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Heterogeneity in Breast Cancer and the Problem of Relevance of findings 53 Mini review Heterogeneity in breast cancer and the problem of relevance of findings ∗ M. Aubele a, and M. Werner b these events has not been established. Furthermore, the a GSF – National Research Center for Environment relationship between histological progression and ge- and Health, Institute of Pathology, Neuherberg, netic events in breast cancer is not yet well defined. Germany This review discusses the cytogenetic and molecular b Technische Universität München, Klinikum rechts genetic findings published within the last years, the der Isar, Institute of Pathology, Munich, Germany problem of correlating molecular-biological data with histology, and, consequently, the difficulties in devel- Received 15 August 1999 oping a model for breast cancer progression. Accepted 16 November 1999 Many attempts are made to identify critical genetic events re- 2. Evidences for intratumoural heterogeneity sponsible for the development and progression of breast can- cer. There is increasing evidence that breast cancer is a het- Intratumour phenotypic heterogeneity is one of the erogeneous disease, both, phenotypically as well as with re- characteristics of breast carcinoma, and genetic mech- spect to its molecular biologically. It is, therefore, extremely anisms are likely to contribute to it [39]. Heteroge- difficult to establish a diagnostically and prognostically rel- neous molecular findings in different parts of a tumour evant tumourigenesis model. Emerging new techniques such may reflect concomitant or successive clonal develop- as microarrays, will provide us with a wealth of additional ment. No studies have yet been carried out to make a data over the next years. The precise sampling of tumour ma- comprehensive analysis of known genetic alterations. terial in clearly defined histopathological lesions will be a The latter, however, would be essential to obtain better prerequisite for the assignment of specific genetic alterations insight into the complex system of interactions in the to defined stages of breast disease. multistep carcinogenesis of breast cancer. 2.1. Morphological aspects 1. Introduction Invasive breast carcinomas represent a heteroge- Breast cancer represents a significant worldwide neous group of different histopathological entities public health problem [29]. Although considerable comprising invasive ductal carcinoma (not otherwise progress has been made in searching for the genetic specified – NOS), invasive lobular carcinoma and events that underlie the progression of many malignan- specific types of breast cancer [36]. In the specific cies [13,18,44], those involved in breast cancer devel- types, e.g., tubular, medullary and mucinous breast opment and progression are still poorly understood [4, carcinoma, the distinct morphological features should 25]. Several molecular genetic analysis have identified amount to at least 75% of the tumour area to decide alterations in breast tumours that are probably involved for the diagnosis. Therefore, the invasive parts of these in carcinogenesis [5,26]. However, the chronology of tumours are in a histological sense rather homogenous. Invasive lobular carcinomas can, besides the ‘classi- *Correspondence to: Dr Michaela Aubele, GSF – Forschungszen- trum, Institut für Pathologie, Ingolstädter Landstraße 1, 85764 cal’ linear growth pattern (indian files), display sub- Neuherberg, Germany. Tel.: +49 89 3187 4132; Fax: +49 89 3187 stantial elements of solid, tubulolobular and alveolar 3360; E-mail: [email protected]. variants [36]. A variable histological pattern is also of- Analytical Cellular Pathology 19 (1999) 53–58 ISSN 0921-8912 / $8.00 1999, IOS Press. All rights reserved 54 M. Aubele and M. Werner / Heterogeneity in breast cancer and the problem of relevance of findings ten found in the invasive ductal carcinoma NOS, which The findings of cytogenetically unrelated clones in represent the majority of breast cancer. These tumours many studies supports the conclusion that a substantial may exhibit microscopic foci of solid, tubular, cribri- proportion of breast tumours may be polyclonal. But form, medullary, mucinous or papillary differentiation. whether they reflect true polyclonal tumourigenesis or Histological grading of invasive ductal carcinoma NOS not, they are unquestionably manifestations of intratu- takes into consideration cytological features of differ- mour genotypic heterogeneity. To understand how the entiation as well as the growth pattern of the invasive various clones interact during mammary carcinogene- tumour, i.e., nuclear hyperchromasia, mitotic rate, and sis will be a major task in future breast cancer research. the extent of tubule formation [11]. The grading is usu- ally expressed in three categories: well differentiated 2.3. FISH (grade I), intermediate (grade II), and poorly differen- tiated (grade III). This approach is only an estimate for Fluorescence in situ hybridization (FISH) analysis is cell differentiation and is based upon the examination a useful technique for investigating genetic abnormali- of multiple tumour areas which may exhibit hetero- ties in interphase nuclei. A wide variety of DNA probes geneous cytological features or growth patterns. In all are available today for FISH, including chromosome- histological breast carcinoma types, however, variable specific probes which hybridize to alpha-satellite peri- amounts of stroma, normal and/or proliferative glands centromeric DNA regions (to detect changes in chro- and ducts, or in situ carcinoma contribute widely to mosome number) and locus-specific probes (to detect an even more heterogeneous image. If not otherwise amplifications, deletions, breakpoints, or rearrange- stated in this review we focus on the heterogeneity of ments) [26,45]. FISH analysis of archival material has ductal carcinoma. been the subject of several studies of breast tissue and polysomy of chromosomes 1, 16, and 18 were re- 2.2. Conventional cytogenetic peatedly found in carcinoma in situ as well as in in- vasive breast cancer [16,26,28,39]. Using a panel of Some of the earliest indications of genetic abnor- centromere specific DNA probes for chromosomes 1, malities in breast cancer have come from karyotypic 3, 7, 8, and 16 clonal numeric alterations were simi- studies [26]. Although several hundred breast cancers larily observed in the primary tumours as well as in were completely karyotyped after short-termed cultur- metastases [39]. Consequently, the authors concluded ing, no specific characteristic cytogenetic abnormality that dominant clones within the primary carcinoma be- has been observed so far [26]. The most common ob- come metastatic. In some of the cases investigated by servations were numerical changes (trisomy of chro- Fiegl et al. [14] using probes for centromere 11 and mosome 7 and 18) and complete or partial monosomy 17 metastases showed more complex numerical alter- of chromosomes 6, 8, 11, 13, 16, 17, 22, and X [26]. ations than those seen in the primary tumour, whereas The most surprising discovery in breast cancer cyto- in other cases fewer aberrations were detected in the genetics has been that cytogenetically unrelated clones metastases. Those results would suggest that hetero- were often found [17,31]. Teixeira et al. [43] first re- geneity evolves in primary and metastatic lesions in ported the localization of karyotypically distinct cell a similar manner. Although several FISH studies have populations to separate intratumourous domains in attempted to identify genetic alterations responsible breast cancer. Comparison between breast carcinomas for breast tumourigenesis and progression no specific and their lymph node metastases [32] has shown that chromosomal alteration could yet be attached to cer- such a polyclonality may exist in both the primary and tain histopathological stages. secondary tumour. Multiclonality has also been docu- mented in a small series of extensively studied multifo- 2.4. CGH cal carcinomas [42,43]. Cytogenetic analysis of in situ carcinoma of the breast has been carried out only in a Comparative genomic hybridization (CGH) is a rel- small number of cases [16,26], and it could be shown atively new molecular-cytogenetic assay [22]. In con- that unrelated clones are a feature of both premalignant trast to FISH, CGH allows for an overview of DNA breast lesions and overt, infiltrating and metastatic car- sequence copy numbers in a single hybridization [19]. cinomas [17]. Therefore, one cannot draw any conclu- Several CGH studies with DNA isolated from paraffin sions whether this phenomenon is more characteristic sections of breast cancers described a series of aberra- for early or late tumourigenesis. tions [19,23,35]. Their results confirm a complex pat- M. Aubele and M. Werner / Heterogeneity in breast cancer and the problem of relevance of findings 55 tern of chromosomal imbalances involving many chro- to detect change in expression under given conditions mosomes with gains of DNA on chromosomal regions [21,38]. For those expression analysis, cDNA-sized 1q, 6p, 8q, 11q, 12q, 17q, and 20q, and losses on 6q and fragments or short (25 nucleotide) oligonucleotides 12q. For this approach, however, several serial sections are spotted onto slides or a nylon membrane, and tu- from the tumour tissue are needed and DNA is iso- mourous RNA is hybridized onto the target slides [21, lated from entire sections. Thus, intratumourous het- 38]. erogeneity can hardly be detected [19,23]. By applying a combination of laser-microdissection and whole ge- 2.6. LOH nomic amplification (DOP-PCR) [1] to examine
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