MYC Gene Amplification in Breast Cancer Metastases Relative to Matched Primary Tumors
AD Singhi, RB Jenkins, F Lin, S Fink, H Nassar, R Vang, A De Marzo, P Argani. The Johns Hopkins Medical Institutions, Baltimore, MD; Mayo Clinic, Rochester, MN
Background: In breast cancer, the MYC proto-oncogene transcription factor is implicated in cell growth, transformation, cell cycle control and angiogenesis. Roles in endocrine resistance and tumor progression have been proposed. MYC gene amplification in primary tumors correlates with aggressive phenotypes (such as high grade and proliferation rates) and poor outcomes. Whether MYC amplification develops in metastases of unamplified tumors has not been systematically addressed.
Design: Fifteen rapid autopsies (post mortem intervals less than 4 hours) were performed on patients who died of metastatic breast carcinoma. Single patient tissue microarrays were constructed from paraffin tissue blocks from the patients' archived primary breast tumors and multiple metastases harvested at autopsy. ER/PR/HER2 and CK5/6 expression was assessed, and the cases characterized as Luminal, Basal-like (BLC) or HER2 based on published criteria. FISH was performed on the 15 TMA slides using a centromere (CEP) 8 probe and a MYC gene probe. The ratio of MYC to CEP8 signals was calculated for each of 145 primary tumor spots, and 778 spots derived from 180 different metastases. MYC duplication was defined as a MYC: CEP8 ratio of 1.3-2.0, and MYC amplification was defined as a MYC: CEP8 ratio of > 2.0. Results from the primary tumors were correlated with those of the patient's matched metastases.
Results: Six of 15 cases (4 Luminal, 1 HER2, 1 BLC) showed no evidence of MYC amplification in the primary or any metastatic site. Three cases (2 Luminal, 1 BLC) demonstrated MYC duplication and 2 cases (1 Luminal, 1BLC) demonstrated MYC amplification in the primary tumor and all metastases. Interestingly, 4 cases (27% of overall cases; 2 BLC, 1HER-2, 1 Luminal) demonstrated MYC amplification in metastases (2.62 to 6.16-fold higher copy number) compared to the matched primary. We were surprised to find relatively little heterogeneity in MYC amplification between different metastases from the same patient.
Conclusions: Amplification of MYC is a frequent event in breast cancer and may occur relatively late in tumorigenesis, present more often in metastatic disease than the corresponding primary. These observations underscore the importance of MYC in breast cancer progression/metastasis, as well as its relevance as a potential therapeutic target in otherwise incurable metastatic disease.
Monday, March 22, 2010 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 35, Monday Morning