The Gallie lab since 1974 has focused on all aspects of the rare children' s eye cancer, retinoblastoma, including molecular pathogenesis and clinical impact. We identified that somatic inactivation of the RB1 gene initiated retinoblastoma tumors, pointing to the role of tumor suppressor genes in cancer. If the first mutant RB1 allele (M1) arises in the germline, it predisposes to bilateral retinoblastoma and multiple other cancers, when the second allele (M2) undergoes somatic inactivation in embryonic retina and other tissues. We went on to characterize key M3 genetic changes in retinoblastoma progression and the genes involved (KIF14, CDH11, E2F3/DEK, and MYCN).
In 1982 we recognized a premalignant precursor of retinoblastoma, called retinoma. In 2008 we showed that loss of both RB1 alleles initiates retinoma, associated with genomic instability that increases as malignant retinoblastoma develops. We also showed that KIF14 oncogene overexpression corresponds to poor outcome in lung and ovarian cancers.
To translate research to efficient and effective technologies to identify the precise and usually unique RB1 mutation in each retinoblastoma family, we developed highly sensitive assays and demonstrated impact of such personalized medicine on health care costs. We founded a genetic testing lab (now Impact Genetics) to provide the highest sensitivity mutation testing for families around the world, that empowered us to lead an international team that in 2013 discovered an unrecognized form of retinoblastoma, without RB1 mutations. While the MYCN gene characteristic of embryonic neural cells is highly expressed in all retinoblastoma tumors, high-level MYCN DNA amplification initiates a subset of retinoblastoma tumors with normal RB1 genes. These RB1+/+MYCNA tumors arise in very young children, driven by the oncogene, grow aggressively. However, the genome of the RB1+/+MYCNA tumors is more stable than RB1-/- tumors.
Twenty-seven years after the RB1 gene was cloned, less than 4% of the families globally have benefited from this knowledge. Our lab now becomes the world, as we work to provide a common level of care for retinoblastoma families everywhere. One Retinoblastoma World is a concept of Global Collaboration, National Strategies, Regional Guidelines, with Personalized Genetic Medicine and Global Point-of-Care Documentation to actualize a path to optimized care for all children and families affected by retinoblastoma.