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Original Article
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Volume 357:2543-2551 December 20, 2007 Number 25
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Breast-Cancer Stromal Cells with TP53 Mutations and Nodal Metastases
Attila Patocs, M.D., Ph.D., Li Zhang, Ph.D., Yaomin Xu, M.S., Frank Weber, M.D., Trinidad Caldes, Ph.D., George L. Mutter, M.D., Petra Platzer, Ph.D., and Charis Eng, M.D., Ph.D.

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ABSTRACT

Background The importance of cross-talk between a cancer and its microenvironment has been increasingly recognized. We hypothesized that mutational inactivation of the tumor-suppressor gene TP53 and genomic alterations in stromal cells of a tumor's microenvironment contribute to the clinical outcome.

Methods We performed TP53 mutation analysis and genomewide analysis of loss of heterozygosity and allelic imbalance on DNA from isolated neoplastic epithelial and stromal cells from 43 patients with hereditary breast cancer and 175 patients with sporadic breast cancer. Compartment-specific patterns and TP53 mutations were analyzed. Associations between compartment-specific TP53 status, loss of heterozygosity or allelic imbalance, and clinical and pathological characteristics were computed.

Results TP53 mutations were associated with an increased loss of heterozygosity and allelic imbalance in both hereditary and sporadic breast cancers, but samples from patients with hereditary disease had more frequent mutations than did those from patients with sporadic tumors (74.4% vs. 42.3%, P=0.001). Only 1 microsatellite locus (2p25.1) in stromal cells from hereditary breast cancers was associated with mutated TP53, whereas there were 66 such loci in cells from sporadic breast cancers. Somatic TP53 mutations in stroma, but not epithelium, of sporadic breast cancers were associated with regional nodal metastases (P=0.003). A specific set of five loci linked to an increased loss of heterozygosity and allelic imbalance in the stroma of sporadic tumors was associated with nodal metastases in the absence of TP53 mutations. No associations were found between any of the clinical or pathological features of hereditary breast cancer with somatic TP53 mutations.

Conclusions Stroma-specific loss of heterozygosity or allelic imbalance is associated with somatic TP53 mutations and regional lymph-node metastases in sporadic breast cancer but not in hereditary breast cancer.


Source Information

From the Genomic Medicine Institute (A.P., L.Z., Y.X., F.W., P.P., C.E.) and the Department of Quantitative Health Sciences, Lerner Research Institute (L.Z., Y.X.), and the Taussig Cancer Center (C.E.), Cleveland Clinic Foundation, Cleveland; the Laboratory of Molecular Oncology, San Carlos University Hospital, Madrid (T.C.); and the Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston (G.L.M.).

Address reprint requests to Dr. Eng at the Genomic Medicine Institute, Cleveland Clinic Lerner Research Institute, 9500 Euclid Ave., NE-50, Cleveland, OH 44195, or at engc{at}ccf.org.

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Related Letters:

Breast-Cancer Stromal Cells with TP53 Mutations
Campbell I. G., Qiu W., Polyak K., Haviv I., Zander C. S., Soussi T., Zalcman G., Bergot E., Hainaut P., Roukos D. H., Patocs A., Platzer P., Eng C.
Extract | Full Text | PDF  
N Engl J Med 2008; 358:1634-1636, Apr 10, 2008. Correspondence

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