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Cancer Genet Cytogenet 103:164–166 (1998)

Elsevier Science Inc., 1998655 Avenue of the Americas, New York, NY 10010

Pentasomy of Chromosome 8 in Chronic Myelomonocytic Leukemia

Yvonne Hamey, Nicole Dean, John V. Catalano, and Lynda J. Campbell

ABSTRACT:

We report the first case of pentasomy of chromosome 8 as the sole cytogenetic abnormal-ity in the bone marrow of a patient with chronic myelomonocytic leukemia, together with a review of theliterature describing polysomy of chromosome 8 in hematological malignancies. © Elsevier ScienceInc., 1998

INTRODUCTION

Polysomy of chromosome 8 is a common phenomenon inhuman cancer [1]. Trisomy 8 is most commonly observedand is found both as the sole genetic abnormality and withother genetic changes both at diagnosis and in the courseof disease progression. Tetrasomy of chromosome 8 is lesscommon. It may be observed with other additional clonalabnormalities, with other abnormal clones, or as the onlygenetic change in a malignancy. It has previously been ob-served as the sole abnormality in cases of acute monocyticand myelomonocytic leukemias [2–4], polycythemia rubravera [5], and therapy-related myelodysplastic syndrome[6]. Recently, hexasomy of chromosome 8, together withan unrelated clone with trisomy 11, was found in a patientwith acute myelomonocytic leukemia (AMMoL-M4) [7].We report a similar case of a patient with chronic my-elomonocytic leukemia (CMMoL) and skin infiltrations,who was found to have pentasomy 8 as the sole chromo-somal anomaly detected by metaphase cytogenetics. Toour knowledge, this is the first reported case of pentasomy8 as a sole abnormality.

CASE HISTORY

Mr. H. M. presented in March 1995 with a history of recur-rent septic episodes over several months, requiring hospi-tal admission and parenteral antibiotics. His full blood ex-amination showed him to be anemic with a hemoglobin of86 g/L, a white cell count of 6.1

3

10

9

/L with hypogranu-

lar neutrophils and some Pelger-Huet forms, and a mono-cytosis of 1.46

3

10

9

/L. His platelet count was 133

3

10

9

/L.Bone marrow examination confirmed a diagnosis ofCMMoL with a blast count of 15%. Clinically, he wasnoted to have skin infiltrates that, on biopsy, were shownto contain monocytic cells.

He suffered repeated septic episodes related to neutro-penia. However, after treatment with intermittent subcuta-neous recombinant human granulocyte colony stimulatingfactor commenced, he attained an adequate neutrophilcount and subsequently remained free of infection. Smalldoses of hydroxyurea controlled the monocytosis and skininfiltrations, and he remained well for 12 months.

He re-presented in April 1996 when his CMMoL trans-formed to acute monocytic leukemia (AMoL M5b). Induc-tion chemotherapy with Idarubicin and cytosine arabino-side had no effect on his disease, and he died 3 monthslater with resistant leukemia.

CYTOGENETICS

Unstimulated bone marrow cells were cultured for 24hours, synchronized with the use of uridine and BrdU,and harvested at 48 hours after a 30-minute colcemidtreatment [8]. Metaphase spreads were banded by usingstandard GTG techniques, and 20 cells were analyzed. Thekaryotype was described according to 1995 ISCN nomen-clature [9].

Cytogenetic analysis showed a major cell line withthree additional chromosomes 8 and one normal malemetaphase. The karyotype at diagnosis was reported as49,XY,

1

8,

1

8,

1

8 [19]/46,XY [1] (see Fig. 1). At transfor-mation to AMoL, the cytogenetics remained unchangedwith persistence of pentasomy 8 and no additional abnor-malities observed.

DISCUSSION

Additional copies of chromosome 8 are among the mostcommon cytogenetic abnormalities seen in hematological

From the Ludwig Institute for Cancer Research, PO RoyalMelbourne Hospital (Y. H.), Parkville, Australia; Victorian Can-cer Cytogenetics Service, St. Vincent’s Hospital (N. D., L. J. C.),Fitzroy, Australia; and the Department of Haematology, MonashMedical Centre (J. V. C.), Clayton, Australia.

Address reprint requests to: Dr. Lynda J. Campbell, VictorianCancer Cytogenetics Service, St. Vincent’s Hospital, 41 VictoriaParade, Fitzroy, 3065, Victoria, Australia.

Received June 11, 1997; accepted September 30, 1997.

Pentasomy of Chromosome 8 in CMMoL

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malignancies, but the vast majority of cases involve tri-somy 8 only. There are now a few reports of tetrasomy 8associated with acute myeloid leukemia (AML) [2, 3, 10–12] and other neoplasias [4–6], some of which have showntetrasomy 8 as the sole abnormality [2–6], whereas othershave been associated with a trisomy 8 clone shown eitherby fluorescence in situ hybridization (FISH) or by conven-tional cytogenetics or by both [10–12]. In other cases, tet-rasomy 8 has been associated with abnormalities of chro-mosome 12 [11] and monosomy 15 [13]. Trautmann et al.[11] presented three patients showing tetrasomy 8, afourth patient with trisomy 8 and one tetrasomy 8metaphase, and a further three patients with trisomy 8 inwhom from 3 to 9% of nuclei were shown by FISH to con-tain four copies of the 8 centromere. La Starza et al. [12]also reported tetrasomy 8 in two cases of AML with smalltrisomy 8 and normal clones. Hexasomy of chromosome 8was recently reported in a patient with another indepen-dent clone showing trisomy 11 [7].

A case similar to ours was that of an 82-year-oldwoman with complete tetrasomy 8 by conventional cyto-genetics, who presented with multiple skin infiltrationsand later progressed to AMoL-M5a [10]. Indeed, of the 13published cases identified with tetrasomy 8 as a soleabnormality, 7 were diagnosed as AMoL-M5 and 2 with

AMMoL-M4, indicating that more than two-thirds of caseshad a monocytic component. The association of monocy-toid disease and multiple copies of chromosome 8 appearsto be frequently seen, but no obvious explanation for thisphenomenon is apparent.

Some tetrasomy 8 clones have been inferred to be di-rectly descended from their trisomic predecessors, becauseboth lines contain the same additional abnormalities [11].Similarly, in the case of an infant with Diamond-Blackfananemia, consecutive gains of an additional chromosome 21up to pentasomy illustrate cumulative clonal evolution [14].

Our data shows no such clonal evolution. Although asingle division with nondisjunction events may give riseto a tetrasomic cell line, this is not possible for the produc-tion of pentasomy without overreplication of genetic ma-terial. It is therefore likely that the pentasomic cell linewas preceded by a tetrasomic or trisomic cell line or both,which went undetected by metaphase cytogenetics.

Trautmann et al. [11] attribute the higher percentage ofmetaphases, compared with interphase nuclei, that showtetrasomy 8 to higher proliferative activity of the tetra-somic cells or to a longer mitotic interval. This may alsobe the reason for such a high degree of pentasomic cellsshown in the metaphase spreads of our patient while tri-somic and tetrasomic cells lie undetected.

Figure 1 Representative G-banded metaphase showing pentasomy 8 (chromosomes 8 indicated by arrows).

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Instances of pentasomy in human malignancy are rare.There are reports of pentasomy in paraffin-embedded sec-tions of mesotheliomas such as those observed by Segerset al. [15]. Pentasomy of chromosome 21 in Diamond-Blackfan anemia [14] and in neonatal acute myeloblasticleukemia [16] also has been reported. In situ hybridizationstudies of minimal residual disease in patients with acutelymphoblastic leukemia showed a small number of penta-somic cells at early relapse that had not been observed bymetaphase analysis at diagnosis [17]. In addition, in a pa-tient with skin infiltrations similar to those of our patient,pentasomy of chromosome 8 at diagnosis was reported in1% of interphase nuclei along with tetrasomy (70%) andtrisomy (22%). The significance of pentasomy at such alow level in interphase nuclei is unclear. The patient laterdeveloped AMoL-M5a and survived only 12 months [10].

In conclusion, we present a case of pentasomy 8 as asole abnormality in a patient with CMMoL, subsequentlyevolving into AMoL-M5. The literature suggests that tetra-somy of chromosome 8 is most frequently associated withAMoL-M5. This case further supports the association ofmultiple copies of chromosome 8 with monocytic leukemias.

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