Colin Collins, PhD

Research Interests

Oncogenomics

The primary research focus in the Collins laboratory is oncogenomics, the application of genomics to basic cancer biology and clinical oncology, with a primary emphasis on understanding and treating prostate cancer. Prostate cancer is diagnosed in approximately 180,000 men per year and kills 30,000. Collins is principal investigator on two NIH funded grants, Project 2 of the UCSF Helen Diller Family Comprehensive Cancer Center Prostate SPORE grant, and an RO1 award funded through June 2010.

The first goal of these projects is to identify prognostic markers with the power to separate prostate cancer patients into lower and higher risk groups, to enable the selection of appropriate therapy, and to identify novel drug targets. To accomplish this, his laboratory is using Array Comparative Genomic Hybridization to generate copy number genotypes of approximately 130 primary and 25 metastatic tumors. They have identified approximately 40 DNA-based biomarkers that occur in primary tumors with a high likelihood of recurring or metastasizing after surgery. The DNA biomarkers are segments of DNA that represent the human genome, bacterial artificial clones (BAC) called Genomic Evaluators of Metastatic Prostate Cancer (GEMCaP) loci. The laboratory has shown that GEMCaP loci are as good at predicting disease recurrence as nomograms, the current gold standard. Collins’ laboratory is developing technologies so that the GEMCaP assay can be performed on tissue biopsies before surgery, to separate men into two groups: those who need definitive therapy and those who would benefit from active surveillance.

The second goal of these projects is to identify drug targets encoded at the GEMCaP loci so that physicians can predict which men need therapeutic intervention and determine the appropriate therapy. It is significant that many of the GEMCaP loci contain proteins with known or hypothesized roles in cancer metastasis.

The third goal of these projects it to test the hypothesis that the GEMCaP loci can predict post surgical recurrence and metastasis in other types of cancer, such as breast, brain, and ovarian cancer.

ZNF217 cancer gene

The ZNF217 breast cancer gene, located on chromosome 20q13.2, was discovered and characterized in Collins’ laboratory. This discovery demonstrates his research process. Chromosome 20q13.2 is amplified in up to 40% of breast tumors and can occur in early-stage disease. High-level amplification is associated with high-grade breast cancer, and short disease-free survival. Collins’ group hypothesized that amplification of a specific gene or genes within the amplified area on Chromosome 20q13.2 would lead to abnormal gene expression as the tumor evolved to a more malignant phenotype. In collaboration with the Department of Energy’s Joint Genome Institute and Los Alamos National Laboratory, Collins’ laboratory determined the sequence of the 1.2 Mb 20q13.2 locus for both human and mouse. Comparative sequence analysis and data visualization was done using software developed in Collins’ laboratory; this software is now available to the scientific community through the UCSF Helen Diller Family Comprehensive Cancer Center. These studies led to the identification of 10 potential genes and associated regulatory elements. ZNF217 was isolated from the potential genes and shown to be the gene responsible for the amplification of chromosome 20q13.2. This was demonstrated by showing that cancer tumors with extra copies of the ZNF217 gene at the DNA level, also showed increased expression of ZNF217 at the RNA level.

Studies in a number of laboratories have established that the gain of an extra chromosome 20q in the cells of the tumor is associated with epithelial cell immortalization, cells growing continually unchecked. Chromosome 20q includes the ZNF217 locus. Collins’ laboratory hypothesis that ZNF217 is a pro-immortalization gene and successfully demonstrated that it allows cultured mammary epithelial cells to grow continually. His laboratory has demonstrated that ZNF217 functions to weaken cell death and that it makes breast and brain cancer cell lines resistant to doxorubicin, a cancer treatment drug. Collins’ laboratory has shown that ZNF217 and Akt can exist in feedback loop. This suggests that abnormal levels of ZNF217 may predict the therapeutic usefulness of drugs that inhibit the PI3K pathway. These findings are significant because they unify genomic, cell biologic, and clinical data collected over the last decade.

End Sequence Profiling

Collins invented, and was awarded a patent for, a new method of analyzing the structure of tumor genomes called End Sequence Profiling (ESP). He transformed ESP from a scientific idea into a dynamic large-scale inter-institutional research project. ESP is a direct result of the Collins laboratory’s growing expertise in computational genomics. ESP is sequence-based analysis of tumor genomes that can deliver approximately 90% of the information of whole genome sequencing, the current standard, for about 1% of the cost.

ESP was developed and refined theoretically using a computer model. Collins’ laboratory then validated the ESP concept with laboratory experiments; they cloned translocations and other chromosomal rearrangements from the breast cancer cell line MCF7. In these experiments, amplifications and deletions were mapped at kilobase resolution. Direct evidence for co-localization of amplified genomic DNA from multiple loci has been obtained for the first time. This discovery may lead to broad-spectrum diagnostics and therapeutics, if not to therapy unique to each individual.

The Collins laboratory has performed ESP on primary breast, brain, ovarian, and prostate tumors; on three additional cell breast cancer lines; and has modified ESP for structural analysis of RNA copied from DNA. Collins’ laboratory is validating translocations and fusion transcriptions, combinations of genes that would not normally be near each other on the chromosome, while exploring the translational applications their discoveries. ESP is one of the motivating factors for the proposed NIH/NCI Human Tumor Genome Project.

return to top