Major karyotype aberrations, including t(3;12), in a patient with myelodysplastic syndrome

M or Karyotype Aberrations, Including t(3;12), in a Patient My odysplastic Syndrome Clare, Marsha Hunke, and Louis J. Manhoff

ABSTRACT:

Cytogenetic analy~s of bone marrow c~Is was performed twice on a pa~ent with myelodysplas~c syndrome, specifically, refractory anemia with excess blasts. The pa~ent had a progressive cours~ with transformation toward acute leukemia and death within 3 months. Chromosome analysis showed majar karyotype abnormalities, in~uding d~ dup ( l p), t(3;12), and a unique breakage of a #15 resul~ng in t(15;18) and dic(15;21~ Involvement of #3 and #12 in a tran~oca~on has been recency reposed, and a comparison with these cases is made with a d~cus~on of the ~gnificance.

INTRODUCTION The m y e l o d y s p l a s ~ c states consist of a diverse group of disorders, having in common cytopenias and dysplastic changes of the hematopoietic precursors. Chromosome analyMs has proved helpful in e ~ a b ~ s h i n g a diagnosis and in predicting the prognosis of such cases. A p p r o x i m a t e l y 50% of these pa~ents will have a c q u ~ e d clonal aberrations Mm~ar to those c o m m o n l y seen in acute leukemia [1, 2]. The patients wRh an abnormal karyotype have a significantly worse prognosis, w ~ h a greater ~keHhood of progression to acute l e u k e m i a or of increased i n c i d e n c e of fatal

complications [3, 4]. N o n r a n d o m involvement of chromosomes in h e m a t o p o i e t i c malignancies has been d e s c ~ b e d for several years. These associations have been invaluable for diagnosis and prognoMs, and more recently, in assigning genes p e ~ a i n i n g to hematologic functions. Chromosomes #3 and #12 have recently been i m p ~ c a t e d as being n o n r a n d o m l y involved in hematologic malignancies [5-7]. Sandberg et a]. [5] have r e p o s e d two cases wRh ffanslocations involving # 3 and #12 and have extensively reviewed the 1Rerature for acquRed aberrations of these chromosomes. The p u r p o s e of this ar~cle is to report a patient wRh m y e l o d y s p l a s t i c s y n d r o m e and m ~ o r k a r y o t y p ~ abnormalities, i n c l u d i n g an u n b a l a n c e d ffanslocation of 12q to 3p and an u n u s u a l break of #15 with t ( 1 5 q - ; 1 8 p ÷ ) and d i c ( 1 5 ~ . The demonstration of these aberrations was i n ~ r u m e n t a l in estab~shing a d i a g n o ~ s of preleukemia. The patient survived only 3 months and s h o w e d evidence of l e u k e m i c ~ a n ~ o r m a t i o n p ~ o r to death.

From the Depa~me~ of P~ho~gy U n ~ of Texas HeMth S~ence Center at San A ~ o ~ Au~e Murphy V ~ a ~ s H~p~M, San A~o~o, T~

and

Address reques~ for repents to D~ N a n ~ Clane, Depa~ment of Path~og~ 7703 Floyd Cu~ D~ve, San AntonY, TX 78284. Received Augu~ 18, 1983; accep~d O~ober 27, 1983.

267 © 1984 by ~ s e ~ S~ence Publis~ng Co., Inc. 52 Vanderbi~ Ave., New Y ~ NY 10017

Cancer G e n ~ s and Cytogene~cs13, 267-27~198~ 0164~60~8~$03.00

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CASE HISTORY

The pa~ent was a 59-year-old wh~e m ~ e who had been in good h e a t h until recent onset of increasing fatigue and ~thargy. The patient had worked for the past 25 y e a ~ as a newspaper di~ributor. He had a 60 pack/year hi~ory of smoking, and he r e p o s e d d~nking 6 beer~day. The p ~ i e n t had no other history of known exposure to toxins or carcinogens. The patient reported that his mother had died of leukemia; however, no fu~her informa~on was availab~. Phy~cM examina~on reve~ed affial fib~lla~on w~h no other pos~ive findings; in particular, no l y m p h d e n o p ~ h y or h e p ~ o s p ~ n o m e g ~ y was present. Labor~ory data reveMed h e m o ~ o b i n 12.5 ~dl; h e m ~ o c r ~ 35.8%; red cell count 3.95 × 106/mm3: wh~e count 150~mm 3 w~h 16% neutrophils, 7% bands, 65% lymphocytes, 9% monocytes, and 3% eosinophils; p l ~ count was 38,00~mm3; SGOT was 152 (normM 7-40 mU/ml); and lac~te dehydrogenase (LDH) was 374 (normM, 100-225 mU/ml). Other h b o r ~ o r y studies including serum B~2 and folate and red cell fol~e, were w~hin normM Hm~s. The p ~ i e n t was a d m ~ d for workup of pancytopenim Bone marrow asp~ation was performed, and a s a m p ~ was ob~ i n e d for cytogenetic anMys~. H i ~ o l o ~ c examin~ion of the bone marrow showed an overall mild h y p o c ~ l u ~ t y and a myeloid:erythroid r ~ i o of 0.2:1. Erythropoiesis showed marked megMoblastoid changes w~h nuc~affcytoplasmic asynchrony, broad c h r o m ~ i n d u m p i n ~ and m u l ~ n u c ~ e d precursors; 6.8% m y ~ o blasts and 6% promye~cytes were counted (Fig. 1). This marrow was felt to be consis~nt w~h a my~odysplastic syndrome, specificMly, reffa~ory anemia w~h excess blasts. The p ~ i e n t was also felt to have liver disease secondary to ~cohol abuse. The atriM fib~H~ion was treated with digoxin. The patient was f o l ~ w e d in the hem~ology clinic. His course was c o m p a c t e d 3 months later w~h an episode of fever to 102°F with a p i c ~ pneumonim p~urM effusion, and p e r ~ e n t pancytopenia. Sputum cukures grew Pseudomonas aeru~-

~ g u ~ 1 B ~ e m~mw ~ i m ~ ~ . 1 wi{h m~Mo~asto~ ~ u~p~eMs wi~ a mu~nude~ed my~oc~e ~).

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Karyo~pe A b ~ r ~ n s

in M y ~ p ~ c

Syn&ome

269

this was a d e q u a c y resolved. A repeat bone marrow at this ~me was ob~ i n e d , and a sample was sent for cytogene~c anMyMs. Pe~pherM blood showed advanced pancytopenia with white blood cell count of 700/mm 3, con~s~ng of 4% neutrophils, 8% bands, 1% my~ocytes, 3% promy~ocytes, 10% ~ y p ~ M mononuclear cells, 5% b ~ s ~ , 35% lymphocytes, 31% monocytes, and 3% eosinophils. Hem o ~ o b i n was 10.3 ~ d l and h e m ~ o c ~ t was 28.3%; p l a t ~ count was 800~mm 3. The bone marrow showed increased blasts of 21%, with other findings b ~ n g the same as previously d e s c ~ b e ~ Morph~ogy of the blasts was consistent w~h m y ~ o blasts. After extensive counseling, the patient and his ~ m i l y decided to refuse chemotherap~ He was discharged from the hosp~al to be followed in clinic; however, he exp~ed at home 11 days after discharge. Autopsy was not performed.

nosa;

MATERIALS AND METHODS

Each of the two bone marrow aspff~e specimens were co~ected in EDTA [8] and were processed dffectly w~hout in ~ t r o cu~ure [9]. Chromosomes were analyzed w~h G- and C~ands, using modified ffypsin-Giemsa [10] banding and C ~ a n d i n g [11] ~chniques. An abnormM clone was defined according to the c~te~a recommended by the First Interna~onal Workshop on Chromosomes in Leukem~ [12]. RESULTS A totM of 31 m~o~c figures were counted from the first marrow a s p i r e , all of which were anMyzed or karyotyped. Upon e x a m i n ~ n of these cells with G- and C~anding, a cell line w~h multiple aberrations was reveMed. The chromosome number was 44, w~h a direct d u p l ~ a t i o n of lp, dir d u p ( ~ ( p 3 1 - - ~ 3 ~ ; translocat o n of a p o t i o n of the long arms of a #12 to the short arms of a #3, t(3~2)(p22;q15), resulting in a loss of the segment 3p22-->pter; complete dele~on of a #5; a unique breakage of a #15, resulting in a ~ansloca~on of a p o t i o n of 15q to 18p, ~ 1 5 ~ 1 4 ~ 1 1 L with a partiM loss of 18p and a ~ a n s l o c a t o n of the rem i n d e r of the #15 to a #21, forming a dicent~c, d i ~ 1 ~ 2 1 ) ~ 1 2 ~ 1 ~ (F~s. 2 and 3). Six cells counted had 46 chromosomes with the dir dup (lp). Two cells had a n o r m ~ karyotype. The second specimen was received 3 months after the in~ial a s p ~ Fo~y-one m ~ o t ~ figures were counted, M1 of which were anMyzed or partiMly anMyzed. The modal chromosome number was 44, with these cells showing the same karyotype abnormMities as those desc~bed in the first specimen. Three cells were iden~fied w~h 46 chromosomes, having the dir dup (lp). Three cells with a normM karyotype were also seen. DISCUSSION

The myelodyspla~ic syndromes consist of a group of disorders with varying degrees of abnormal or dysplastic maturation of the hematopoietic precursor cells. These disorders have also been referred to as preleukemia, and the diagno~s and prediction of prognosis in each case has been a difficuh task. There has been a recent attempt to classify and describe the various entries by the French-AmericanB~fish cooperative Study Group [13], and using this classification, the patient presented here would qualify as refractory anemia with excess blasts. There have been several reports on the usefulness of cytogenetic analys~ of bone marrow cells to aid in the actual diagno~s and prognosis of such patients [1-4]. The finding of an acquired, clonal aberration indicates the presence of a malignant

270

N. Clare et al.

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cell line in the bone m ~ m w and correlates w ~ h a ~ a ~ y worse progno~s. Pafien~ w ~ h a c h r o m o s o m e a b e ~ a f i o n tend to have a sho~er sur~vM, e~her w i t h ~ u k e m ~ progression or w ~ h fatM ~ m ~ s . The aberra~ons ~ e ~ y seen are very M m f l ~ ~ those iden~fied ~ p ~ e ~ s w ~ h ~ e ~ y m ~ c ~ukemia, except for the specific ~ r ~ s , such as t(15;17) in acute ~ o m ~ l ~ c ~ukem~ (M3) and t(8;21) in acute m ~ c ~ c ~ u k e m ~ (M2) [4]. C ~ c analysis of the bone m ~ m w cells in tMs p a ~ e ~ shows s e v ~ M m ~ o r ~r~s, wRh evidence of clonM e v o ~ f i o n from 4 6 ~ Y ~ dff dup (lp) ~ m ~ o r ~r~s. This sugges~ that the dff dup (lp) was the o ~ n M c h r o m o s o m e event. C ~ o m o ~ m e #1 has ~ e ~ y been involved in h e m ~ o ~ c mM~nan~, M• ough, in the m ~ o ~ of cases, the a b ~ r ~ n s ~ v o N e the long arm of #1 [1417]. Of great interest is the recent article by Sandberg et al. [5] that reports two pat i e n t , one with a m ~ w o ~ disorder and one w ~ h acute ~ u k e m ~ (M4), each having a ~ a n s l o c a t i o n ~ v o N ~ g c ~ o m o ~ m ~ #3 and #12. These a u t h o ~ have sffessed the i m p ~ n c e of the donor c h m m ~ o m e having the key role. Their p ~ e ~ no. 2 had a more m M ~ n a ~ c o u p e , w ~ h c h m m o ~ m e # 3 being the donor, and ~ e y t h e o ~ z e d that sub~antiM dele~ons of #3 may be r e l i e d to an aggressive

K~y~ype Ab~r~ns

~ M y ~ o d ~ p ~ s ~ c Syndrome

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Figure 3 Partial karyotype of chromosomes #1 and #21. Top line, leh, ~ypsin-Giemsa bandin~ dirdup~)(p31--~p36) and a normal #1; ~ght, dic(15~(p12;p12) and a normal #21. Bottom line, same aberrations with C-banding.

course and/or toxic exposure. The patient presented in this article had an aggressive course, with leukemic progression in 3 months. Although, in this case, chromosome #12 is the donor, there is a substan~al dele~on of 3p, supporting their theory. We have previously reposed a case of acute myelofibroMs in which there were m~or chromosome abe~ations, including a partial dele~on of 3p,del(3)(p2~, which is very Mmflar to the present repo~ [18]. The patient with acute myelofibros~ also had a fulminant course and exp~ed 3 weeks after diagnosis. Several cases of hematologic disorders have been reposed with thrombocytosis having a fairy specific aberra~on of chromosome #3, in~3;3)(q27;q21q2~ [6, 7], with the authors speculating that ~ is the long arm and not the short arm of #3 that is associated with platelet control. The present case does not involve 3q and showed con~nued thrombocytopenia. Chromosome #15 has been reposed to be involved in many cases of hematologic disorders, with aberra~ons including trisomy [19], pa~tal and total dele~ons [20-22], and transloca~ons [23]. Included in these abnormalities is the t(15;17), which is specific for acute promyelocytic ~ukemia and involvement in unusual [24] and complex Philadelphia ffansloca~ons [25]. The present case shows a unique aberration of a #15, w~h a break in band q14, resulting in the distal p o t i o n of 15q translocating to 18p and the segment 15q14 -* p12 ffan~ocating to a #21, forming a dicentric chromosome. There is no apparent loss of 15q; however, a small deletion at the breakpoint cannot be ruled out. Pe~pheral blood was not obtained in this case to rule out the possibility that some of the aberra~ons represent a congenital abnormally. This is very unlikely w~h the deletions of DNA noted in the absence of phy~cal and mental s~gmata. The abnormal karyotype seen in this patient indicates the presence of a malignant clone in the bone marrow, and the - 5 and t(3;12) are suggestive of previous exposure to carcinogens. Chromosome aberrations in patients with exposure to toxic substances usually show hypodiploidy with partial or total dele~on of #5 or #7 [26] and involvement of #3 [27]. This patient had significant exposure to cigarette smoke, alcohol, and possibly solvents in a newspaper plant.

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