Giwercman A, Lundin KB, Eberhard J, Stahl O, Cwikiel M, Cavallin-Stahl E, Giwercman YLLinkage between androgen receptor gene CAG trinucleotide repeat length and testicular germ cell cancer histological type and clinical stage. Eur J Cancer 40: 2152-2158
Sex hormones and/or gonadotropins may play a crucial role in the development of testicular germ cell cancer (TGCC). A direct link between this malignancy and endocrine factors has not been confirmed. We tested whether CAG and GGN repeats of the androgen receptor gene (AR) play a role in the aetiology or pathogenesis of TGCC. Eighty-three TGCC patients and 220 controls were included. Mean CAG or GGN lengths did not differ between the TGCC cases and controls. The proportion of males with CAG lengths above 25, indicative of reduced androgen sensitivity, was significantly lower among patients with pure seminomas and in the combined group of seminomas and mixed tumours compared with non-seminomas and controls. The median CAG length was higher if the tumour was metastasing at diagnosis. This is the first study showing an association between the AR polymorphism and histological type as well as the progression rate of TGCC.
"socialstyrelsen.se). Polymorphisms in genes regulating hormone and growth factor levels have been associated with disease progression and therapeutic outcome in several cancers arising from tissues under hormonal influence (Giwercman et al, 2004; Piersma et al, 2007; Sissung et al, 2011). "
[Show abstract][Hide abstract] ABSTRACT: The androgen receptor (AR) is frequently expressed in breast cancers. The AR genotype may affect disease-free survival and response to endocrine therapy.
In all, 634 women undergoing breast cancer surgery between 2002 and 2008 were followed until 30 June 2010. Six haplotype-tagging single-nucleotide polymorphisms in the AR, and the resulting AR diplotypes, were examined in relation to breast cancer patient characteristics, tumour characteristics, disease-free survival, and response to endocrine treatment.
Five common AR diplotypes were found. Seventeen rare variants were combined into a composite group. The resulting six AR diplotype groups were clustered into two subgroups, groups A (n=128) and B (n=499), with three diplotypes in each. Patients in group B had larger total breast volume (P=0.024), higher body mass index (BMI) (P=0.050), more axillary lymph node involvement (P(trend)=0.020), and higher histological grade (P(trend)=0.031). There were 59 breast cancer events in the 569 patients with invasive cancers and no preoperative treatment. Patients in group B also had shorter disease-free survival (P=0.037) than patients in group A. Among patients in group B with oestrogen receptor α positive tumours, tamoxifen (TAM) treatment was associated with longer disease-free survival (P=0.008), while treatment with aromatase inhibitors (AIs) was not (P=0.94). Response to endocrine treatment could not be predicted based on BMI, suggesting that the effect of AR diplotypes went beyond that of a higher BMI.
A marker for a group of patients who responded to TAM, but not to AIs, was identified. If this finding is confirmed, AR genotyping may provide useful information for selection of endocrine treatment of breast cancer patients.
British Journal of Cancer 11/2011; 105(11):1676-83. DOI:10.1038/bjc.2011.441 · 4.84 Impact Factor
"More recently, studies have investigated variants in genes involved in modulating the action of sex hormones . For example, no association has been found between the length of the CAG trinucleotide repeat in the androgen receptor gene and testicular cancer risk in two case–control studies including about 100 cases each (Rajpert-De Meyts et al., 2002; Giwercman et al., 2004). A case–parent study from the US investigated several genes encoding enzymes involved in the oestrogen metabolism , evaluating both the maternal and the index subject's variants, on the assumption that relevant exposures should act during the foetal period (Starr et al., 2005). "
[Show abstract][Hide abstract] ABSTRACT: Germ-cell testicular cancer has a well-characterized descriptive epidemiology, whereas the aetiology remains largely unknown. It is believed that exposures acting prenatally are instrumental to germ-cell cancer development, although no specific exposure has been identified. Several epidemiological studies have investigated a number of indicators of prenatal exposures, such as birth order, gestational duration, birth weight, maternal age and nausea during pregnancy, but results are inconsistent. This paper briefly reviews the current support for genetic and environmental factors in testicular cancer aetiology. In particular, we have summarized the evidence suggesting a strong role of inherited susceptibility, which is probably carried by the effect of several unknown moderate-risk genes. We have illustrated inconsistencies in the previous studies on prenatal factors by estimating the heterogeneity and pooled odds ratios among twelve studies investigating the association between low birth weight and testicular cancer. We have discussed the possibility that puberty is another time window during which environmental factors may increase the risk of testicular cancer. Finally, we have reviewed the results from studies on cryptorchidism and impaired fertility in relation to risk for testicular cancer. In conclusion, we propose that future aetiological studies on testicular cancer should take postnatal exposures acting during puberty into account and, whenever possible, investigate both main effects and interactions among prenatal factors, genetic factors and postnatal factors.
International Journal of Andrology 09/2007; 30(4):230-40; discussion 240-1. DOI:10.1111/j.1365-2605.2007.00760.x · 3.70 Impact Factor
"Testicular cancer was investigated for the androgen receptor polymorphism in three studies only (Rajpert-De Meyts et al., 2002b; Giwercman et al., 2004; Garolla et al., 2005). Neither found an association of the cancer risk with the length of the CAG repeat alone, however, Giwercman et al. (2004) reported a possible link between the longest CAG repeats and the tumour progression to non-seminomas as well as clinically more aggressive disease, whereas Garolla et al. (2005) found that the combination CAG=20/GGC=17 was significantly more frequent in patients with testicular cancer than in controls. As far as genital malformations and undermasculinization are concerned, there is a better but not perfect consensus among the few published studies . "
[Show abstract][Hide abstract] ABSTRACT: Carcinoma in situ testis (CIS), also known as intratubular germ cell neoplasia (ITGCN), is a pre-invasive precursor of testicular germ cell tumours, the commonest cancer type of male adolescents and young adults. In this review, evidence supporting the hypothesis of developmental origin of testicular germ cell cancer is summarized, and the current concepts regarding aetiology and pathogenesis of this disease are critically discussed. Comparative studies of cell surface proteins (e.g. PLAP and KIT), some of the germ cell-specific markers (e.g. MAGEA4, VASA, TSPY and NY-ESO-1), supported by studies of regulatory elements of the cell cycle (e.g. p53, CHK2 and p19-INK4d) demonstrated a close similarity of CIS to primordial germ cells and gonocytes, consistent with the pre-meiotic origin of CIS. Recent gene expression profiling studies showed that CIS cells closely resemble embryonic stem cells (ESCs). The abundance of factors associated with pluripotency (NANOG and OCT-3/4) and undifferentiated state (AP-2gamma) may explain the remarkable pluripotency of germ cell neoplasms, which are capable of differentiating to various somatic tissue components of teratomas. Impaired gonadal development resulting in the arrest of gonocyte differentiation and retention of its embryonic features, associated with an increasing genomic instability, is the most probable model for the pathogenesis of CIS. Genomic amplification of certain chromosomal regions, e.g. 12p, may facilitate survival of CIS and further invasive progression. Genetic studies, have so far not identified gene polymorphisms predisposing to the most common non-familial testicular cancer, but this research has only recently begun. Association of CIS with other disorders, such as congenital genital malformations and some forms of impaired spermatogenesis, all rising in incidence in a synchronous manner, led to the hypothesis that CIS might be a manifestation of testicular dysgenesis syndrome (TDS). The aetiology of TDS including testicular cancer remains to be elucidated, but epidemiological trends suggest a primary role for environmental factors, probably combined with genetic susceptibility.
Human Reproduction Update 05/2006; 12(3):303-23. DOI:10.1093/humupd/dmk006 · 10.17 Impact Factor
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