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Assessment of Clonality in Human Tumors: a Review J [CANCER RESEARCH 50, 1355-1360, March 1, 1990] Review Assessment of Clonality in Human Tumors: A Review J. S. Wainscoat1 and M. F. Fey Department of Haematology, John Radcliffe Hospital. Oxford, United Kingdom [J.S.W.], and Institut fur Medizinische Onkologie, Inselspital, CH-3010, Bern, Switzerland [M. F. F.] Abstract "traditional" methods and those based on various types of DNA analysis. The various methods of determination of the clonali) y of human tumors Both DNA and traditional methods depend upon the dem are described. There are three major approaches based on X-chromosome onstration that a cell population is homogeneous with respect inactivation analysis, lymphocyte analysis, and somatic mutation analy to a particular marker. Since at the time of presentation tumors sis. For each of these approaches there are established methods and may have undergone extensive genetic change and continuing more recent methods based on DNA analysis. The increasing number of methods available increases the scope of clonality determination to most selection of particular subclones may have occurred, clonality tumors. All the methods have inherent advantages and disadvantages, as assessed by any of the currently available methods may still and these are discussed in relation to their clinical application. not necessarily reflect the earliest events in tumorigenesis. A tumor may have originated from several cells, the progeny of one of these cells (bearing the marker) eventually having out grown all the others (4). The clonality of human tumors has direct relevance to theo ries of carcinogenesis and has practical implications for both diagnosis and subsequent studies of disease progression. The X-Chromosome Inactivation purpose of this review is to discuss the different methods of In females inactivation of one X chromosome occurs in each clonality determination, in particular those based on DNA somatic cell in early embryonic development and is passed onto analysis, and to illustrate their use in human tumors. the progeny of the cell in a stable fashion (5-7). Females A clonal population of cells is defined as those cells arising heterozygous for polymorphic X-chromosome genes are there from the mitotic division of a single somatic cell (1). Although fore mosaics with respect to X-chromosome activity (8, 9). this definition seems straightforward, it must be recognized that There is evidence that X-chromosome inactivation is related to the assessment of clonality may be dependent on the technique differential methylation of cytosine in the DNA of X-chromo used. For example, the investigation of two cell populations some genes (10). The exact role of gene methylation in the may suggest two independent clones by immunoglobulin gene various aspects of X-chromosome inactivation has been exten analysis but a single clone by X-linked DNA polymorphism analysis, reflecting the earlier occurrence in development of X- sively reviewed elsewhere and a detailed discussion of the mech anisms of X-chromosome inactivation is beyond the scope of chromosome inactivation. A further consideration which com this review (5, 7, 11-13). From the point of view of clonality plicates the analysis of clonality is that the cells constituting a assessment in tumors it is sufficient to recognize that the single clone are not necessarily genetically identical since clonal inactivation or methylation patterns of X-chromosome genes evolution may occur within such populations of cells (2). can be used for the detection of clonality of tumors in females It is now widely agreed that most tumors have a monoclonal heterozygous for a particular X-linked polymorphism. composition consistent with the somatic mutation theory of G6PD Isoenzyme Analysis. The first studies of human tumor carcinogenesis which assumes that a tumor results from the clonality using the G6PD isoenzyme system were reported by progeny of a single cell having acquired one or more somatic Linder and Gartler (14, 15) and Beutler et al. (9) in uterine mutations (3). The methods used to determine clonality of leiomyomas and malignant tumors, respectively. This form of human tumors have been most readily applicable to leukemias clonality assessment was extended to the analysis of a large and lymphomas, although some techniques, for example, G6PD2 isoenzyme analysis, have been used on solid tumors. variety of human tumors in the now classic work of Fialkow (16). This form of analysis is based upon the fact that a female However, several methods have been developed over recent patient heterozygous for a polymorphism of the X-linked en years which enable a higher proportion of a wide variety of zyme G6PD will express both the normal type of GdB and a tumors to be analyzed for clonality. The analysis of clonality in variant type of GdA or GdA~ in her normal tissues but only a tumors can provide clonal markers which are valuable in as single G6PD isoenzyme in each individual cell. Therefore, a sessing disease progression and in providing insight into the neoplasm arising from a single cell will show a single G6PD nature of disease remission. isoenzyme phenotype, whereas a polyclonal neoplasm will have The methods of clonality determination can be broadly cate gorized into the following groups: X-chromosome inactivation, a double G6PD enzyme phenotype (17). The majority of human cancers analyzed by this technique lymphocyte analysis, detection of somatic mutations, and viral have been shown to be monoclonal (including breast cancer, integration analysis. Table 1 divides these approaches into carcinoma of the colon, carcinoma of the uterine cervix, ovarian Received 5/2/89; revised 10/20/89; accepted 11/27/89. teratomas, and many hematological neoplasms (16, 18-20). The costs of publication of this article were defrayed in part by the payment G6PD studies have been particularly useful in the investigation of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. of chronic myeloid leukemia since RBCs and platelets cannot ' To whom correspondence should be addressed. be investigated by cytogenetic or DNA analysis as they have no 2The abbreviations used are: G6PD. glucose-6-phosphate dehydrogenase; nuclei. A few exceptional cases of malignant tumors with double ANLL, acute nonlymphocytic leukemia; TCR, T-cell receptor; VNTRs, variable numbers of tandem repeats; RFLP, restriction fragment length polymorphism; enzyme phenotypes including colonie carcinomas, breast can EBV, Epstein-Barr virus. cers, and a hepatoma have been reported. These rare cases may 1355 Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 1990 American Association for Cancer Research. CLONALITY IN HUMAN TUMORS Table 1 Methods ofclonality determination Polyclonal Monoclonal Methods General approach Traditional DNA X-chromosome G6PD isoenzymes X-linked RFLPs BamHI BamHI BamHI BamHI inactivation Lymphocyte analysis Immunoglobulin light Immunoglobulin and TCR Hpa II Hpa II chain analysis gene analysis Somatic mutation Cytogenelic analysis Detection of chromosome loss by RFLP analysis Detection of chromosome Paternal translocations by breakpoint cluster probes Detection of somatic muta tions by DNA fingerprint ing Detection of specific point mutations Viral integration Analysis of genomic EBV ter analysis mini Maternal be explained by an admixture of normal cells in the tumor sample analyzed (17, 21). This might be a possible explanation for conflicting results of clonality studies in parathyroid ade noma; the demonstration of a polyclonal origin of parathyroid adenomas by G6PD isoenzyme studies (22) has not been con firmed by more recent work using molecular analysis with DNA markers (23). Nevertheless some hereditary tumors such as Fig. 1. Principle of a Southern blot X-linked RFLP clonality study. Boxes. alíeles;shaded areas, methylated fraction. Left, DNA from a polyclonal cell trichoepitheliomas (24) and neurofibromas (25) do have a dou population of a female heterozygous for an X-linked RFLP. Both the paternal ble enzyme phenotype. The polyclonal composition of these and the maternal alíelesofthe gene are methylated to some extent. The RFLP is tumors is presumably related to the different time course and detected by BamHI; the nonmethylated parts of each alíelearecut by the enzyme Hpa\\ and, therefore, the intensity of both fragments is reduced on autoradiog- mechanism of tumorigenesis. Similarly a multiclonal origin of raphy. Right, DNA from a monoclonal cell population of a female heterozygous colorectal adenomas in Gardner's syndrome (familial adenom- for the same X-linked RFLP. In this particular case only the paternal alíeleof the gene is methylated and is. therefore, not cleaved by ////«ILHowever, the atous polyposis syndrome) has been proposed based on the nonmethylated maternal alíeleis digested completely by this enzyme and hence analysis of G6PD mosaic-ism (26). However, more recent data is not detectable. The fact that in this cell population only one of the two alíeles on the clonality of colorectal adenomas collected by DNA is methylated is evidence ofclonality. polymorphism analysis suggest that at least some adenomas are clonal tumors (27). These divergent results may be due to clonal composition one of the two allelic fragments is com the fact that in the study using recombinant techniques contam pletely digested resulting in its disappearance while the other inating nonneoplastic cells were removed from the tumor by remains unaltered. The principle of this approach is illustrated histological analysis of cryostat sections. in Fig. 1. X-linked gene polymorphisms useful for such studies include The G6PD approach has until recently been limited to the GdA and GdA~ variants in blacks which are easily distinguisha RFLPs of the hypoxanthine phosphoribosyltransferase gene (35) and the phosphoglycerate kinase gene (32). The heterozy- ble from the normal B enzyme by starch gel electrophoresis. More recently, it has been possible to extend this approach to gosity rate of these genes is approximately 30% which is a individuals heterozygous for the Mediterranean variant of limiting factor in their practical application.
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