Fujii H, Marsh C, Cairns P, Sidransky D, Gabrielson E
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21224, USA.
Cancer Res. 1996 Apr 1;56(7):1493-7.
The progression of ductal carcinoma in situ (DCIS) to infiltrating and metastatic cancer of the breast is thought to be a consequence of clonal expansions of neoplastic cells with progressively more genetic alterations. To study this progression, we first dissected multiple foci from each of 23 breast tumors with DCIS only and 20 cases with synchronous DCIS and infiltrating cancer. We than tested microsatellite markers by PCR for allelic losses in the individual foci for loci on chromosomes 6q, 9p, 11q, 13q, 16q, 17q, and 17p. The patterns of allelic losses identified in the in situ cancers were generally conserved in the synchronous infiltrating tumors, supporting the paradigm that the infiltrating tumors are clonally derived from the in situ lesions. However, in 8 (40%) of the 20 cases with synchronous in situ and invasive cancer, heterogeneous patterns of allelic loss at one or more chromosomal loci were observed in adjacent DCIS foci. Moreover, some of the allelic losses recognized in in situ portions of the tumors were not conserved in the clonal progression to the synchronous invasive tumor. Such allelic loss heterogeneity was noted in only 1 of the 20 infiltrating tumors and only 3 of the 23 cases of DCIS without invasion that were studied in a similar manner. This heterogeneity indicated genetic divergence during the clonal evolution of breast cancer, particularly at the time when in situ cancers progress to invasive cancers.
导管原位癌（DCIS）进展为浸润性和转移性乳腺癌被认为是肿瘤细胞克隆性扩增并伴有逐渐增多的基因改变的结果。为了研究这一进展过程，我们首先从23例仅患有DCIS的乳腺肿瘤以及20例同时患有DCIS和浸润性癌的病例中分别解剖多个病灶。然后，我们通过聚合酶链反应（PCR）检测微卫星标记，以确定6号染色体长臂、9号染色体短臂、11号染色体长臂、13号染色体长臂、16号染色体长臂、17号染色体长臂和17号染色体短臂上各基因座在各个病灶中的等位基因缺失情况。原位癌中所确定的等位基因缺失模式在同步浸润性肿瘤中通常是保守的，这支持了浸润性肿瘤是原位病变克隆性衍生而来的范例。然而，在20例同时患有原位癌和浸润性癌的病例中，有8例（40%）在相邻的DCIS病灶中观察到一个或多个染色体基因座存在等位基因缺失的异质性模式。此外，肿瘤原位部分所识别的一些等位基因缺失在向同步浸润性肿瘤的克隆进展过程中并不保守。在以类似方式研究的20例浸润性肿瘤中，只有1例出现这种等位基因缺失异质性，在23例无浸润的DCIS病例中也只有3例出现这种情况。这种异质性表明乳腺癌克隆进化过程中存在基因分歧，特别是在原位癌进展为浸润性癌的时候。
