Genetic Classification of Breast Cancer based on Unilateral Chromosomal Loss

Cho, Hyun A; Rhyu, Mun Gan; Choi, Seung Hye; Yun, Sang Seob; Lee, Seong; Jung, Sang Seol; Choi, Sang Wook; Seo, Eun Joo

Abstract

PURPOSE
The extent of the loss of heterozygosity (LOH) has been used as the genetic parameter for the classification and staging of some solid tumors. Breast cancers such as ductal carcinoma in situ (DCIS), and invasive and metastatic lesions, are frequently observed to contain heterogeneous tumor foci. To delineate the relation between the LOH and the progression of breast cancers, three successive histological sites in a tumor lesion were analyzed for LOH events. METHODS: We tested 111 tumor site including DCIS, and invasive, and metastatic lymph nodes from 50 breast cancers for LOH using 5 microsatellite makers on 8 chromosomal arms (3p, 4p, 5q, 8p, 9p, 13q, 17p, & 18q). RESULTS: Twenty-four of 34 breast cancers showing intratumoral histological heterogeneity had common chromosomal losses in the heterogeneous tumor sites, as well as having divergent losses that were restricted to a part of tumor lesion (mean divergent loss, 2.32). The number and frequency of heterogeneous chromosomal losses were not significantly related with age, tumor size, and stage. Overall, at least one chromosomal loss was detected in 48 cases, and incidences of LOH in each chromosome were 27.1~63.3%. A large fraction (58%) of breast cancer patients had 2 to 4 chromosomal losses, and chromosome 8p was most frequently lost (63%). When comparing the number of chromosomal losses in nine cases with all of three progressive lesions, the lost extent was greater in the DCIS (mean losses, 4.44) than in the invasive sites (mean losses, 3.1) and the metastatic lymph nodes (mean losses, 2.9). Moderate-level chromosomal losses involving 3-5 chromosomes were significantly related with lymph node metastasis (p=0.006) and the advanced tumor stage (p<0.005), whereas low-level losses involving 1~2 chromosomes and high-level losses involving 6~7 chromosomes were more common in DCIS and early-stage diseases. CONCLUSION: The DCIS, invasive, and metastatic sites of a breast cancer patient contained common and divergent chromosomal losses. This indicates the concurrent expansion of different subclones was derived from a common ancestor clone, in which an optimal range of chromosomal losses, rather than high-level chromosomal losses, was more frequently associated with lymph node metastasis and the advanced tumor stages.