Background
Our research mission is focused on a rare but highly malignant cancer of children and young adults termed BRD4-NUT carcinoma, which usually arises within midline structures of the head, neck, or trunk, such as the mediastinum, upper airways, and bladder. This cancer is often mistaken for other types of tumors, but is clinically distinct in its highly aggressive behavior. In the cases we have identified to date, the mortality rate is close to 100%, and the median survival is only around 6 months. Most of these these tumors are diagnosed as poorly differentiated carcinomas, but they are sometimes so primitive that they are mistaken for other kinds of tumors, such as Ewing's sarcoma/primitive neuroectodermal tumor (PNET).

The defining feature of these cancers is the presence of a chromosome translocation, t(15;19)(p13.1;q14), which involves the genes BRD4 and NUT and creates a BRD4-NUT fusion oncogene. Work in our laboratory suggests that the Brd4-NUT fusion protein plays a central role in causing this cancer. The only reliable means of diagnosis is the detection of the Brd4-NUT fusion gene.

What We Offer
Our laboratory is dedicated to a better understanding of this disease, with the ultimate goal of developing rational therapies that target the Brd4-NUT protein. We offer free molecular diagnostic testing for all cases that fall within the clinical spectrum of this type of cancer *. These tests can be performed on paraffin sections cut from formalin-fixed, paraffin-embedded tumor biopsies *.

*The tests are not as yet CLIA approved. Cases are requested to be de-identified. Results will be reported informally and shall not be included in official diagnostic reports.

POST-DOCTORAL POSITION
We are presently offering a post-doctoral position open to U.S. citizens with M.D. or M.D./Ph.D..

Selected References
Mertens F, et al. Pediatr Blood Cancer. 2006 Jan 24. [Epub ahead of print]

 French CA, et al. Midline Carcinoma of Children and Young Adults With NUT Rearrangement, J Clin Oncol. 2004;22: 4135-4139. [view pdf file] [J Clin Oncol link]

French CA, et al. BRD4-NUT Fusion Oncogene A Novel Mechanism in Aggressive Carcinoma, Cancer Res. 2003;63:304-7. [view pdf file] [Cancer Res link]

Contact
Chris French, M.D.

Brigham and Women’s Hospital
Harvard Medical School
Department of Pathology
75 Francis St.
Boston, MA 02115

Email: cfrench@partners.org
Office: 617 525-7824
Lab: 617 732-7483
Fax: 617 738-6996

 
               This site is dedicated to Mrs. Hayley Carter,
               (1974-2006), a BRD4-NUT1 carcinoma patient.
               We were deeply touched by her desire and
               willingness to assist in research aimed at the
               causes and treatments of this disease.

               The BRD4-NUT research group: Lisa Chiu,
               Chris French, and Krishan Taneja.
               Dr. French's work is devoted to improved
               diagnosis and therapy of this disease.
     
     
Site Design by Kristine Estrada
 
Translocation t(15;19)(q13, p13.1) characterizes a rare, aggressive, and lethal carcinoma arising in midline organs of young people. The translocation results in a heretofore uncharacterized fusion oncogene. As described previously, we have determined that the chromosome 19 translocation breakpoint targets the BRD4 bromodomain gene, whereas the chromosome 15 breakpoint involves a 9-kb region on chromosome band 15q13. BRD4 is expressed normally as two alternative transcripts with identical 5' ends; but the coding sequence of the longer BRD4 transcript is approximately twice the length of the shorter transcript. Both BRD4 transcripts encode the NH2-terminal bromodomains, whereas the longer BRD4 transcript encodes COOH-terminal lysine-rich regions that are not encoded by the shorter BRD4 transcript. Notably, the t(15;19) translocation breakpoint transects the coding sequence of the longer BRD4 gene, whereas the shorter BRD4 transcript is unperturbed. In vitro and in vivo studies of the murine BRD4 have revealed a critical role in the regulation of cell cycle progression and cellular proliferation. BRD4 associates with chromatin and binds replication factor C. Notably, whereas BRD4 expression regulates G2-M transition, BRD4 overexpression inhibits G1-S phase transition. In addition, in vivo studies suggest a pivotal role for BRD4 in cellular proliferation during embryogenesis. To fully characterize the molecular mechanism of oncogenesis in t(15;19)-associated carcinomas, we undertook mapping and cloning of the chromosome 15 translocation target. Herein, we demonstrate that the chromosome 15 translocation rearranges the novel gene, NUT, resulting in a BRD4-NUT fusion oncogene. We also report expression profiles for NUT and BRD4 in normal tissues. These studies reveal the first known fusion oncogene in a highly malignant form of epithelial neoplasia. keywords: Dr. French, Chris French, Dr. Chris French, BRD4-NUT, BRD4, NUT, cancer, fusion oncogene