In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 3376-3376
Abstract:
Aberrant crypt foci (ACF) are the earliest detectable premalignant lesion within the colon. A majority of ACF harbor somatically acquired mutations to cancer-related genes. ACF may be an indicator for a colonic mucosa at-risk for cancer development, however only a small subset of ACF have the potential to progress to malignancy. We believe that the majority of ACF activate growth inhibitory programs that ultimately result in their growth arrest and regression. In order to begin to define the gene expression changes that occur within these early microscopic lesions and their underlying stroma, we have developed a novel method that combines laser capture micro-dissection with targeted RNA-seq analysis. In the following study, gene expression profiles of thirteen human ACF biopsy specimens harboring known oncogenic mutations (K-ras, B-raf, N-ras, and APC) were compared to matched normal mucosa. Two gene panels were used to assess the status of important cell regulatory pathways: an apoptosis panel comprised of 267 genes and a customized cell senescence panel consisting of 20 genes. In the apoptosis panel, the expression of 81 genes were differentially expressed in ACF compared to matched normal mucosa. Expression of HRK, a potent activator of apoptosis, was the most significantly down-regulated gene (6.75-fold, q & lt;0.01) in every ACF when compared to normal mucosa. Inactivation of HRK function occurs in a variety of tumor types, including prostate cancer, astrocytomas and lymphomas. ACF with mutations occurring within the MAP-K pathway (K-ras, B-raf, N-ras) showed strong activation of downstream ras-associated genes and down-regulation of cell cycle regulators (CDK4 (p = 0.01), CCNB1 (p = 0.04), CCNA2 (p = 0.01), and TP53 (p = 0.04)). Interestingly, these expression panels were distinct from ACF harboring somatic mutations to APC. Analysis of microdissected stroma directly underlying the aberrant crypt structures revealed 25 differentially expressed genes, with dysregulation of several inflammatory mediators (IL2, IL2RA, IL6, TGFB2, BMP4) and extracellular matrix remodeling targets (TIMP1, TIMP2). Our findings suggest that ras-activated ACF may cause significant changes in cell cycle regulation, as well as alterations in stromal extracellular matrix maintenance and inflammatory response. Citation Format: Allen Mo, Nicole A. Horelik, Stephen Jackson, Thomas J. Devers, Daniel W. Rosenberg. Ras activation in aberrant crypt foci is associated with decreased expression of cell cycle regulators and disruption of stromal homeostasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3376. doi:10.1158/1538-7445.AM2015-3376
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2015-3376
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2015
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2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
