Analysis of the 10q11 cancer risk locus implicates MSMB and NCOA4 in human prostate tumorigenesis

Mark M. Pomerantz, Yashaswi Shrestha, Richard J. Flavin, Meredith M. Regan, Kathryn L. Penney, Lorelei A. Mucci, Meir J. Stampfer, David J. Hunter, Stephen J. Chanock, Eric J. Schafer, Jennifer A. Chan, Josep Tabernero, José Baselga, Andrea Richardson, Massimo Loda, William K. Oh, Philip W. Kantoff, William C. Hahn, Matthew L. Freedman

Research output: Contribution to journalArticle

Abstract

Genome-wide association studies (GWAS) have established a variant, rs10993994, on chromosome 10q11 as being associated with prostate cancer risk. Since the variant is located outside of a protein-coding region, the target genes driving tumorigenesis are not readily apparent. Two genes nearest to this variant, MSMB and NCOA4, are strong candidates for mediating the effects of rs109939934. In a cohort of 180 individuals, we demonstrate that the rs10993994 risk allele is associated with decreased expression of two MSMB isoforms in histologically normal and malignant prostate tissue. In addition, the risk allele is associated with increased expression of five NCOA4 isoforms in histologically normal prostate tissue only. No consistent association with either gene is observed in breast or colon tissue. In conjunction with these findings, suppression of MSMB expression or NCOA4 overexpression promotes anchorage-independent growth of prostate epithelial cells, but not growth of breast epithelial cells. These data suggest that germline variation at chromosome 10q11 contributes to prostate cancer risk by influencing expression of at least two genes. More broadly, the findings demonstrate that disease risk alleles may influence multiple genes, and associations between genotype and expression may only be observed in the context of specific tissue and disease states.

Original languageEnglish (US)
Article numbere1001204
JournalPLoS Genetics
Volume6
Issue number11
DOIs
StatePublished - Nov 2010
Externally publishedYes

Fingerprint

carcinogenesis
Prostate
Carcinogenesis
loci
neoplasms
gene
allele
Genes
Alleles
prostatic neoplasms
Neoplasms
alleles
genes
breasts
chromosome
Prostatic Neoplasms
Protein Isoforms
Breast
epithelial cells
Chromosomes

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Pomerantz, M. M., Shrestha, Y., Flavin, R. J., Regan, M. M., Penney, K. L., Mucci, L. A., ... Freedman, M. L. (2010). Analysis of the 10q11 cancer risk locus implicates MSMB and NCOA4 in human prostate tumorigenesis. PLoS Genetics, 6(11), [e1001204]. https://doi.org/10.1371/journal.pgen.1001204

Analysis of the 10q11 cancer risk locus implicates MSMB and NCOA4 in human prostate tumorigenesis. / Pomerantz, Mark M.; Shrestha, Yashaswi; Flavin, Richard J.; Regan, Meredith M.; Penney, Kathryn L.; Mucci, Lorelei A.; Stampfer, Meir J.; Hunter, David J.; Chanock, Stephen J.; Schafer, Eric J.; Chan, Jennifer A.; Tabernero, Josep; Baselga, José; Richardson, Andrea; Loda, Massimo; Oh, William K.; Kantoff, Philip W.; Hahn, William C.; Freedman, Matthew L.

In: PLoS Genetics, Vol. 6, No. 11, e1001204, 11.2010.

Research output: Contribution to journalArticle

Pomerantz, MM, Shrestha, Y, Flavin, RJ, Regan, MM, Penney, KL, Mucci, LA, Stampfer, MJ, Hunter, DJ, Chanock, SJ, Schafer, EJ, Chan, JA, Tabernero, J, Baselga, J, Richardson, A, Loda, M, Oh, WK, Kantoff, PW, Hahn, WC & Freedman, ML 2010, 'Analysis of the 10q11 cancer risk locus implicates MSMB and NCOA4 in human prostate tumorigenesis', PLoS Genetics, vol. 6, no. 11, e1001204. https://doi.org/10.1371/journal.pgen.1001204
Pomerantz MM, Shrestha Y, Flavin RJ, Regan MM, Penney KL, Mucci LA et al. Analysis of the 10q11 cancer risk locus implicates MSMB and NCOA4 in human prostate tumorigenesis. PLoS Genetics. 2010 Nov;6(11). e1001204. https://doi.org/10.1371/journal.pgen.1001204
Pomerantz, Mark M. ; Shrestha, Yashaswi ; Flavin, Richard J. ; Regan, Meredith M. ; Penney, Kathryn L. ; Mucci, Lorelei A. ; Stampfer, Meir J. ; Hunter, David J. ; Chanock, Stephen J. ; Schafer, Eric J. ; Chan, Jennifer A. ; Tabernero, Josep ; Baselga, José ; Richardson, Andrea ; Loda, Massimo ; Oh, William K. ; Kantoff, Philip W. ; Hahn, William C. ; Freedman, Matthew L. / Analysis of the 10q11 cancer risk locus implicates MSMB and NCOA4 in human prostate tumorigenesis. In: PLoS Genetics. 2010 ; Vol. 6, No. 11.
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