Dr. Marc Ladanyi is an active investigator in molecular pathology and sarcoma biology. Over the past 12 years, his research work has centered on the interface of molecular pathology and surgical pathology, reflecting his training and board certification in both anatomic pathology and clinical molecular genetics.

Dr. Ladanyi, a Canadian, received his M.D. in 1984 at the age of 23 from McGill University in Montreal with the distinction of University Scholar (summa cum laude). Interestingly, the same class produced two other active members of the academic pathology community, Poul Sorensen and Robert Odze! Throughout medical school Dr Ladanyi planned a career in Neurology, but decided to spend a year in Pathology after graduating in order to gain a more solid understanding of disease. As he began Pathology training, Neurology soon lost its appeal and he committed himself to Anatomic Pathology. In the course of his Pathology Residency at McGill his interest in the emerging field of cancer genetics was fostered by stints in the laboratories of Serge Jothy and Tom Seemayer. In 1987 he sought to complete his Anatomic Pathology training with a fellowship at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York City, where he then acquired additional training in Genetics and Cytogenetics, followed by research on lymphoma translocations in the laboratory of Raju Chaganti. In 1993, he joined the staff at MSKCC and since 1994 he has been Director of the Laboratory of Diagnostic Molecular Pathology in the Department of Pathology.

Dr. Ladanyi has received several awards, including the College of American Pathologists Foundation Scholar Award, an American Cancer Society (ACS) Clinical Oncology Career Development Award, the Benjamin Castleman Award of the USCAP (1995), as well as the Boyer Award for Clinical Research at MSKCC (2001). He is currently funded as a principal investigator on grants from the NIH (and previously the ACS). He is particularly active as a peer reviewer, both on several journal editorial boards and in grant review committees [NIH, ACS, MRC (Canada)]. He also functions as Associate Editor at the Journal of Molecular Diagnostics and at the Journal of Clinical Pathology. Dr Ladanyi has authored or co-authored over 120 research papers and more than 20 reviews or chapters and recently co-edited with William Gerald the first book on gene expression profiling of human tumors, Expression profiling of human tumors: Diagnostic and research applications (2003).

Chromosomal translocations have been at the core of his research efforts, as this class of alterations has provided the richest source of practical diagnostic markers as well as many important insights into tumor biology. From the beginning of his independent research, at the encouragement of Andrew Huvos, he has focused in particular on sarcomas with translocations. Several recurrent themes run through his laboratory output, including translocation breakpoint cloning, the practical application of translocation testing through RT-PCR assays or surrogate immunohistochemical assays, the use of molecular translocation testing to clarify the clinicopathologic spectrum of existing entities and to define new ones, the biologic and clinical correlates of fusion gene structure, the functional aspects of fusion genes that encode chimeric transcription factors and how they impact on cellular phenotype and gene expression profiles, and the contrasting biology of translocation-associated sarcomas and non-translocation sarcomas with complex karyotypes. His experimental approaches have utilized almost exclusively human tumor material and human cancer cell lines, reflecting his view that it for this type of research that investigators with an anatomic pathology background are uniquely qualified. In 2003, he was selected to be a member of the Sarcoma Progress Review Group convened to advise the National Cancer Institute on future sarcoma research initiatives.

In the area of translocation breakpoint cloning, his laboratory has been involved in the cloning of several novel fusion oncogenes, including EWS-WT1, ASPL-TFE3, CLTC-TFE3, ATIC-ALK, and EWS-SP3. Detection of the EWS-WT1 fusion has become a widely used molecular diagnostic test for the desmoplastic small round cell tumor. He and his collaborators recently established immunohistochemistry for TFE3 as a practical diagnostic assay that can substitute for molecular testing for ASPL-TFE3 and otherTFE3 gene fusions in alveolar soft part sarcoma and TFE3 translocation carcinomas of the kidney. They have more recently demonstrated that staining for TFEB can likewise be used as an assay for the related renal carcinomas with the Alpha-TFEB translocation. His group has also established and published RT-PCR assays for these and many other gene fusions.

In the area of biologic and clinical correlates of fusion gene structure, his laboratory demonstrated the relationship of EWS-FLI1 fusion structure to transactivation, proliferative rate, and survival in Ewing sarcoma, and of SYT-SSX structure to epithelial differentiation and survival in synovial sarcoma. These findings have strengthened the notion that these gene fusions play a central role in the biology of their respective sarcomas.

In studies more directly relevant to surgical pathology, his group has employed molecular translocation testing to contribute to the definition, delineation, or clarification of the clinicopathologic spectrum of numerous entities, including Ewing sarcomas, olfactory neuroblastoma, skeletal and extraskeletal myxoid chondrosarcomas, classic myxoid/round cell liposarcoma and predominantly myxoid well-differentiated liposarcoma, endometrial stromal neoplasms, primary renal synovial sarcoma, and TFE3/TFEB translocation carcinomas of the kidney. Indeed, his studies, with Pete Argani of Johns Hopkins, on renal TFE3 translocation carcinomas and renal synovial sarcomas led to their acceptance as new and distinct tumor entities and their inclusion in the most recent WHO classification of renal tumors.

His work has also contributed to the understanding of translocation-associated sarcomas by highlighting the special impact of p53 (and p16/CDKN2A) alterations in these tumors, their distinctive pattern of telomere maintenance mechanisms, as well as their highly specific gene expression profiles. He was among the first to highlight how these and other features of translocation-associated sarcomas contrast sharply with those of non-translocation sarcomas with complex karyotypes, such as osteosarcoma and mesothelioma, both of which have also been the subject of studies in his laboratory. His group work in mesothelioma has shown that p16/CDKN2A homozygous deletion, the key genetic alteration in this tumor, can be used as a diagnostic marker in pleural effusion cytology. Their demonstration in mesotheliomas of very frequent co-deletion of MTAP, a gene adjacent to p16/CDKN2A, formed the basis for including this cancer in a national trial of targeted chemotherapy in MTAP-deficient cancers.

Dr. Ladanyi has not shied away from controversy, having participated in responses to various contentious PCR-based findings. In this his perspective is informed by his experience both in cancer genetics and in the practical pitfalls of molecular diagnostics. Most recently his team debunked the proposed association of SV40 and mesothelioma and proposed an explanation for the high risk of false positive SV40 PCR results in the testing of this and other human tumors.

He is an active member of USCAP and the Association for Molecular Pathology and was responsible for its application for companion society status and the organization of its inaugural companion meeting at USCAP in 2001.