Biological and clinical significance of genomic rearrangements in cancer

Frederic G. Barr, MD PhD Senior Investigator and Deputy Chief Laboratory of Pathology, CCR, NCI

Confidential (distribute only to Laboratory of Pathology Strategic Visioning Committee Members)

Primary Research Area(s)

Genomic rearrangements in cancer
Gene fusions and amplification events

Current focus on rhabdomyosarcoma as a model system

Multi-disciplinary approach
Genome-wide scans identify and characterize rearrangements

PCR and FISH assays for detection in clinical material

Cooperative oncology group determine clinical significance Cell culture & animal models dissect biological role

Mutation and Amplification in RMS Subsets

Rhabdomyosarcoma
Gene fusion PAX3-FOXO1 PAX7-FOXO1 Point mutation Amplification Overall Recurrent
PAX3-FOXO1

Fusion-positive

Fusion-negative

4% 60% 50%
PAX7-FOXO1

24% 35% 3%

p=0.03

p=0.04 p=0.0001

Amplicon 2p24 12q13-q14 13q14 13q31

Fusion-negative

18% 24% 9% 8%

22% 4% 93% 67%

2% 0% 0% 5%

Research Implications
Larger context of genomic rearrangements in cancer
Basic research questions
Steps in cancer pathogenesis Collaboration between genetic events Etiology of genomic rearrangements

Clinical applications
Diagnostic markers Prognostic markers Therapeutic predictors Minimal disease markers

Future Directions
Future directions of research programs
Applications to rhabdomyosarcoma research Identify generalizable aspects
Reagents Technique Expertise

Apply to genomic rearrangements in other cancer categories

Sarcomas Leukemia and lymphomas Carcinomas Other categories

Current challenges & obstacles

High throughput approaches Bioinformatics

Collaborators
Laboratory of Pathology - CCR
Svetlana Pack, PhD Stephen Hewitt, MD, PhD Mark Raffeld, MD

Pediatric Oncology Branch CCR

Javed Khan, MD Chand Khanna, DVM, PhD Lee Helman, MD

Childrens Oncology Group

Soft Tissue Sarcoma Committee

University of Pennsylvania
Department of Pathology and Laboratory Medicine