Early Genetic Mutations Strongly Influence Later Cancer Phenotypes
Early Genetic Mutations Strongly Influence Later Cancer Phenotypes
A review of Heterogeneity of mammary lesions represent molecular differences
Note: This is a review of the published article listed below. All information, quotes, figures, methods, and findings mentioned in this review are from that article, and are the property of its authors and/or the publication in which the article originally appeared.
Traditionally, cancer was believed to be a multi-step process with multiple molecular changes as the disease progresses through the full pathological cycle. New research suggests this traditional view may not be true. A team of researchers in California led by Ruria Namba (2006) combined expression analysis and high-resolution array CGH (aCGH) to investigate a mouse model of ductal carcinoma in situ that consists of unique lines of mammary intraepithelial neoplasia (MIN) outgrowths, the premalignant lesions in the mouse that progress to invasive carcinoma, to understand the molecular changes that are characteristic to certain phenotypes. The group used Agilent’s Mouse Whole Genome CGH Microarray Kit 44A, consisting of roughly 43,000 60-mer oligonucleotide probes that cover both exonic and intronic sequences. These arrays were used to analyze the MIN-Os and tumors from each line. The group then designed a custom Agilent CGH array to better define the length and boundaries of interstitial regions that were identified as deleted or amplified. The findings of this work suggest that the early lesions associated with carcinoma carry the important genetic changes that reflect the major phenotypic information, while additional genetic changes that accumulate in the invasive carcinoma are less associated with the overall phenotype.
Figure 1. Mouse whole genome CGH microarray data from MIN-Os and tumors.
A) Summary of array CGH data by MIN-O lines. Agilent mouse whole genome CGH microarray was used for genomic DNA from different MIN-O and tumor pairs from 4w-4, 4w-11, 8w-B and 8w-D MIN-O mice. The graphs were generated with a smoothing average of 50 MB. Each Pair of MIN-O and corresponding tumor from the same animal is represented with the same color (n = 4 for 4w-4, n = 3 each for 4w-11, 8w-B and 8w-D). 4w-4 and 8w-B samples have multiple whole chromosome gains. 4w-11 and 8w-D samples are relatively genetically stable. B-E) Frequency of whole chromosome gains found in MIN-Os and tumors by array CGH. B) Distribution of whole chromosome gains in all MIN-Os studied with array CGH (n = 14). The most frequent gain is found on chromosome 2, followed by chromosome 1 and 11. C) Distribution of chromosome gains in all tumor samples studied with array CGH (n = 14). Tumors have the same whole chromosome gains found in MIN-Os with a few additional gains. D) Frequency of whole chromosome gain events associated with MIN-O to tumor transition. Whole chromosome gains in tumors that are not found in the corresponding MIN-O samples are presumed to be acquired during the transition from MIN-O to tumor. E) Frequency of chromosome gains in 8w-B and 4w-4 samples (n = 8 for MIN-Os and tumors each). The majority of whole chromosome gains were found in the 8w-B and 4w-4 MIN-O lines.
Figure 2. High resolution custom CGH microarray data on selected regions on chromosomes 2, 3 and 17.
Small deletions in 2F, 3E, and 17E in MIN-Os and tumors from the 8w-D line were confirmed with the custom designed "zoom-in" array with average spacing of 547 bp. The specific breakpoints were determined as follows: chr2:130,621,986-131,735,939, chr3:83,909,586-84,292,657, chr17:72,077,340-72,137,044.
Title: Heterogeneity of mammary lesions represents molecular differences
Authors: Ruria Namba , Jeannie E Maglione , Ryan R Davis , Colin A Baron, Stephenie Liu, Condie E Carmack , Lawrence JT Young , Alexander D Borowsky, Robert D Cardiff and Jeffrey P Gregg.
Journal: BMC Cancer 2006, 6:275
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