Association of Megalin Genetic Polymorphisms with Prostate Cancer Risk and Prognosis

Abstract

Purpose: Megalin, an endocytic receptor expressed by prostate epithelial cells, can internalize biologically active androgens bound to sex hormone binding globulin. Genetic variation within megalin could potentially influence levels of steroid hormone uptake. Experimental Design: Forty haplotype-tagging single-nucleotide polymorphisms (htSNP) were analyzed in a population-based, case-control study of 553 Caucasian men who were diagnosed with prostate cancer between the ages of 40 and 64 years from the Seattle-Puget Sound region and 534 control men. Prostate cancer risk was estimated using adjusted unconditional logistic regression for both individual SNPs and haplotypes. Risks of disease recurrence/ progression and prostate-specific cancer mortality were estimated using Cox proportional hazards regression. Results: We found no strong evidence of altered risk of developing prostate cancer for any of the htSNPs when they were assessed individually or in haplotypes. However, three htSNPs were significantly associated with both disease recurrence/progression and mortality. Risk of recurrence/progression alone was also associated with five additional htSNPs, and six other htSNPS showed evidence of modification by primary androgen deprivation therapy. Two additional htSNPs were significantly associated with altered risk of death from prostate cancer. Conclusions: Preliminary results suggest that common genetic variation within the megalin gene could alter both risk of recurrence/progression and prostate-specific cancer mortality. In addition, androgen deprivation therapy effectiveness may be modified by the activity of this gene. To our knowledge, this is the first study that has examined polymorphisms within the megalin gene for associations with prostate cancer risk and outcomes.Androgens are believed to contribute to both the etiology and progression of prostate cancer (1). Previously, it was thought that the only way the androgen hormone entered the cell and became biologically active was after disassociation from its plasma carrier protein, sex hormone binding globulin, and subsequent internalization of the lipophilic compound via free diffusion (2). A recent study by Hammes and colleagues (3) showed that megalin, a member of the LDL receptor gene family located on chromosome 2q24-q31, may play a role in the internalization of androgen into the prostatic cell. These researchers showed that megalin, a multiligand endocytic receptor, carries a specific binding site for androgen still bound to sex hormone binding globulin and serves as an active uptake mechanism of the entire steroid hormone complex. The role of megalin in the uptake of androgen in the mature healthy human prostate cell is not known, but our preliminary immunohistochemical assay studies of megalin gene expression have found increased levels of the protein in malignant relative to benign prostate cells. 5Polymorphisms within the megalin gene [low density lipoprotein -related protein 2 (LRP2)] could potentially alter the activity of the encod...

Minireview: SLCO and ABC Transporters: A Role for Steroid Transport in Prostate Cancer Progression

“…Immunohistochemical assays demonstrated increased megalin gene expression in malignant vs benign prostate cells (Mostaghel, E. A., unpublished data), and several polymorphisms within the megalin gene have been associated with PCa recurrence/progression and mortality (61). Functional studies directly demonstrating a role for megalin in androgen uptake in PCa tissue, however, have not been reported to date.…”

Personalized genomic disease risk of volunteers

“…Two volunteers diagnosed with breast cancer had different allele associations in BRCA2 (43,44). Single cases of early onset prostate (LRP2) (45) and follicular thyroid cancer (TPR) cancer were identified (46,47). A volunteer with nonsyndromic deafness was found to have risk alleles in two genes associated with autosomal dominant (AD) deafness and had a three-generation positive family history of deafness (48).…”

Vitamin D-Related Genetic Variants, Interactions with Vitamin D Exposure, and Breast Cancer Risk among Caucasian Women in Ontario

“…18 of these genotyped candidate SNPs were in 4 well-established vitamin D related genes: GC (rs7041, rs4588), VDR (rs731236, rs739837, rs1544410, rs1989969, rs2228570, rs7975232, rs11568820, rs2107301, rs2238135), CYP24A1 (rs2181874, rs2296241, rs4809958, rs6013905) and CYP27B1 (rs703842, rs4646536, rs10877012). Other candidate SNPs in the megalin gene, LRP2, were selected based on one previous study that evaluated megalin in relation to prostate cancer; four LRP2 SNPs showed some associations with prostate cancer risk (rs831003, rs2239598, 2268373, rs3944004) (28). We also included one SNP (rs1907362) in the CUBN gene that has been shown to have some functional importance in another pathway (29).…”