Pattern of Chromosome 16q Loss Differs between an Atypical Proliferative Lesion and an Intraductal or Invasive Ductal Carcinoma Occurring Subsequently in the Same Area of the Breast

Abstract

Atypical proliferative lesions of the breast, such as atypical ductal hyperplasia and atypical papilloma, are considered to be precursors of breast carcinomas and have frequently been shown to have loss of heterozygosity (LOH) on chromosome 16q at the DNA level. We evaluated whether an atypical proliferative lesion and a carcinoma that subsequently occurred in the same area of the ipsilateral breast were of identical clonal origin in seven patients. Using DNA isolated from microdissected archival tissue of epithelial components of both the biopsy specimen of the atypical proliferative lesion and the mastectomy specimen of the carcinoma, the pattern of LOH on 16q was compared between these two lesions using polymerase chain reaction -microsatellite LOH analysis. As a control, LOH on 16q was examined in 13 cases of usual ductal hyperplasia, 10 usual papillomas, and 6 atypical ductal hyperplasias. In the seven cases, LOH on 16q was detected in three of the six atypical proliferative lesions and in five of the seven carcinomas, but the allele with LOH or a deleted region always differed between the two. LOH was detected in both atypical proliferative lesions and carcinomas in one case, only in the atypical proliferative lesion in two cases, and only in carcinomas in three cases. In the controls, LOH on 16q was absent in usual ductal hyperplasias or usual papillomas but was detected in two of six atypical ductal hyperplasias. Although atypical proliferative lesions were frequently confirmed to be of clonal nature with LOH on 16q, these lesions and carcinomas were considered to be clones, probably originated from a field with these clones. KEY WORDS: Breast cancer, Chromosome 16, Loss of heterozygosity, Natural history, Precancer lesions. Mod Pathol 2001;14(5):382-388Intraductal carcinomas, or ductal carcinomas in situ (DCIS), are considered to be the early, preinvasive stage of breast cancer, and, if followed up, are often found to progress eventually to invasive cancers (1, 2). DCIS are subclassified into low-grade noncomedo type (i.e., cribriform, papillary, and low-papillary types) and high-grade comedo type. Atypical ductal hyperplasia (ADH) is defined as a small lesion of atypical epithelial cells with structural atypia but where the degree of atypia is not sufficient to classify DCIS. ADH is a risk factor for breast cancer occurrence, which becomes four times as likely as in women without the lesion (3, 4). Therefore, ADH stands in an intermediate position both histologically and as a cancer risk factor between the hyperplasia without atypia and DCIS. Atypical papillomas, or papillomas with an atypical or borderline part, which are frequently the feature of multiple papillomas, are also shown often to be accompanied by cancer and/or to be a risk factor of breast cancer (5-7). Loss of heterozygosity (LOH) on chromosome 16q frequently occurs in human breast cancers, including low-grade DCIS (8 -11). ADH is also reported to show LOH frequently on chromosomes 16q and 17p (12). Therefore, ADH is demonstrated to be a...

Gene and chromosomal alterations in sporadic breast cancer: correlation with histopathological features and implications for genesis and progression

“…Atypical ductal hyperplasia (ADH), defined by Page, is very similar to cribriform-type DCIS in its histological features, but its size is 2.0 mm or less, and the degree of structural atypia is a little weaker than in cribriform type DCIS. Although ADH is generally considered to be a precancerous condition, LOH on 16q is already detectable [88,89].…”

Chromogenic and fluorescent in situ hybridization in breast cancer

“…Loss of 16q and gain of 1q are well documented as features of the low-grade family of breast carcinomas, including flat epithelial atypia; lobular neoplasia; lowgrade DCIS; and invasive lobular, tubular, cribriform and low-grade ductal carcinomas [1][2][3][4][8][9][10]46,139,[164][165][166]. Although gain of 1q is one of the most frequent genomic changes in breast cancer and has been extensively studied, the mechanisms leading to this genomic aberration are still poorly characterized.…”

Intracystic Papillary Carcinoma of Breast Harbors Significant Genomic Alteration Compared with Intracystic Papilloma: Genome-wide Copy Number and LOH Analysis Using High-Density Single-Nucleotide Polymorphism Microarrays

“…Tsuda et al (7,8) reported that papillary carcinomas have frequent changes in gene copynumber and loss of heterozygosity (LOH), while papillomas did not show any gene copy-number alteration or LOH at 16q and 1q. Boecker et al (9) also reported that conventional comparative genomic hybridization (CGH) did not reveal any gene copynumber change in papillomas.…”