A. John Iafrate, MD, PhD
Massachusetts General Hospital
Associate Professor of Pathology
Harvard Medical School
The genetic understanding of cancer continues to progress at a rapid rate. We have attempted to translate the wealth of genetic research data into advances in patient therapies. To accomplish this we have established a broad cancer genotyping platform, termed SNAPSHOT, which detects recurrent mutations in DNA from archived pathology specimens. This platform is allowing for a molecular stratification of cancer patients, and in some cases allowing for placement of patients into trials of novel agents that target specific mutated gene products.
A. John Iafrate, MD, PhD, Director
Initially we have focused on lung cancer, but are in the process of expanding this approach to all malignancies. Within the lung cancer group we have recently focused on a specific newly-discovered genetic subtype, those with rearrangement of the ALK gene. We have defined the clinico-pathologic characteristics of ALK positive tumors, which we now know occur in younger patients that are never or light smokers and have a specific histologic appearance with a predominance of signet ring cells. Identification of ALK-positive patients prospectively has been the foundation of an on-going clinical trial of a novel ALK kinase inhibitor, with encouraging preliminary results. We hope to have continued success in seeding future clinical trials through our genotyping efforts.
Our laboratory also studies more basic aspects of human genetics, with a focus on the understanding of copy number variation. Copy number variants (CNVs) are now appreciated to be a major source of variation in our genomes, and may underlie many of the phenotypic differences in human individuals. We have recently developed a set of genetic tools based on CNVs that allow one to define genetic identity in situ. These are FISH probes that correspond to CNVs that exist as completely deleted sequences in some individuals, and are termed polymorphic deletion probes (PDPs). We are currently applying these PDPs to the in situ study of cellular chimerism in transplantation, including chronic rejection and graft versus host disease.