Loss of Heterozygosity in Benign Breast Epithelium in Relation to Breast Cancer Risk

Abstract

The multistage model of breast carcinogenesis suggests that errors in DNA replication and repair generate diversity in the breast epithelium (the mutator phenotype), resulting in selection and expansion of premalignant clones with an acquired survival advantage. We measured loss of heterozygosity (LOH) in breast epithelial cells obtained by random fine-needle aspiration (FNA) biopsy from 30 asymptomatic women whose risk of breast cancer had been defined by the Gail model. Polymorphic microsatellite markers were selected on the basis of their relevance to breast cancer. Breast epithelium of 11 (37%) of 30 women had normal cytology, and that of 19 (63%) had proliferative cytology (eight with atypia and 11 without atypia). LOH was detected in two women with normal cytology and in 14 women (seven with atypia and seven without atypia) with proliferative cytology (P =.007). The frequency of LOH was associated with the cytological diagnosis, as well. The mean proportion (range) of informative markers demonstrating LOH was 0.02 (0-0.20) for the 11 women with normal cytology, as compared with 0.15 (0-0.50) for the 19 women with proliferative cytology (P =.02). Mean lifetime risk for developing breast cancer, as calculated by the Gail model, was 16.7% for women with no LOH compared with 22.9% for women with any LOH (P =.05). These observations support a multistage model of breast carcinogenesis where the initiating events are those that result in genomic instability. Accurate individualized breast cancer risk assessment may be possible based on molecular analysis of breast epithelial cells obtained by random FNA.

Lipid Metabolism Genes in Contralateral Unaffected Breast and Estrogen Receptor Status of Breast Cancer

“…These findings were confirmed using qRT-PCR, validated in an independent set of 24 case samples, and compared to rFNA samples from 12 healthy controls. This report on a total of 66 women is larger than other studies of molecular features of normal breast epithelium, where total sample size has generally been under 50 women (23). Thus, our present findings based on 54 cases and 12 healthy controls constitute one of the largest of these challenging studies.…”

Evaluation of Genomic Instability as an Early Event in the Progression of Breast Cancer

“…This finding parallels our previous studies in tumors of the prostate and their matched TA-HN tissues, 28 and is in agreement with the work of previous investigators who reported that genetic alterations, including telomere attrition and loss of heterozygosity, occur in histologically normal tissues adjacent to breast tumors. [34][35][36][37][38][41][42][43][44] In these previous studies, the sites of telomere attrition, loss of heterozygosity, and AI were physically distant from one another and from the tumors, albeit in most cases at undefined distances from the corresponding tumor lesions. 24,[42][43][44] In contrast, and to our knowledge, the findings in cohort 1 represent the first study in breast cancers that analyzes genomic instability at defined distances (1 cm and 5 cm) from the visible tumor margins.…”

“…[34][35][36][37][38][41][42][43][44] In these previous studies, the sites of telomere attrition, loss of heterozygosity, and AI were physically distant from one another and from the tumors, albeit in most cases at undefined distances from the corresponding tumor lesions. 24,[42][43][44] In contrast, and to our knowledge, the findings in cohort 1 represent the first study in breast cancers that analyzes genomic instability at defined distances (1 cm and 5 cm) from the visible tumor margins. Consequently, this study reveals that genomic instability in tumor adjacent, histologically normal breast tissues is a function of distance from the tumor lesion, showing decreasing extent of genomic instability with increasing distance from the tumor margin.…”

“…27,31,32 In addition, telomere attrition and other measures of genomic instability, such as allelic imbalance and loss of heterozygosity, demonstrate that genomic instability occurs within atypical breast hyperplasias, [33][34][35] histologically normal tissue proximal to breast tumors, [36][37][38][39][40][41][42] and, in some instances, breast tissue from women with benign breast disease. 43 Loss of heterozygosity and allelic imbalance have also been found in the stromal compartment of cancer-associated breast tissues. 41,44 In addition, our own recent results identified fields of telomerase-positive cells within histologically normal tissues adjacent to breast tumors that could represent areas of pre-malignant cell populations.…”

Ductal carcinoma in situ of the breast with different histopathological grades and corresponding new breast tumour events: Analysis of loss of heterozygosity

“…We cannot tell whether the ipsilateral subsequent events in this (14)) LOH 9p 3/6 (50)) 2/13 (15)) LOH 11p 0/6 (0)) 1/15 (7)) LOH 11q 1 5/6 (83)) 3/17 (18)) LOH 16q 2 5/11 (45) It was recently demonstrated that a higher proportion of LOH detected in benign breast epithelial cells correlated with an increased breast cancer risk [36]. The present LOH study, however, did not show that an overall increased frequency of LOH would indicate a higher risk of recurrences or new subsequent breast cancers, as allelic loss was more common in DCIS grade 1 than in DCIS grade 3.…”