Proposal for a sixgroup translocation cyclin D classification of multiple myeloma tumors

In addition to determining the expression level of cyclin D1, 2 and 3, gene expression profiling can effectively identify MM tumors that overexpress the oncogenes dysregulated by the five recurrent IgH translocations: 11q13 (cyclin D1); 6p21 (cyclin D3); 4p16 (MMSET and usually FGFR3); 16q23 (c-maf); and 20q11 (mafB). We propose six translocation/ cyclin D (TC) groups (Table 11.1) that can be distinguished on the basis of five recurrent Ig translocations and cyclin D expression. (1) The 11+6 group (19%) expresses high levels of either cyclin D1 or cyclin D3 as a result of an Ig translocation. (2) The D1 group (31%) ectopically expresses low to moderate levels of cyclin D1 despite the absence of a t(11;14) translocation. (3) The D1+D2 group (8%) expresses low levels of cyclin D1 and moderate levels of cyclin D2. (4) The D2 group (19%) is a mixture of tumors that do not fall into one of the other groups; most of them express cyclin D2 but a few also express very low levels of each D cyclin. (5) The 4p group (16%) expresses high levels of cyclin D2 and also multiple myeloma SET domain (MMSET) [and in most cases

Table 11.1 Translocation and cyclin D (TC) molecular classification of multiple myeloma of 231 newly diagnosed and 30 relapsed multiple

myelomas.

Primary

Gene(s)

Multiple

Proliferation

TC group

translocation at breakpoint

Cyclin

trisomies1 (%)

index >0.22 (%)

Frequency (%)

11+6

11q13

CCND1

D1

0

18

16

6p21

CCND3

D3

29

14

3

D1

None

None

D1

93

5

31

D1+D2

None

None

D1+D2

86

43

8

D2

?

?

D2

40

16

19

4p

4p16

FGFR3/MMSET

D2

29

21

16

MAF

16q23

c-maf

D2

16

32

7

20q11

mafB

'Percentage of samples with gene expression profiling evidence for three or more trisomies of chromosomes 3, 5, 7, 9, 11

, 15, 19 or 21;

2percentage of samples with a

gene expression profiling proliferation index greater than 0.2. The proliferation index was greater than 0.2 in

67% of relapsed samples and

10% of newly diagnosed

multiple myelomas.

fibroblast growth factor receptor 3 (FGFR3)] as a result of a t(4;14) translocation. (6) The Maf group (7%) expresses the highest levels of cyclin D2 and also high levels of either c-Maf or MafB, consistent with evidence that both Maf transcription factors upregulate the expression of cyclin D2. With the exception of the 4p group, the focus of this classification is the increased expression of cyclin D1 (11q, D1, D1+D2 groups), cyclin D2 (Maf, D1+D2, D2 groups) or cyclin D3 (6p group). In fact, even though we do not understand the mechanism(s) responsible, the 4p group invariably shows increased expression of cyclin D2. Although this classification is not unequivocally established, we think that the basis for it is focussed on very early, if not initiating, oncogenic events, but the D1+D2 group might represent an exception.

The D1 and D1+D2 groups share several key features, including biallelic expression of cyclin D1, a very high incidence of hyperdiploidy with associated multiple trisomies of odd chromosomes, and a similar gene expression signature. The D1+D2 group is strikingly different from the D1 group, not only in the increased expression of cyclin D2 but also in the lack of increased expression of some genes that cluster with the D1 group and the increased expression of some genes that cluster with the D2 group. In addition, more than 40% of tumors in the D1+D2 group have a high proliferation index, whereas only 5% of tumors in the D1 group have a high proliferation index. Although more evidence is needed, we suspect that some tumors in the D1 group progress to the D1+D2 group.

The clear correlation of the various groups with ploidy provides significant support for this six-group classification. The supervised clustering also provides evidence that unique patterns of gene expression can be identified for each of the major groups, with the exception of the D2 group, which may well be a heterogeneous default group. Most importantly, the unsupervised cluster results demonstrate that the Maf, 4p and D1 groups (and to a lesser extent the 11+6 group) mostly associate as tight clusters. This implies to us that the ultimate phenotype of the tumor is determined mainly by early events, and is consistent with the possibility that MM represents several disease entities with distinct pathways of pathogenesis.

In addition to tumor mass and secondary features, which represent a host response to MM (anemia, thrombocytopenia, bone disease, immunodeficiency, etc.), the intrinsic properties of the tumor cell are also informative in predicting the prognosis and the response to existing therapies. For example, it has been well documented that an unfavorable outcome is associated with each of the following: increased plasma cell labeling index; the generation of tumor cells with an abnormal karyotype (perhaps a surrogate for increased proliferation); hypodiploidy compared with hyperdiploidy; monosomy of chromosome 13/13q; monosomy of chromosome 17/dele-tion of p53; and lack of cyclin D1 expression. It also has been reported and independently confirmed that activating mutations of K-Ras (but not N-Ras) represent an adverse prognostic factor. More recently, it has become clear that specific IgH translocations also have a profound prognostic significance (Table 11.1). In particular, patients with tumors that have a t(4;14) translocation have substantially shortened survival, either with standard or high-dose therapy (median overall survival 26 and 33 months respectively), and patients with a t(14;16) have a similarly poor if not worse prognosis (median overall survival 16 months with conventional therapy). By contrast, patients with tumors that have a t(11;14) translocation appear to have a marginally better survival after conventional chemotherapy (median overall survival 50 months) but apparently a remarkably better survival after intense therapy (predicted overall survival at 80 months, 88%). These results suggest that the TC classification, which appears to be based on the earliest events in pathogenesis, may be a clinically useful way to classify patients into groups that have distinct subtypes of MM (and MGUS) tumors. The TC classification identifies clinically important molecular subtypes of MM with different prognoses and with unique responses to different treatments (e.g. high-dose therapy and 11+6, microenvi-ronment-directed therapy and D1, FGFR3 inhibitor and 4p, maf dominant-negative and Maf).

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