Table 5 Cytogenetic and molecular alterations in fatty tumours

Histological type

Translocation

Genes

Myxoid liposarcoma

Round cell liposarcoma Atypical lipomatous tumours

Lipoma Lipoblastoma Spindle cell and pleomorphic lipomas Angiolipoma t(12;16)(ql3;pll) t(12;22)(ql3;pl2) (rare) t(12;16)

Ring and giant chromosomes, often with abnormalities of 12q13-q15 Abnormalities of 12q, 6p,13q 8q rearrangements Aberrations of 16q and/or 13q

Normal

TLS/CHOP EWS/CHOP TLS/CHOP

HMGIC/LPP

Table 6 Translocations used in the diagnosis of sarcomas

Sarcoma Translocation Genes involved Available molecular test

Table 6 Translocations used in the diagnosis of sarcomas

Ewing sarcoma

t{11;22)

Flil/EWS

PCR, FISH

Clear cell sarcoma

t{12;22)

ATF1/EWS

PCR, FISH

Myxoid chondrosarcoma

t{9;22)

CHN/EWS

PCR, FISH

Desmoplastic round cell tumour

t{11;22)

WT1/EWS

PCR, FISH

Synovial sarcoma

t{X;18)

SSX1/SYT

PCR, FISH

Alveolar rhabdomyosarcoma

t{2;13)

PAX3/FKHR

PCR

t{1:13)

PAX7/FKHR

with the previous morphological classification schemes. Of the common types of lipomas only angiolipomas have a normal karyotype. The common fatty lipomas of adults often have rearrangements involving 12ql3-15. The breakpoint on chromosome 12 involves a gene, HMGIC, that codes for a member of the high-mobility group of proteins. These are small, acidic, nonhistone chromatin associated proteins that bind to AT-rich regions of the DNA. They have no inherent transcriptional activity but function by altering the nuclear chromatin, probably through interactions with other proteins. This alters the DNA structure and facilitates the assembly of transcrip-tional complexes. Spindle cell/pleomorphic lipomas usually have abnormalities of chromosome 16q or 13q, validating their histological separation from common lipomas and atypical lipomatous tumours.

Characteristic translocations have also been found by cytogenetic and molecular methods in a number of sarcomas (Ladanyi and Bridge, 2000) that are concordant with morphological and immunohistological categorization (Table 6). In some cases, a better understanding of the molecular defects found in a tumour have led to more accurate recognition of these rare tumours. For example, identification of the characteristic translocation t(X;18) in poorly differentiated spindle cell lesions by FISH analysis helps to discriminate monophasic and poorly differentiated synovial sarcomas from other spindle cell sarcomas.

Unfortunately, none of the common epithelial tumours of adults have simple genetic or cytogenetic changes underlying the malignant transformation. These tumours often have multiple changes in multiple pathways with no simple association with the current histological classifications. Microarray technology permits the expression of thousands of genes to be analysed simultaneously in a single tumour. The beginning of a molecular non-morphological classification of tumours is seen in the pioneering work of Alizadeh et al. (Alizadeh et al., 2000). Diffuse large cell lymphoma is a common type of non-Hodgkin lymphoma of adults and is clinically a heterogeneous group with some patients responding well to chemotherapy and others rapidly dying of their disease. Using a DNA array constructed primarily from B cell libraries, they demonstrated that two distinct subgroups could be identified by differential expression patterns. One group expressed genes characteristic of germinal centre B cells and had a 76% survival after 5 years whereas the other group had an expression pattern resembling activated B cells with only 16% survival after 5 years. Golub and colleagues (Golub et al., 1999) developed an expression-based microarray technology that discriminates and correctly classifies acute lymphoid and acute myeloid leukaemia without morphological evaluation. These are among the first but undoubtedly not the last examples of tumour classifications by gene expression profiles and the application of this technology to the common epithelial malignancies is to be expected in the near future.

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