Dana-Farber / Brigham and Women's Cancer Center

Pioneering New Discoveries in Genetic Risk Profiling in Prostate Cancer

3 Doctors

At Dana-Farber/Brigham and Women’s Cancer Center, groundbreaking research studies in genetic risk profiling in prostate cancer span somatic and germline mutations and are designed to identify new targeted therapies for prostate cancer, distinguish aggressive prostate cancer from indolent forms of the disease, and predict who is at higher risk for the disease.

Dr. HahnWilliam C. Hahn, MD, PhD, Director of the Center for Genome Discovery at Dana-Farber/Brigham and Women's Cancer Center and Deputy Chief Scientific Officer at Dana-Farber Cancer Institute, is leading studies of new targeted cancer therapies.

“To maximize the benefits from genomic cancer research requires collaboration among investigators in a number of areas,” said William C. Hahn, MD, PhD, Director of the Center for Genome Discovery at Dana-Farber/Brigham and Women’s Cancer Center and Deputy Chief Scientific Officer at Dana-Farber Cancer Institute. “Our goal in bringing together the many essential pieces of this research puzzle is to improve how we diagnose, treat, and prevent prostate cancer, not just here but everywhere.”

Tumor Genomic Profiling

Launched in 2011 by Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Profile® is one of the nation’s most comprehensive personalized cancer medicine initiatives. To date, more than 12,000 patients have enrolled in the project. The initial phase of Profile® includes the analysis of 471 somatic mutations in 41 genes using “OncoMap,” developed by a team led by medical oncologist and researcher Levi Garraway, MD, PhD. Profile®’s next phase, which is currently underway, expands the project’s platform to interrogate copy number variations and selected rearrangements known to be common in prostate cancer.

“Based on results generated from Profile®, we will be able to identify the targeted therapies that are most likely to be effective in individual patients, representing the true nature of personalized medicine,” said Philip W. Kantoff, MD, Principal Investigator for Profile®, Director of the Center for Genitourinary Oncology at Dana-Farber/Brigham and Women’s Cancer Center, and Chief Clinical Research Officer at Dana-Farber Cancer Institute.

Insights gleaned from Profile® are expected to increase as additional mutations, variations, and arrangements are added, and some patients have already been identified with actionable mutations. The database of tumor genomic profiling data derived from a large number of patients linked to clinical information makes Profile® a powerful tool for discovery and personalized cancer medicine, supporting proposals for new research studies and clinical trials.

Whole Genome Sequencing

Dr. Garraway has performed whole exome or whole genome sequencing of more than 100 aggressive prostate cancers and has characterized the genomic architecture of aggressive localized prostate cancer. His efforts include the use of genomic and functional approaches to uncover possible new treatment avenues for prostate cancer patients who have progressed on hormone therapy.

“Genome sequencing gives us new understanding as to why prostate cancers arise and evolve and teaches us how best to use this full spectrum of information to determine the genes that serve as drivers in individual prostate tumors,” said Dr. Garraway. “It is this knowledge that will enable us to design the precise clinical trials for that disease.”

Significant findings based on whole genome and whole exome sequencing research in prostate cancer performed by Dr. Garraway and his colleagues include:

  • Genomic rearrangements may arise from transcriptional or chromatin aberrancies and engage prostate tumorigenic mechanisms (Nature 2011 Feb 10;470(7333):214-20.);
  • Prostate cancers with mutant SPOP lacked ETS family gene rearrangements and show a distinct pattern of genomic alterations, therefore, SPOP mutations may define a new molecular subtype of prostate cancer (Nat Genet. 2012 May 20;44(6):685-9. doi: 10.1038/ng.2279.).

A Closer Look at Risk Variants

Researcher Matthew L. Freedman, MD, is studying how inherited variants, such as single nucleotide polymorphisms (SNPs), influence disease risk and prognosis.

“Genome wide association studies have uncovered almost 80 variants that are associated with prostate cancer risk. An unanticipated complexity is that most of these variants are outside of known protein coding regions,” said Dr. Freedman. “Our understanding of the non-protein coding portion of the genome is more rudimentary than our understanding of the protein coding region.”

Dr. Freedman and his team have been at the forefront of connecting the risk alleles with their target genes. They were among the first to connect the chromosome 8q24 prostate risk loci with the proto-oncogene MYC (ProcNatlAcadSci USA. 2010 May 25;107(21):9742-6) and performed one of the largest studies to reveal the genes for an additional four prostate cancer risk loci (ProcNatlAcadSci USA. 2012 Jul 10;109(28):11252-7.). They also articulated a clear strategy to pursue this type of work (Nat Genet. 2011 Jun;43(6):513-8.) In addition, Dr. Freedman and his team have studied associations between previously identified prostate risk variants and prostate cancer-specific mortality and discovered that two common polymorphisms, rs2735839 at chromosome 19q13 and rs7679673 at 4q24, are associated with prostate cancer-specific mortality (Cancer Prev Res (Phila). 2011 May;4(5):719-28. Epub 2011 Mar 2.).

“In order to fully utilize inherited variants associated with prostate cancer risk in the clinical setting, it is critical to understand the implications of carrying these risk alleles,” said Dr. Freedman. “We developed this study to determine whether these variants can differentiate men who develop low-risk, indolent forms of the disease from men who develop lethal prostate cancer.”

Researchers at the Center for Genitourinary Oncology also are using risk variants to identify patients at increased risk of developing prostate cancer in order to consider new interventions, screening approaches, counseling, and other prevention measures.

“Ultimately, these studies will have great implications on clinical decision making and on outcomes for patients,” said Adam S. Kibel, MD, Surgical Director of the Center for Genitourinary Oncology at Dana-Farber/Brigham and Women’s Cancer Center and Chief of Urology at Brigham and Women’s Hospital.

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