repping S et al.The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes.Nature. 2003; 423: 825-837Crossref PubMed Scopus (1524) Google Scholar). Genes within the ampliconic portion of the MSY are expressed predominantly or exclusively in the testis and are believed to contribute to the development and proliferation of germ cells (Reijo et al. Reijo et al., 1995Reijo R Lee T-Y Salo P Alagappan R Brown LG Rosenberg M Rozen S Jaffe T Straus D Hovatta O de la Chapelle A Silber S Page DC Diverse spermatogenic defects in humans caused by Y chromosome deletions encompassing a novel RNA-binding protein gene.Nat Genet. 1995; 10: 383-393Crossref PubMed Scopus (1089) Google Scholar). Given the important function of these genes in spermatogenesis, the known deletions in the region, and the link between infertility and TGCT, it has been postulated that the deletions in AZF might be associated with TGCT. However, neither AZF deletions nor Y-chromosome haplotypes have previously been associated with TGCT case status (Frydelund-Larsen et al. Frydelund-Larsen et al., 2003Frydelund-Larsen L Vogt PH Leffers H Schadwinkel A Daugaard G Skakkebaek NE Rajpert-De Meyts E No AZF deletion in 160 patients with testicular germ cell neoplasia.Mol Hum Reprod. 2003; 9: 517-521Crossref PubMed Scopus (23) Google Scholar; Quintana-Murci et al. Quintana-Murci et al., 2003Quintana-Murci L Weale ME Thomas MG Erdei E Bradman N Shanks JH Krausz C McElreavey K Y chromosome haplotypes and testicular cancer in the English population.J Med Genet. 2003; 40: e20Crossref PubMed Scopus (16) Google Scholar). A novel, Y-chromosome 1.6-Mb deletion, designated “gr/gr,” was described recently and has been found to be associated with spermatogenic failure (Repping et al. Repping et al., 2003Repping S Skaletsky H Brown L van Daalen SK Korver CM Pyntikova T Kuroda-Kawaguchi T de Vries JW Oates RD Silber S van der Veen F Page DC Rozen S Polymorphism for a 1.6-Mb deletion of the human Y chromosome persists through balance between recurrent mutation and haploid selection.Nat Genet. 2003; 35: 247-251Crossref PubMed Scopus (354) Google Scholar; Machev et al. Machev et al., 2004Machev N Saut N Longepied G Terriou P Navarro A Levy N Guichaoua M Metzler-Guillemain C Collignon P Frances AM Belougne J Clemente E Chiaroni J Chevillard C Durand C Ducourneau A Pech N McElreavey K Mattei MG Mitchell MJ Sequence family variant loss from the AZFc interval of the human Y chromosome, but not gene copy loss, is strongly associated with male infertility.J Med Genet. 2004; 41: 814-825Crossref PubMed Scopus (127) Google Scholar; de Llanos et al. de Llanos et al., 2005de Llanos M Ballesca JL Gazquez C Margarit E Oliva R High frequency of gr/gr chromosome Y deletions in consecutive oligospermic ICSI candidates.Hum Reprod. 2005; 20: 216-220Crossref PubMed Scopus (89) Google Scholar; Ferlin et al. Ferlin et al., 2005Ferlin A Tessari A Ganz F Marchina E Barlati S Garolla A Engl B Foresta C Association of partial AZFc region deletions with spermatogenic impairment and male infertility.J Med Genet. 2005; 42: 209-213Crossref PubMed Scopus (158) Google Scholar; Hucklenbroich et al. Hucklenbroich et al., 2005Hucklenbroich K Gromoll J Heinrich M Hohoff C Nieschlag E Simoni M Partial deletions in the AZFc region of the Y chromosome occur in men with impaired as well as normal spermatogenesis.Hum Reprod. 2005; 20: 191-197Crossref PubMed Scopus (130) Google Scholar; Lynch et al. Lynch et al., 2005Lynch M Cram DS Reilly A O'Bryan MK Baker HW de Kretser DM McLachlan RI The Y chromosome gr/gr subdeletion is associated with male infertility.Mol Hum Reprod. 2005; 11: 507-512Crossref PubMed Scopus (97) Google Scholar). The gr/gr deletion removes part of the AZFc region, including two copies of DAZ (deleted in azospermia [MIM 400003]) and one copy of CDY1 (chromodomain protein, Y-linked 1 [MIM 400016]), as well as several other transcription units. Since father-to-son transmission is observed, the gr/gr deletion likely results in subfertility rather than complete infertility. The deletion was observed to be in association with numerous Y haplotypes, which suggests multiple independent recombination events (Repping et al. Repping et al., 2003Repping S Skaletsky H Brown L van Daalen SK Korver CM Pyntikova T Kuroda-Kawaguchi T de Vries JW Oates RD Silber S van der Veen F Page DC Rozen S Polymorphism for a 1.6-Mb deletion of the human Y chromosome persists through balance between recurrent mutation and haploid selection.Nat Genet. 2003; 35: 247-251Crossref PubMed Scopus (354) Google Scholar). We hypothesized that the gr/gr deletion may play a role in TGCT susceptibility, and we have assessed this genetic factor in a large, international, multicenter study of men with and without TGCT. We studied 4,441 males obtained from numerous sources that we grouped into four categories (table 1), as follows.Table 1Prevalence of the gr/gr Deletion in TGCT-Affected and Unaffected MalesPrevalence of gr/gr DeletionSubject Groupn%Probands of multiple-case familiesaExcludes one member from each of 12 MZ twin pairs.: ITCLC family probands13/3963.3 Case-series family probandsbNine of the case-series probands were part of the ITCLC and are included in table 2. 0/35 0 Total13/4313.0TGCT sporadic case seriescIndividuals with solitary or bilateral TGCT and no family history of TGCT.: London12/4192.9 Leeds (United Kingdom)2/263.8 Rotterdam4/3111.3 Toronto2/1414.3 Hungary0/180 Other (Germany, Ireland, and Russia)dThese sites are contributors to the ITCLC. 0/8 0 Total20/1,0331.9TGCT sporadic cases from case-control series: Philadelphia3/993.0 Washington StateeDoes not include 23 individuals with unknown family history.5/1673.0 Total8/2663.0Affected individuals: With solitary TGCTfPatients ascertained because of family history of UDT.0/170 With bilateral TGCTgPatients ascertained as bilateral cases with no family history of TGCT.0/610 Total0/780Unaffected males: U.K. control series I3/1352.2 U.K. control series II1/514.2 U.K. control series III1/225.4 U.K. control series IV7/4001.7 Philadelphia5/518.9 Washington State8/4351.6 Hungary 8/394 2.0 Total33/2,5991.3a Excludes one member from each of 12 MZ twin pairs.b Nine of the case-series probands were part of the ITCLC and are included in table 2.c Individuals with solitary or bilateral TGCT and no family history of TGCT.d These sites are contributors to the ITCLC.e Does not include 23 individuals with unknown family history.f Patients ascertained because of family history of UDT.g Patients ascertained as bilateral cases with no family history of TGCT. Open table in a new tab The International Testicular Cancer Linkage Consortium (ITCLC) has obtained genomic DNA from at least one affected individual from 418 pedigrees with two or more members who have TGCT (Rapley et al. Rapley et al., 2000Rapley EA Crockford GP Teare D Biggs P Seal S Barfoot R Edwards S et al.Localization to Xq27 of a susceptibility gene for testicular germ-cell tumours.Nat Genet. 2000; 24: 197-200Crossref PubMed Scopus (216) Google Scholar). The pedigree structures and the sources of these families are shown in table 2. All cases of TGCT with DNA sampled from TGCT pedigrees in the ITCLC were genotyped in the present study; however, only the proband case designated by the local site was counted for statistical analysis. Probands were index cases from which the pedigree was ascertained. The ITCLC has also collected genomic DNA from 61 males affected with bilateral TGCT and 17 males with TGCT and a family history of UDT—both groups without a family history of TGCT. In addition, 35 probands with a family history of TGCT were identified from one of the case series described below, 10 of which were referred to the ITCLC and counted as one of their 418 pedigrees. From the United Kingdom, 682 TGCT-affected patients without a family history were recruited as members of two case series. The first was a consecutive series of patients with TGCT who attended the Royal Marsden National Health Service Trust Hospital testicular cancer clinic (London) from 1996 onward. The second case series was recruited from patients with TGCT who attended the outpatient clinic at Cookridge Hospital (Leeds) during the period from September 1999 to May 2002. In The Netherlands, 311 cases were collected from 12 different hospitals in Rotterdam and surrounding districts between 1991 and 2004. The 18 Hungarian cases were collected from the National Institute of Oncology (Budapest) from 2001 to 2004. The 14 cases from Canada were patients at the Princess Margaret Hospital Testis Clinic (Toronto) collected from 2002 to 2004. Consecutive cases of TGCT were ascertained from the University of Pennsylvania Health System (UPHS), and controls were ascertained from UPHS General Medicine and Student Health clinics and were frequency-matched by age and race; 60% of cases are incident, and the remainder are prevalent. The Fred Hutchinson Cancer Research Center (FHCRC) study is a population-based study of patients with first primary TGCT newly diagnosed between 1999 and 2002 among 18–44-year-old residents of three urban counties of western Washington State. Control subjects were frequency-matched by age and were ascertained from the general population of the three counties by use of random-digit telephone dialing. In the FHCRC study, family history of TGCT was determined only among first-degree relatives. Because there were only a few individuals of minority ethnicity in these two studies, and to remain consistent with the assumed predominate ethnicity of the case probands from other ascertainment centers for whom ethnicity is unknown, only non-Hispanic whites from the two case-control studies were included in the analyses. Four series of otherwise healthy white British males were identified. Series I consists of male spouses of patients with cancer who attended the Royal Marsden Hospital National Health Service Trust. Series II consists of spouses of female patients who were recruited as part of the National Cancer Research Network Trial (1999–2002), the Royal Marsden National Hospital Service Trust/Institute of Cancer Research Family History and DNA Registry (1999–2004), or the case-control Genetic Lung Cancer Predisposition Study (1999–2004). Series III consists of male children from the North Cumbria Community Genetics Project from whom umbilical cord blood was obtained. Series IV consists of human male random control DNA panels that were purchased from the European Collection of Cell Cultures. Donors were ethnically matched to cases (U.K. whites) but were not age matched. Unaffected series of healthy Hungarian males were recruited from the Department of Physical Education and Sport at Semmelweis University (Budapest). In addition, 354 race-matched but not age-matched, cancer-free males ascertained through the UPHS General Medicine clinics were genotyped. Regardless of the source, patients with TGCT and unaffected males donated biological samples and medical information with fully informed consent and local or national ethics review board approval. We typed the gr/gr deletion by using a multiplex PCR that ensured that a failure of PCR was not designated as a deletion (see fig. 1A). The STSs sY1201 (outside the AZFc region) and sY1291 (a marker of the gr/gr deletion) (see fig. 1B) were amplified together in a 25-μl PCR reaction. The PCR mix included 12.5 pmol of each primer, 2.5 μl of 10× NH4/MgCl2 buffer (Taq-Pro DNA Polymerase [Denville Scientific]), 6.25 nmol of each dNTP, 15 ng of genomic DNA, and 1.25 U of Taq-Pro DNA Polymerase. The PCR conditions were an initial cycle at 95°C for 5 min; 40 cycles at 95°C for 30 s, 60°C for 30 s, and 72°C for 30 s; and a final step at 72°C for 10 min (see NCBI UniSTS database for all PCR primer sequences). The same conditions were used to type DNA extracted from white blood cells and buccal swabs. A total of 7 μl of the PCR product was sized on a 1% agarose gel, with the use of a 100-bp ladder as a standard. All samples positive for the deletion were repeated at least twice and were tested for sY1206 and sY1191 to determine whether they carried the larger AZFc or the b1/b3 deletion, respectively (fig. 1B) (Repping et al. Repping et al., 2004Repping S Korver CM Oates RD Silber S van der Veen F Page DC Rozen S Are sequence family variants useful for identifying deletions in the human Y chromosome?.Am J Hum Genet. 2004; 75: 514-517Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar). One unaffected male with an AZFc deletion was omitted from further analysis. All gr/gr deletion genotyping was performed at two centers—the Institute of Cancer Research and the University of Pennsylvania. The two centers typed 33 samples in common. To determine whether gr/gr deletions occurred on the same haplotype, we genotyped the markers (in sequence order) DYS393, DYS19, DYS391, DYS390, DYS385a, DYS385b, and DYS392 for cases and controls demonstrating a gr/gr deletion (Ensembl and National Center for Biotechnology Information Web sites). Markers were end-labeled with [γ-32P] ATP by use of T4 polynucleotide kinase, were amplified under standard conditions, and were electrophoresed on standard denaturing polyacrylamide gels, dried, and exposed to x-ray film. All samples were run across a single gel (per marker), to allow easy comparison of alleles between samples. We classified each patient with TGCT on the basis of the histological diagnosis of his tumor: seminoma or nonseminoma germ cell tumor (NSGCT, including choriocarcinoma, embryonal, teratoma, and mixed cell-type TGCT), and we included only gonadal primaries. Since the Y chromosome is hemizygous, we could determine whether affected family members shared a common Y chromosome by examination of the pedigree. We designated an inheritance pattern of “paternal lineage” for those probands who had at least one affected male relative who shared the same Y chromosome (i.e., identical by descent). In contrast, “maternal lineage” designated probands with affected male relatives who did not share a common Y chromosome. All analyses were performed using SAS v9.1 (SAS Institute). Using unconditional logistic regression, we determined odds ratio (OR) estimates as measures of the relative risk of TGCT associated with the gr/gr deletion after adjustment for geographic region or ascertainment center (Philadelphia, western Washington State, other North America, Hungary, United Kingdom, and other Europe or Australia; hereafter referred to collectively as “study centers”); 95% CIs around the ORs were estimated using the logarithmic transformation and asymptotic theory. Data on study centers were entered in the model as a series of indicator variables. To estimate and compare the associations for the outcomes of familial versus sporadic TGCT, seminoma versus NSGCT, and paternal versus maternal lineage, we used a multinomial logit model to obtain simultaneously the OR and 95% CI for the association between the gr/gr deletion and each level of outcome, adjusting for study center. Age at diagnosis of TGCT was compared nonparametrically using the Kruskal-Wallis test. After adjustment for study center, TGCT cases were significantly more likely to carry the gr/gr deletion, compared with unaffected males (aOR = 2.1; 95% CI 1.3–3.6; P=.005) (table 3). Among the study centers contributing both TGCT cases and unaffected males to the analysis, the distribution of the gr/gr deletion did not differ (χ2=3.3; 3 df; P=.35). The center-specific ORs were 1.7 (western Washington State; 95% CI 0.58–5.0), 1.8 (Hungary; 95% CI 0.37–8.6), 2.3 (United Kingdom; 95% CI 1.1–4.7), and 2.8 (Philadelphia; 95% CI 0.66–12). When analysis was restricted to these centers, the center-adjusted OR was very similar to that which included all data (aOR 2.1; 95% CI 1.3–3.5). In an analysis restricted to the two case-control studies that concurrently enrolled healthy controls and cases without selection for family history, the estimated center-adjusted OR was 2.3 (95% CI 0.89–6.2).Table 3Associations of the Y Deletion gr/gr and TGCTgr/gr DeletionSubject Groupn%OR (95% CI)aORaAdjusted for study center (Philadelphia, western Washington State, other North America, Hungary, United Kingdom, and other Europe or Australia). (95% CI)aORbIncludes only those study centers that contributed both patients with TGCT and unaffected men (Hungary, Philadelphia, United Kingdom, and western Washington State) and is adjusted for those study centers. (95% CI)Unaffected mencReference group for all comparisons. (n=2,599)331.31.01.01.0TGCT cases (n=1,842):422.31.8 (1.1–2.9)2.1 (1.3–3.6)2.1 (1.3–3.5) Positive family historydInformation on family history of TGCT was not available for 23 cases (17 seminoma and 6 nonseminoma), including 1 gr/gr deletion carrier. In addition, 12 cases (4 seminoma, 2 nonseminoma, and 6 of unknown tumor type) with an affected MZ twin were excluded from analyses of family history. (n=431)133.02.4 (1.3–4.6)3.2 (1.5–6.7)2.9 (1.2–6.9) Negative family historydInformation on family history of TGCT was not available for 23 cases (17 seminoma and 6 nonseminoma), including 1 gr/gr deletion carrier. In addition, 12 cases (4 seminoma, 2 nonseminoma, and 6 of unknown tumor type) with an affected MZ twin were excluded from analyses of family history. (n=1,376)282.01.6 (.97–2.7)1.9 (1.1–3.3)1.9 (1.1–3.4) Paternal lineageeInformation on six TGCT cases with a" @default.
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• W2045087913 date "2005-12-01" @default.
• W2045087913 modified "2023-10-17" @default.
• W2045087913 title "The Y Deletion gr/gr and Susceptibility to Testicular Germ Cell Tumor" @default.
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• W2045087913 doi "https://doi.org/10.1086/498455" @default.

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