Research Summary
Dr. Isaacs’ lab is working to characterize consistent alterations in the structure and expression of the genome of human prostate cancer cells as a means of identifying genes critical in the pathways of prostatic carcinogenesis. They are focusing on somatic genomic alterations occurring in sporadic prostate cancers, as well as germline variations that confer increases in prostate cancer risk. Both genome wide and candidate gene approaches are being pursued, and cancer associated changes in gene expression analyses of normal and malignant prostate cells are being cataloged as a complementary approach in these efforts.
As an approach to identify high-risk prostate cancer susceptibility alleles, the lab has identified a large number of families having multiple men affected with prostate cancer. Linkage analysis in these families has provided evidence of susceptibility genes located on chromosomes 1 and 8; RNASEL (1q24-25) and MSR1 (8p22) have been identified as candidate prostate cancer susceptibility genes on these chromosomes. The involvement of these genes in the innate immune system suggests an important role for genetic variability of host response in determining individual prostate cancer risk. Current efforts are aimed at characterizing the role of these genes in prostate carcinogenesis, and the identification of additional prostate cancer gene loci.
It is anticipated that this work will assist in providing more effective methodologies to identify men at high risk for this disease in general, and in particular to identify new markers of prognostic and therapeutic significance that could lead to more effective management of this common disease.
Selected Publications
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Tan HL, Sood A, Rahimi HA, Wang W, Gupta N, Hicks J, Mosier S, Gocke CD, Epstein JI, Netto GJ, Liu W, Isaacs WB, De Marzo AM, Lotan TL. “Rb Loss Is Characteristic of Prostatic Small Cell Neuroendocrine Carcinoma.” Clin Cancer Res. 2014 Jan 27. [Epub ahead of print]
Hurwitz LM, Heaphy CM, Joshu CE, Isaacs WB, Konishi Y, De Marzo AM, Isaacs SD, Wiley KE, Platz EA, Meeker AK. “Telomere length as a risk factor for hereditary prostate cancer.” Prostate. 2014 Apr;74(4):359-64. doi: 10.1002/pros.22755. Epub 2013 Nov 28.
Teerlink CC, Thibodeau SN, McDonnell SK, Schaid DJ, Rinckleb A, Maier C, Vogel W, Cancel-Tassin G, Egrot C, Cussenot O, Foulkes WD, Giles GG, Hopper JL, Severi G, Eeles R, Easton D, Kote-Jarai Z, Guy M, Cooney KA, Ray AM, Zuhlke KA, Lange EM, Fitzgerald LM, Stanford JL, Ostrander EA, Wiley KE, Isaacs SD, Walsh PC, Isaacs WB, Wahlfors T, Tammela T, Schleutker J, Wiklund F, Grönberg H, Emanuelsson M, Carpten J, Bailey-Wilson J, Whittemore AS, Oakley-Girvan I, Hsieh CL, Catalona WJ, Zheng SL, Jin G, Lu L, Xu J; International Consortium for Prostate Cancer Genetics, Camp NJ, Cannon-Albright LA. “Association analysis of 9,560 prostate cancer cases from the International Consortium of Prostate Cancer Genetics confirms the role of reported prostate cancer associated SNPs for familial disease.” Hum Genet. 2013 Oct 26. [Epub ahead of print].
Beebe-Dimmer J, Isaacs WB, Zuhlke KA, Yee C, Walsh PC, Isaacs SD, Johnson AM, Ewing CE, Humphreys EB, Chowdhury WH, Montie JE, Cooney KA. “The Prevalence of the HOXB13 G84E Prostate Cancer Risk Allele in Men Treated with Radical Prostatectomy.” BJU Int. 2013 Oct 21. doi: 10.1111/bju.12522. [Epub ahead of print]
Haffner MC, Mosbruger T, Esopi DM, Fedor H, Heaphy CM, Walker DA, Adejola N, Gürel M, Hicks J, Meeker AK, Halushka MK, Simons JW, Isaacs WB, De Marzo AM, Nelson WG, Yegnasubramanian S. “Tracking the clonal origin of lethal prostate cancer.” J Clin Invest. 2013 Nov 1;123(11):4918-22. doi: 10.1172/JCI70354. Epub 2013 Oct 25.
