De Association of the polymorphism of the CAG repeat in the mitochondrial DNA polymerase gamma gene (POLG) with testicular germ-cell cancer.

Department of Growth and Reproduction, Rigshospitalet, Blegdamsvej, Copenhagen, Denmark.
Annals of Oncology (Impact Factor: 7.04). 11/2008; 19(11):1910-4. DOI: 10.1093/annonc/mdn407
Source: PubMed


A possible association between the polymorphic CAG repeat in the DNA polymerase gamma (POLG) gene and the risk of testicular germ-cell tumours (TGCT) was investigated in this study. The hypothesis was prompted by an earlier preliminary study proposing an association of the absence of the common 10-CAG-long POLG allele with testicular cancer as well as previously reported in some European populations' association with male subfertility, which is a condition carrying an increased risk of TGCT.
The number of CAG repeats in both POLG alleles was established in 243 patients with TGCT and in 869 controls by the analysis of the genomic DNA fragment.
A significantly higher proportion of men homozygous allele of other than the common 10 CAG repeats was found among the patients with TGCT in comparison to the controls (4.9% versus 1.3%, respectively, P = 0.001). The vast majority of the homozygous patients had a seminoma (11 of 12; 97%), despite that only about half (55%) of the studied patients had this tumour type.
The findings indicate that the POLG polymorphism may be a contributing factor in the pathogenesis of TGCT particularly in seminoma, but the mechanisms remain to be elucidated.

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Available from: Gedske Daugaard, Dec 29, 2013
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    • "The stretch of 13 glutamine residues encoded by 10 CAG codons localized near the N-terminus of the DNA polymerase is called POLG CAG trinucleotide repeat (Ropp & Copeland, 1996). These are associated to idiopathic sporadic Parkinson's disease (Luoma et al., 2007), testicular cancer (Blomberg Jensen et al., 2008) and male infertility (Jensen et al., 2004). Point mutation at position 8344 in the mtDNA produces an impaired function of the oxidative phosphorylation complex IV leading to development of lipomas and has been associated to multiple symmetrical lipomatosis (MSL) (Becker-Wegerich et al., 1998). "
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    • "Since the clearly dominating repeat length in the human population is 10, selective pressure seems to occur to conserve this length [73]. Men with homozygous deviations from this dominating repeat length were recently shown to have an increased risk of developing testicular germ cell cancer, mainly seminomas [74]. No correlation of repeat length with other clinico-pathological features was observed. "
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    ABSTRACT: Hypokinesia, rigidity, tremor, and postural instability are the cardinal symptoms of Parkinson s disease (PD). Since these symptoms are not specific to PD the diagnosis may be uncertain in early PD. Etiology and pathogenesis of PD remain unclear. There is no neuroprotective therapy. Genetic findings are expected to reveal metabolic routes in PD pathogenesis and thereby eventually lead to therapeutic innovations. In this thesis, we first aimed to study the usefulness and accuracy of 123I-b-CIT SPECT in the diagnosis of PD in a consecutive clinic-based material including various movement disorders. We subsequently a genetic project to identify genetic risk factors for sporadic PD using a candidate gene approach in a case-control setting including 147 sporadic PD patients and 137 spouse controls. Dopamine transporter imaging by 123I-b-CIT SPECT could distinguish PD from essential tremor, drug-induced parkinsonism, dystonia and psychogenic parkinsonism. However, b-CIT uptake in Parkinson plus syndromes (PSP and multiple system atrophy) and dementia with Lewy bodies was not significantly different from PD. 123I-b-CIT SPECT could not reliably differentiate PD from vascular parkinsonism. 123I-b-CIT SPECT was 100% sensitive and specific in the diagnosis of PD in patients younger than 55 years but less specific in older patients, due to differential distribution of the above conditions in the younger and older age groups. 123I-b-CIT SPECT correlated with symptoms and detected bilateral nigrostriatal defect in patients whose PD was still in unilateral stage. Thus, in addition to as a differential diagnostic aid, 123I-b-CIT SPECT may be used to detect PD early, even pre-symptomatically in at-risk individuals. 123I-b-CIT SPECT was used to aid in the collection of patients to the genetic studies. In the genetic part of this thesis we found an association between PD and a polymorphic CAG-repeat in POLG1 gene encoding the catalytic subunit of mitochondrial polymerase gamma. The CAG-repeat encodes a polyglutamine tract (polyQ), the two most common lengths of which are 10Q (86-90%) and 11Q. In our Finnish material, the rarer non-10Q or non-11Q length variants (6Q-9Q, 12Q-14Q, 4R+9Q) were more frequent in patients than in spouse controls (10% vs. 3.5 %, p=0.003), or population controls (p=0.001). Therefore, we performed a replication study in 652 North American PD patients and 292 controls. Non-10/11Q alleles were more common in the US PD patients compared to the controls but the difference did not reach statistical significance (p=0.07). This larger data suggested our original definition of variant length allele might need reconsideration. Most previous studies on phenotypic effects of POLG1 polyQ have defined 10Q as the only normal allele. Non-10Q alleles were significantly more common in patients compared to the controls (17.3% vs. 12.3 %, p= 0.005). This association between non-10Q length variants and PD remained significant when compared to a larger set of 1541 literature controls (p=0.00005). In conclusion, POLG1 polyQ alleles other than 10Q may predispose to PD. We did not find association between PD and parkin or DJ-1, genes underlying autosomal recessive parkinsonism. The functional Val158Met polymorphism, which affects the catalytic effect of COMT enzyme, and another coding polymorphism in COMT were not associated with PD in our patient material. The APOE e2/3/4 polymorphism modifies risk for Alzheimer s disease and prognosis of for example brain trauma. APOE promoter and enhancer polymorphisms 219G/T and +113G/C, and APOE e3 haplotypes, have also been shown to modify the risk of Alzheimer s disease but not reported in PD. 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Toisaalta menetelmä ei erotellut Parkinson + -oireyhtymiä tai Lewyn kappale dementiaa sairastavia potilaita PD-potilaista. 123I-b-CIT SPECT ei myöskään varmuudella auta vaskulaarisen parkinsonismin ja PT:n erotusdiagnostiikassa. 123I-b-CIT SPECT yli 100 % sensitiivinen ja spesifinen PD-diagnoosissa alle 55-vuotiaassa aineistossa mutta vähemmän spesifinen vanhemmassa potilasaineistossa yllämainittujen diagnoosien ikäjakaumasta johtuen. 123I-b-CIT SPECT korreloi oireiden vakavuuden kanssa ja havaitsi bilateraalisen DAT-tiheyden aleneman jo siinä vaiheessa kun potilaan oireet vielä rajoittuivat toiselle puolelle. 123I-b-CIT SPECTiä voitaneenkin käyttää, paitsi erotusdiagnostiikassa, myös etsimään PT:a riskihenkilöiltä jo motorisia oireita edeltävässä vaiheessa. 123I-b-CIT SPECTiä käytettiin apuna potilasvalinnassa työn geneettiseen osioon. Geneettisessa potilas-verrokkiaineistossa oli 147 sporadista suomalaista parkinsonpotilasta ja 137 puolisoa kontrolleina. Mitokondriaalista polymeraasi gamma-entsyymiä koodaavan POLG1 geenin eksonissa 2 olevasta polymorfisesta CAG-toistojaksosta löytyi todennäköinen PT:n riskitekijä. Tämä CAG-toisto koodaa polyglutamiiniketjua (polyQ), jonka yleisimmät pituudet ovat 10Q (86-90%) ja 11Q. Suomalaisilla potilailla polyQ-alleellit, jotka olivat lyhyempiä kuin 10Q tai pidempiä kuin 11Q (non-10/11Q) olivat yleisempiä kuin kontrolleilla (10 vs. 3.5 %, p= 0.003). Teimme replikaatiotutkimuksen pohjoisamerikkalaisessa aineistossa (652 PT-potilasta, 292 kontrollia). Non-10/11Q alleelit olivat potilailla yleisempiä kuin kontrolleilla, mutta ei merkittävästi (p=0.07). Monissa aiemmissa POLG1 polyQ:ta muissa ilmiasuissa tutkineissa töissä ainoastaan 10Q alleelia on pidetty normaalina alleelina. Non-10Q-alleelit olivat selvästi yleisempiä PT-potilailla kuin kontrolleilla (17.3% vs. 12.3 %, p= 0.005) tai 1541 kirjallisuuskontrollilla (p=0.00005). 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