Chromosomal alterations associated with the transition from in situ to invasive breast cancer
ABSTRACT Ductal carcinoma in situ (DCIS) is a preinvasive lesion of the breast with an inherent but nonobligatory tendency for progression to invasive breast cancer. Although the transition from in situ to invasive disease is critical to the development of breast cancer, molecular and biological changes responsible for this transition are not well characterized.
Chromosomal alterations at 26 regions were assayed in 66 DCIS lesions and 111 invasive ductal carcinomas. Levels and patterns of allelic imbalance (AI) were compared between grade 1 DCIS and well-differentiated breast carcinomas, and between grade 3 DCIS and poorly differentiated invasive breast carcinomas, using Fisher's exact and Student's t-tests.
Levels of AI were significantly lower (P < 0.01) in grade 1 DCIS (11.9%) compared to well-differentiated carcinomas (19.2%), but were not significantly different between grade 3 DCIS and poorly differentiated tumors. No significant differences were detected at any of the 26 chromosomal regions between low-grade DCIS and invasive tumors; however, AI events at chromosomes 1p36, 11q23, and 16q11-q22 could discriminate high-grade in situ from invasive disease.
Lower levels of AI in low-grade in situ compared with invasive disease may reflect the protracted time to progression associated with low-grade DCIS. Increased levels of AI at chromosomes 1p36 and 11q23 in poorly differentiated carcinomas may harbor genes associated with invasiveness, while loss of chromosome 16q11-q22 may prevent the transition from in situ to invasive disease. Further characterization of these changes may provide molecular assays to identify DCIS lesions with invasive potential as well as targets for molecular therapeutics.
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ABSTRACT: Pathological grade is a useful prognostic factor for stratifying breast cancer patients into favorable (low-grade, well-differentiated tumors) and less favorable (high-grade, poorly-differentiated tumors) outcome groups. Under the current system of tumor grading, however, a large proportion of tumors are characterized as intermediate-grade, making determination of optimal treatments difficult. In an effort to increase objectivity in the pathological assessment of tumor grade, differences in chromosomal alterations and gene expression patterns have been characterized in low-grade, intermediate-grade, and high-grade disease. In this review, we outline molecular data supporting a linear model of progression from low-grade to high-grade carcinomas, as well as contradicting genetic data suggesting that low-grade and high-grade tumors develop independently. While debate regarding specific pathways of development continues, molecular data suggest that intermediate-grade tumors do not comprise an independent disease subtype, but represent clinical and molecular hybrids between low-grade and high-grade tumors. Finally, we discuss the clinical implications associated with different pathways of development, including a new clinical test to assign grade and guide treatment options.Clinical Medicine: Oncology 07/2009; 3:77-85.
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ABSTRACT: We used a combination of spectral karyotyping, array comparative genomic hybridization, and cDNA microarrays to gain insights into the structural and functional changes of the genome in the MCF10 human breast cancer progression model cell lines. Spectral karyotyping data showed several chromosomal aberrations and array comparative genomic hybridization analysis identified numerous genomic gains and losses that might be involved in the progression toward cancer. Analysis of the expression levels of genes located within these genomic regions revealed a lack of correlation between chromosomal gains and losses and corresponding up-regulation or down-regulation for the majority of the approximately 1,000 genes analyzed in this study. We conclude that other mechanisms of gene regulation that are not directly related to chromosomal gains and losses play a major role in breast cancer progression.Cancer Research 08/2009; 69(14):5946-53. DOI:10.1158/0008-5472.CAN-09-0420 · 9.28 Impact Factor
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ABSTRACT: As is well established in invasive breast disease, it is becoming increasingly clear that molecular heterogeneity, both between and within lesions, is a prevalent, distinct phenotype of premalignant lesions of the breast. Key pathways of tumorigenesis modulate critical features of premalignant lesions such as proliferation, differentiation, stress response, and even the generation of diversity. Current studies show that evaluation of these lesions may provide clinically useful information on future tumor formation as well as biological insights into the origin and functional significance of this distinct phenotype.Cancer Prevention Research 05/2010; 3(5):579-87. DOI:10.1158/1940-6207.CAPR-10-0073 · 5.27 Impact Factor