Scientific Accomplishments

A.Balmain J.Witte
Program Leader: John Witte, PhD
Program Co-Leader: Allan Balmain, PhD

> Genetics of Cancer Susceptibility, Progression, and Response
> Cancer Genome and Epigenome
> Functional Genomics
> Systems Genetics of Cancer

Theme 1: Genetics of Cancer Susceptibility, Progression, and Response

Drs. Joe Wiemels, Margaret Wrensch, Paige Bracci, and John Wienke continue to collaborate closely on cancers of the brain. They discovered a new locus associated with risk of high-grade glioma and showed that it and the risk loci near TERT are both associated with longer telomeres (Walsh et al., Nat Genet, 2014).

Dr. John Witte has shown for the first time that the high-penetrance prostate cancer G84E mutation in HOXB13 has pleiotropic effects on multiple other common cancers, even more so in cases diagnosed with multiple cancer types (Hoffmann et al., PLoS Genet, 2015). This study leveraged data on 83,285 Kaiser subjects.

Dr. Elad Ziv identified a novel polymorphism that is found almost exclusively in Latin American populations and originates from Indigenous American (Native American) ancestry. This allele is strongly protective against breast cancer, with 40% risk reduction for overall breast cancer for each additional allele and 65% risk reduction for estrogen-receptor negative breast cancer (Fejerman et al., Nat Commun, 2014).

Theme 2: Cancer Genome and Epigenome

Dr. Joe Costello is Director of the UCSF-based NIH Roadmap Epigenome Mapping Center to comprehensively map epigenomes of select human cells with significant relevance to complex human disease. This effort has resulted in tens of terrabytes of raw data now in the public domain at (Roadmap Epigenomics et al., Nature, 2015). Dr. Costello has made a major advance in our understanding of the genetics of glioma progression. The results were published in Science (Johnson et al., Science, 2014), and highlighted in several editorials in other journals. This analysis demonstrated that temozolomide therapy contributes to, or possibly causes, the malignant transformation of otherwise indolent grade II astrocytomas to aggressive glioblastoma.

Theme 3: Functional Genomics

Dr. Kevan Shokat is well known for his work on development of small molecule drugs for inhibition of targets in the RAS pathway. Members of the MYC family of transcription factors are important cancer targets but generally thought to be “undruggable”. In collaboration with Dr. William Weiss (Neurologic Oncology, Pediatric Malignancies Programs), Dr. Shokat developed a means of targeting these proteins. By targeting the Myc-associated kinase Aurora-A, they disrupted an allosteric interaction between Aurora-A and NMyc, leading to loss of function (Gustafson et al., Cancer Cell, 2014).

Theme 4: Systems Genetics of Cancer

Dr. Alan Balmain’s laboratory has carried out a comparison of the genome-wide mutation spectrum of chemically and genetically induced mouse lung adenocarcinomas (Westcott et al., Nature, 2015). Adenocarcinomas induced by chemical mutagens that mimic environmental exposures display a large number of carcinogen-specific point mutations, in contrast to genetic cancer models, which are widely used for testing drug candidates in vivo but do not show any significant point mutations.