Mastracci Teresa L, Shadeo Ashleen, Colby Sarah M, Tuck Alan B, O'Malley Frances P, Bull Shelley B, Lam Wan L, Andrulis Irene L
Fred A. Litwin Centre for Cancer Genetics, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
Genes Chromosomes Cancer. 2006 Nov;45(11):1007-17. doi: 10.1002/gcc.20368.
The identification of genomic alterations occurring in neoplastic lesions provides insight into both lesion occurrence and disease progression. In this study, we used microarray comparative genomic hybridization (CGH) to investigate genetic changes in atypical lobular hyperplasia (ALH) and lobular carcinoma in situ (LCIS), as the presence of these lobular neoplastic lesions is an indicator of risk in the development of invasive breast cancer. DNA was extracted from microdissected archival breast tissue containing ALH or LCIS, lacking adjacent invasive carcinoma, and subjected to whole-genome tiling path microarray-CGH using the submegabase resolution tiling set (SMRT)-array platform. Twelve ALH and 13 LCIS lesions were examined. Copy number alterations were identified using statistical criteria and validated with Real-Time PCR and fluorescence in situ hybridization. From statistical analysis, a greater number of alterations were observed in ALH compared to LCIS. Alterations common to ALH include gain at 2p11.2 and loss at 7p11-p11.1 and 22q11.1. Alterations common to LCIS include gain at 20q13.13 and loss at 19q13.2-q13.31. In both ALH and LCIS, we observed loss of 16q21-q23.1, an altered region previously identified in lobular neoplasia and invasive carcinoma. The validation of select alterations reinforces the genomic signature. This study represents the first whole-genome investigation of lobular neoplastic breast lesions using clinical archival specimens. The identified genomic signature includes copy number alterations not previously identified for lobular neoplasia. This genomic signature, common to ALH and LCIS, suggests a role for the acquisition of novel genomic alterations in the aberrant cellular proliferation that defines lobular neoplasia.
肿瘤性病变中发生的基因组改变的鉴定有助于深入了解病变的发生和疾病进展。在本研究中，我们使用微阵列比较基因组杂交（CGH）来研究非典型小叶增生（ALH）和小叶原位癌（LCIS）中的基因变化，因为这些小叶肿瘤性病变的存在是浸润性乳腺癌发生风险的一个指标。从含有ALH或LCIS且无相邻浸润性癌的显微切割存档乳腺组织中提取DNA，并使用亚兆碱基分辨率平铺集（SMRT）-阵列平台进行全基因组平铺路径微阵列-CGH。检查了12个ALH病变和13个LCIS病变。使用统计标准鉴定拷贝数改变，并通过实时PCR和荧光原位杂交进行验证。通过统计分析，与LCIS相比，在ALH中观察到更多的改变。ALH常见的改变包括2p11.2的增益以及7p11-p11.和22q11.1的缺失。LCIS常见的改变包括20q13.13的增益以及19q13.2-q13.31的缺失。在ALH和LCIS中，我们都观察到16q21-q23.1的缺失，这是先前在小叶肿瘤和浸润性癌中鉴定出的一个改变区域。对选定改变的验证强化了基因组特征。本研究代表了首次使用临床存档标本对小叶肿瘤性乳腺病变进行全基因组研究。鉴定出的基因组特征包括先前未在小叶肿瘤中鉴定出的拷贝数改变。这种ALH和LCIS共有的基因组特征表明，获得新的基因组改变在定义小叶肿瘤的异常细胞增殖中起作用。
