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Research at Mass General
A. John Iafrate, MD, PhD
Professor of Pathology, Harvard Medical SchoolPathologist, Massachusetts General Hospital
Molecular Pathology UnitMassachusetts General Hospital55 Fruit StreetBoston, MA 02114Phone: 617-726-0166Fax: 617-726-5079Email: firstname.lastname@example.org
Our lab has focused efforts on translating highly complex molecular analyses of tumor genetics using novel technologies into clinical use. We have previously developed the SNaPshot genotyping assay, which has enabled Mass General to make personalized cancer medicine a priority. We have a strong interest in the clinical implementation of genetic screening technologies that can help direct targeted therapies, focusing on lung, pancreatic and brain tumors. Our recent contributions in the treatment of a subset of lung tumors with rearrangements of the ALK tyrosine kinase and with rearrangements of the ROS1 tyrosine kinase with a small molecule kinase inhibitor underscore the promise of personalized cancer care. Our long term goal is to develop high-throughput genetic screening approaches for all cancer patients. To address this need, we have developed a novel next generation sequencing technique termed "anchored multiplex PCR (AMP)", that is especially powerful at detection gene fusion events from clinical specimens. We have shown that AMP is a sensitive as FISH in diagnosing ALK, ROS1 and RET fusions in lung cancer, and does not require knowing both fusion partners. In addition, AMP can be used for genomic DNA target enrichment, and is scalable and cost effective. Current work focuses on ultrasensitive detection of mutations in blood and urine.
We have also continued prior studies of tumor heterogeneity, by studying gene amplification of receptor tyrosine kinases in glioblastoma. This work has revealed a new subclass of brain tumors with mosaic gene amplification of up to 3 kinases in distinct but intermingled cell populations within the same tumor. We are exploring the therapeutic implications of such driver gene heterogeneity in model systems of glioblastoma using patient derived cell lines and xenografts. A major effort here has been the development of multiplexed in situ genetic analysis using FISH. These techniques will allow us to analyze many more genes, and map copy number heterogeneity onto histology sections.
Our laboratory has also focused on human germline genetics, namely on copy number variation (CNVs). These polymorphisms involve copy number gains or losses of large genomic regions (kilobases up to several megabases), and were identified using high-resolution genomic microarrays to compare the genomes of phenotypically normal individuals. Our continuing work is focused on the detailed structural analysis of CNVs using high resolution fluorescence microscopy imaging techniques, quantitative PCR and BAC sequencing. We have developed novel FISH probes based on deletion CNVs that can be used to determine genetic identity in situ. These probes are being applied to chimerism analysis in transplantation and will aid in the study of engraftment, rejection, and graft versus host disease. Importantly, these probes are located on autosomes, so for the first time chimerism analysis can be performed in same sex transplants.
Read more about the Iafrate Lab from the Center for Cancer Research Annual Report. and the Pathology Basic Science Research Brochure.
A. John Iafrate, MD, PhD, Director
Long Phi Le, MD, PhD Director of Technology DevelopmentMaristela Onozato, PhD Research ScientistJu Cheng, PhD Visiting FellowJesse Lee Research Technician IVarun Chahal Research Technician I
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.
Bibliography of A. John Iafrate via PubMed
Anchored multiplex PCR for targeted next-generation sequencing. Zheng Z, Liebers M, Zhelyazkova B, Cao Y, Panditi D, Lynch KD, Chen J, Robinson HE, Shim HS, Chmielecki J, Pao W, Engelman JA, Iafrate AJ, Le LP. Nat Med. 2014 Dec;20(12):1479-84.
ROS1 Rearrangements Define a Unique Molecular Class of Lung Cancers. Kristin Bergethon, Alice T. Shaw, Sai-Hong Ignatius Ou, Ryohei Katayama, Christine M. Lovly, Nerina T. McDonald, Pierre P. Massion, Christina Siwak-Tapp, Adriana Gonzalez, Rong Fang, Eugene J. Mark, Julie M. Batten, Haiquan Chen, Keith D. Wilner, Eunice L. Kwak, Jeffrey W. Clark, David P. Carbone, Hongbin Ji, Jeffrey A. Engelman, Mari Mino-Kenudson, William Pao, A. John Iafrate. J Clin Oncol. 2012 Mar 10; 30(8): 863–870.
Mosaic amplification of multiple receptor tyrosine kinase genes in glioblastoma. Snuderl M, Fazlollahi L, Le LP, Nitta M, Zhelyazkova BH, Davidson CJ, Akhavanfard S, Cahill DP, Aldape KD, Betensky RA, Louis DN, Iafrate AJ. Cancer Cell. 2011 Dec 13;20(6):810-7.
Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B, Maki RG, Ou SH, Dezube BJ, Jänne PA, Costa DB, Varella-Garcia M, Kim WH, Lynch TJ, Fidias P, Stubbs H, Engelman JA, Sequist LV, Tan W, Gandhi L, Mino-Kenudson M, Wei GC, Shreeve SM, Ratain MJ, Settleman J, Christensen JG, Haber DA, Wilner K, Salgia R, Shapiro GI, Clark JW, Iafrate AJ. N Engl J Med. 2010 Oct 28;363(18):1693-703. Erratum in: N Engl J Med. 2011 Feb 10;364(6):588.
Rapid targeted mutational analysis of human tumours: a clinical platform to guide personalized cancer medicine. Dias-Santagata D, Akhavanfard S, David SS, Vernovsky K, Kuhlmann G, Boisvert SL, Stubbs H, McDermott U, Settleman J, Kwak EL, Clark JW, Isakoff SJ, Sequist LV, Engelman JA, Lynch TJ, Haber DA, Louis DN, Ellisen LW, Borger DR, Iafrate AJ. EMBO Mol Med. 2010 May;2(5):146-58.
Detection of large-scale variation in the human genome. Iafrate AJ, Feuk L, Rivera MN, Listewnik ML, Donahoe PK, Qi Y, Scherer SW, Lee C. Nat Genet. 2004 Sep;36(9):949-51.
Massachusetts General Hospital
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