Abstract 2134: Copy number variation in low- and high-grade breast tumors

Abstract

Abstract Objective Histological grade classifies breast carcinomas into low-, intermediate- and high-grade. Developmental pathways for high-grade disease remain controversial; clinical data have been used to describe both linear models, in which high-grade tumors evolve from low-grade precursors, as well as models that depict low- and high-grade carcinomas as distinct molecular diseases. Genome-wide copy number alterations were examined in low- and high-grade breast tumors to identify genetic changes associated with the etiology of low- and high-grade breast carcinomas. Methods Tumors were diagnosed and characterized by a single, dedicated breast pathologist. DNA was isolated after laser microdissection from low- (n= 53) and high-grade (n=68) tumors. Genotype data were generated using Human Mapping 250K Sty arrays (Affymetrix). Copy number alterations and LOH were detected using GenomeConsole 3.0.2 (Affymetrix). Results The most common alterations in low-grade carcinomas were gain of chromosomes 1q (75%) and 16p (58%) and loss of chromosome 16q (86%). These alterations were frequently simple and included the entire chromosomal arm. In contrast, patterns of alterations were complex in high-grade tumors, frequently with alternating gains and losses on a single chromosomal arm. In high-grade tumors, the most frequent alterations included gain of chromosome 1q (85%), 8q (84%), and loss of chromosomes 8p (54%), 14q (57%) and 17p (69%). Loss of 16q (P<0.0000005) and gain of 16p (P<0.005) occurred significantly more frequently in low- compared to high-grade tumors, while gain of 8q24 (P<0.000005) and 10p15-p14 (P<0.00005) and loss of chromosome 17p13 (P<0.00005) occurred significantly more frequently in high- compared to low-grade tumors. Only two samples, one low- and one high-grade, had a “flat” profile with no detectable chromosomal alterations. Conclusion Low- and high-grade breast tumors are genetically different. Gain of chromosome 1q is common in both low- and high-grade tumors, and may be an early event in tumorigenesis. Given the significantly different patterns of alterations, especially significantly higher loss of chromosome 16q in high- compared to low-grade tumors, high-grade disease may not arise from dedifferentiation of low-grade but rather represent a separate disease defined by unique genetic alterations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2134.