Memorial Hospital Research Laboratories // Human Oncology & Pathogenesis Program

Jorge S. Reis-Filho, MD, PhD

The focus of my laboratory is on the identification of the drivers of special histological types of breast cancer, rare forms of the disease that together account for up to 25 percent of all invasive breast cancers, using a combination of massively parallel sequencing and functional genomics approaches. These rare forms of breast cancer have been shown to be less transcriptomically and genomically heterogeneous than the common type of the disease, the so-called invasive ductal carcinomas.

Our hypothesis is that the analysis of phenotypically homogeneous subsets of breast cancers will lead to the identification of novel drivers of the disease and pathognomonic mutations. Our goals are to develop a predictive classification system for these rare types of breast cancer and to define potential therapeutic targets that can be used to manage not only tumors of each of these special histological types but also subsets of the common types of the disease.

Our laboratory also investigates the impact of intratumor genetic heterogeneity on the biology and clinical behavior of breast cancers. Our hypothesis is that breast cancers are mosaics composed of cancer cell clones that, in addition to the founder genetic events, harbor private mutations, and that these mutations play a role in the ability of cancer cells to metastasize and become resistant to chemotherapy and targeted agents.

Our goal is to use this knowledge to develop and validate diagnostic, prognostic, and predictive biomarkers. We are currently investigating whether circulating DNA and/or circulating tumor cells can be used to define the entire constellation of mutations found in primary and metastatic breast cancers and how the genetic analyses of these biological materials could complement the information obtained from the analysis of primary tumor samples for clinical decision making.

Publications

Weigelt B, Mackay A, A'hern R, Natrajan R, Tan DS, Dowsett M, Ashworth A, Reis-Filho JS. Breast cancer molecular profiling with single sample predictors: a retrospective analysis. Lancet Oncol. 2010 Apr;11(4):339-49. doi: 10.1016/S1470-2045(10)70008-5. Epub 2010 Feb 22.

Mackay A, Weigelt B, Grigoriadis A, Kreike B, Natrajan R, A'Hern R, Tan DS, Dowsett M, Ashworth A, Reis-Filho JS. Microarray-based class discovery for molecular classification of breast cancer: analysis of interobserver agreement. J Natl Cancer Inst. 2011 Apr 20;103(8):662-73. doi: 10.1093/jnci/djr071. Epub 2011 Mar 18.

Natrajan R, Mackay A, Lambros MB, Weigelt B, Wilkerson PM, Manie E, Grigoriadis A, A'hern R, van der Groep P, Kozarewa I, Popova T, Mariani O, Turajlic S, Furney SJ, Marais R, Rodruigues DN, Flora AC, Wai P, Pawar V, McDade S, Carroll J, Stoppa-Lyonnet D, Green AR, Ellis IO, Swanton C, van Diest P, Delattre O, Lord CJ, Foulkes WD, Vincent-Salomon A, Ashworth A, Henri Stern M, Reis-Filho JS. A whole-genome massively parallel sequencing analysis of BRCA1 mutant oestrogen receptor-negative and -positive breast cancers. J Pathol. 2012 May;227(1):29-41. doi: 10.1002/path.4003. Epub 2012 Feb 23.

Dhomen N, Reis-Filho JS, da Rocha Dias S, Hayward R, Savage K, Delmas V, Larue L, Pritchard C, Marais R. Oncogenic Braf induces melanocyte senescence and melanoma in mice. Cancer Cell. 2009 Apr 7;15(4):294-303. doi: 10.1016/j.ccr.2009.02.022.

Geyer FC, Weigelt B, Natrajan R, Lambros MB, de Biase D, Vatcheva R, Savage K, Mackay A, Ashworth A, Reis-Filho JS. Molecular analysis reveals a genetic basis for the phenotypic diversity of metaplastic breast carcinomas. J Pathol. 2010 Apr;220(5):562-73. doi: 10.1002/path.2675.