Alterations in LMTK2, MSMB and HNF1B gene expression are associated with the development of prostate cancer.
BACKGROUND
Genome wide association studies (GWAS) have identified several genetic variants that are associated with prostate cancer. Most of these variants, like other GWAS association signals, are located in non-coding regions of potential candidate genes, and thus could act at the level of the mRNA transcript.


METHODS
We measured the expression and isoform usage of seven prostate cancer candidate genes in benign and malignant prostate by real-time PCR, and correlated these factors with cancer status and genotype at the GWAS risk variants.


RESULTS
We determined that levels of LMTK2 transcripts in prostate adenocarcinomas were only 32% of those in benign tissues (p = 3.2 x 10(-7)), and that an independent effect of genotype at variant rs6465657 on LMTK2 expression in benign (n = 39) and malignant tissues (n = 21) was also evident (P = 0.002). We also identified that whilst HNF1B(C) and MSMB2 comprised the predominant isoforms in benign tissues (90% and 98% of total HNF1B or MSMB expression), HNF1B(B) and MSMB1 were predominant in malignant tissue (95% and 96% of total HNF1B or MSMB expression; P = 1.7 x 10(-7) and 4 x 10(-4) respectively), indicating major shifts in isoform usage.


CONCLUSIONS
Our results indicate that the amount or nature of mRNA transcripts expressed from the LMTK2, HNF1B and MSMB candidate genes is altered in prostate cancer, and provides further evidence for a role for these genes in this disorder. The alterations in isoform usage we detect highlights the potential importance of alternative mRNA processing and moderation of mRNA stability as potentially important disease mechanisms.
Harries
Lorna W
LW
Institute of Biomedical and Clinical Sciences, Peninsula NIHR Clinical Research Facility, University of Exeter, Peninsula Medical School, Exeter, Devon, UK. L.W.Harries@exeter.ac.uk
Perry
John R B
JR
McCullagh
Paul
P
Crundwell
Malcolm
M
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000368:Aged; D000369:Aged, 80 and over; D020022:Genetic Predisposition to Disease; D005838:Genotype; D051539:Hepatocyte Nuclear Factor 1-beta / Q000235:genetics*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D011470:Prostatic Hyperplasia / Q000235:genetics* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D029584:Prostatic Secretory Proteins / Q000235:genetics*; D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
C496495:HNF1B protein, human; D008565:Membrane Proteins; D029584:Prostatic Secretory Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; C043076:beta-microseminoprotein; D051539:Hepatocyte Nuclear Factor 1-beta; C470798:LMTK2 protein, human; D017346:Protein Serine-Threonine Kinases