Association between polymorphisms in the aryl hydrocarbon receptor repressor gene and disseminated testicular germ cell cancer

Abstract

In the Western world, testicular germ cell cancer (TGCC) is the most common malignancy of young men. The malignant transformation of germ cells is thought to be caused by developmental and hormonal disturbances, probably related to environmental and lifestyle factors because of rapidly increasing incidence of TGCC in some countries. Additionally, there is a strong genetic component that affects susceptibility. However, genetic polymorphisms that have been identified so far only partially explain the risk of TGCC. Many of the persistent environmental pollutants act through the aryl hydrocarbon receptor (AHR). AHR signaling pathway is known to interfere with reproductive hormone signaling, which is supposed to play a role in the pathogenesis and invasive progression of TGCC. The aim of the present study was to identify whether AHR-related polymorphisms were associated with risk as well as histological and clinical features of TGCC in 367 patients and 537 controls. Haplotype-tagging single-nucleotide polymorphisms (SNPs) were genotyped in genes encoding AHR and AHR repressor (AHRR). Binary logistic regression was used to calculate the risk of TGCC, non-seminoma versus seminoma, and metastasis versus localized disease. Four SNPs in AHRR demonstrated a significant allele association with risk to develop metastases (rs2466287: OR = 0.43, 95% CI 0.21–0.90; rs2672725: OR = 0.49, 95% CI: 0.25–0.94; rs6879758: OR = 0.27, 95% CI: 0.08–0.92; rs6896163: OR = 0.34, 95% CI: 0.12–0.98). This finding supports the hypothesis that compounds acting through AHR may play a role in the invasive progression of TGCC, either directly or through modification of reproductive hormone action.

Unwinding of the C‐Terminal Residues of Neuropeptide Y is critical for Y2 Receptor Binding and Activation

“…The critical importance of R 33 and R 35 for NPY activity [5] is also well reflected in our model. While R 33 makes narrow ionic contacts to D 6.59 , [17] R 35 is positioned in a mixed acidic-aromatic pocket of W 5.26 and Y 5.38 coordinated by E 5.24 , in agreement with earlier studies that highlighted the requirement of aromatic properties at R 35[20] and explaining difficulties to identify its interaction partner within the binding pocket.…”

“…[5] Receptor binding of NPY is suggested to be a two-step process. [6] According to this model, NPY first binds to the lipid membrane to increase its effective concentration, and is then recognized by the Y 2 R. [6] …”

“…[5] Due to the deep binding mode of NPY, the side chain of Q 34 is fairly restricted, and is oriented towards a small polar patch within TM2/3. Our model suggests a prominent interaction with Q 3.32 , which also participates in an extensive hydrogen bond network involving the amidated C-terminus (CONH 2 ).…”

“…NMR measurements revealed NPY to undergo remarkable structural changes within the C-terminus, and the C-terminal pentapeptide takes part in an extensive, but also fragile interaction network. Accordingly, changes in the C-terminal amino acids can easily disturb receptor binding or switch receptor selectivity as observed in numerous earlier structure-activity studies (reviewed in [5] ). Moreover, our study indicates that also larger peptide ligands, even though not a priori expected to bind deep in the transmembrane bundle, share the proposed common ligand binding cradle of rhodopsin-like GPCRs, [1] thus having more general implications also for other peptide GPCR systems.…”

Testis cancer: genes, environment, hormones

“…One report reviewed the current knowledge on the biology of the postnatal germ cell development (12), another one looked for possible modifications, caused by copy number variations, in genes involved in cell migration of primordial germ cells (13), and Brokken and colleagues showed that polymorphisms in the aryl hydrocarbon receptor repressor gene (that modulates the effects of environmental pollutants) are associated with progression of TGCT to invasive forms (14).…”