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15 The cancer chromosome registry - solid tumors
Abstracts
15
105
1"7
THE CANCER CHROMOSOME REGISTRY - SOLID TUMORS Felix Mitclman, Department of Clinical Genetics, University of Lund, Lund, Sweden
Clonal chromosome abnormalities identifiedby banding techniqueshave been reported in 2 955 solidtumors, compnsing 21% of the totaldam base. The distribution according to tumor site is presented below. P~t~ory
~
Nleo~a=~nx L=rynx
F~ad~ emit
II
Phmm
16 toa "/'3
D~Imave~ M~m
II
Modmmm~m
6
Over Ul=rg=, ¢~11~l ~ , ¢ln'~= Viii MaJe m
Salw.r~ I,.nd Liver P~ncr.io
0¢~s~6~ S~J¢.~
163 $
5
Smili iami~m
It 19 3
Large :ma,m m ~
1445
Utimu~ trms
)GdaIv
346
~_~_-_e
9"/
Bfmm ~x.
fcm~
B~mm.nm~.
98 2
oq~m
T~
9t
~
19
Peme
8
F~Jocrum ~]uem P ~ ~ Tlil~m~li
I t33 39
~llymlm
2
N~s, m m ~ m ~ m C ~ m s 0 r.~.--.~.dsym-m
P ~
~
Skalml. ~o4~tim~, *=.,* *~-. Sk~evm. toA t ~ l e
~
U~mm~
~ I6
37 373
115
U ~ k P --= ma
16
185, 17| lO I
m~a
22 17
GENETIC INSTABILITY (GD: BIOLOGIC RELEVANCE IN 185 BONE AND SOFT TISSUE (B&ST) TUMORS. Fletcher JA, Corson JM, Kozakewich HP, Morton CC. Dept of Pathology, Harvard Medical School, Boston, MA Many B&ST tumors contain nonclonal chromosome aberrations which arc presumed to result from defects in DNA replication, division, and/or repair. A consequence of this genetic heterogeneity, or GI, may be accelerated acquisition of adverse biologic features. We prospectively evaluated GI in consecutive, successfully cultured, benign (n ffi 54) and malignant (n = 131) B&ST tumors. GI was assessed using a grading system (Cancer Res 1990; 50:4092-4097) in which grades I, II, III, and IV, denoted tumors having unique, nonclonal, aberrations in 0-10%, 11-49%, 50-90%, and > 90%, of metaphases, respectively. Virtually all benign tumors were GI grade I (n -- 49), whereas malignant tumors were grade I (n = 30), grade II (n = 24), grade III (n = 24), and grade IV (n = 53). Certain malignant tumors, e.g. malignant fibrous histiocytomas and malignant schwannomas, were always GI grade IV; others, e.g. Ewing's sarcomas, were always GI grade I. Preliminary clinical correlation suggested that tumors with low-grade GI enlarged more rapidly than tumors with similar in vivo mitoticactivityand high-grade GI. This observation indicates thathigh-grade GI might retard tumor growth in the short term due to lethalcellulargenetic events. Our findingsindicatethathigh-grade GI is not an inevitable consequence of malignant transformation. High-grade GI might be essentialto progression in certainmalignant tumors, but unnecessary, and perhaps counterproductive to growth, in others.
Is KARYOTYPE AN INDEPENDENT PROGNOSTIC INDICATOR IN BLADDER CANCER?
VR Babu, 8 Tllley, A WIktor, T ~'umh~ler and 8J IVUles. Medical Genetics and Birth D e f ~ s C.,4KWW, D ~ m 4 m ~ of L.}fo~y ~ Bio~atiatlcs, Henry Ford Hospital, O~rcll, MJchigen. Tr~,s~on~ cedl c..wcmoma of the bladder (TCCB) is a hme¢ogeneous disease anti currer~y thece w'e no ratable prognostic InOic,ators Ka~otype has been prove1 to be an Inclepenclen¢ prognos~c indicmor in hemmc~ogJc malignancies. We concluaeO• mx yew cytogec~mc atuay witch comprised a to~al of 170 new4y dia0noesO pe~ects v~tll TCCB. The study des4gn consJsted of 1] chromosome ~ of pnmacy ~. w ~ as reourre41 tumocs 2) statistical testing for s) esloOatloct ~ ka~olype, chromosome mmkers and tumo," grade and stage b) ¢ocraation 10e~vNn kmyolype, chromosome ma~kers and c.J=n~c..~Cutcorne - rK:utreoc, e, progress=on and uitim~e survival. A complexity system akin to the one used for I~mlMolog=c rnalJgnanaes was used to c...lassJty the patier~s i,e.. r~'mal - no changes; ..mp~e - 1 change; com~ex - 2-5 changes: ve~ complex - > 5 changes Lo~-Rank tests for unNa/iate analys~s and Cox. Regression nl~;Jei8 for multivariate analys~s w~e used foe statistical testing. The median f~low-up was 1.5 years. Reflecting the c~n~cal hete~ogenedy, sevsral chromosome ma~kecs were idantnf~ed. Most of the c . J ' v o ~ : x ~ changes were un~8/snced w~th deletions predon~nsting the dup41c~ions. Majority of the common ove¢lapping regions of demt=ons coinode with the location of known Or putative tumor suppressor genes. FOur rK:urrtn 0 trm~KxT,~ns were observed. C~ede and stage i t the tumor srlowe~ atrorlO es,sooation wdh c'ylogsn~ic complexity of the tumor (p < 0.001). Low grade, nonlnvesa~ tumors tend to ~ norm= Or rumple ka~otype~ whereas high grade, Inva=ve tumors tend to have comglex or ve~/ complex km'yoCyp~m. A ~ ct~omosome mark.s, l i d 5p, del 6¢1, trisomy 20. de~ 2q, de~ ~1, dsl tp, din ~ snowecI strong essoc~ation (p < 0.005). V~th resDe,~ to c~i~c~ outcom~ the following correlations wine ohse~n~d. Patients w~th a) trtsomy 7 t ~ to ~ less recurrertce (p <0.03); b) I'~ghe¢ complexity kafyo~ypes tend to p r o g r ~ wlth recurrence (p < 0.02'); c) no~mal karyotype tend to n i l c / ' ~ e grade Or stage w~th re¢.urranc@ (p < 0.05); d) iso 5p, del lp and tnsomy lS h a w • poo¢ sup~vaL Thu~k OUt results strongly in~cate that s~r~laf to I~er~MIe~o~c rnalignandes, klu~fotype is an inclepeoclent prognoshc indicato¢ In 10laddie cancer and therefore, r~g~ be usef~ in the management cf bladd~ cancer pa~ents.
18
ABNORMALrrIES OF CHROMOSOME I AND LOSS OF H~-I~ROZYGOSITY l i p DISTALI IN PRIMARY HEPATOCELLULAR CARCINOM A. D a m e l a S i m o n . A n d r e a s W e i t h ' , a n d B a r b a r a B. Knowles. The W l s t a r i n s t i t u t e . P h i l a d e l p h i a . PA a n d " R e s e a r c h I n s t i t u t e for M o l e c u l a r Pathology. Vienna. Austria. C y t o g e n e t i c a n a l y s i s of m e t a p h a s e c h r o m o s o m e s , o b t a i n e d d i r e c t l y from a s i n g l e b l o p m e d h e p a t o c e l l u l a r c a r c i n o m a a n d from e i g h t cell Lines d e r i v e d f r o m s e p a r a t e h u m a n p r m m r y liver t u m o r s revealed many different chromosomal abnormalities. However. c h r o m o s o m e I w a s t h e o n l y c h r o m o s o m e c o n s i s t e n t l y f o u n d to be a b n o r m a l m e a c h c a s e . D e l e t i o n s a n d / o r t r a n s l o c a t i o r m w e r e the m o s t c o m m o n c h r o m o s o m e I a b n o r m a l i t i e s d e t e c t e d ; e i g h t of t h e 15 IdentLfied b r e a k p o i n t s w e r e in fragile s i t e [FS} r e g i o n s . The m o s t f r e q u e n t b r e a k - p o i n t s were located at I p 2 1 - p22 In all c a s e s p s e u d o t r l s o m y to p s e u d o h e x a s o m y of c h r o m o s o m e i w a s f o u n d w i t h i n t h e h y p e r d i p l o i d to h y p o t e t r a p l o l d cell. T h e s e r e s u l t s s e r v e d to f o c u s o u r m o l e c u l a r s t u d i e s to t h e d i s t a l r e g i o n of c h r o m o s o m e Ip. To d e t e r m i n e w h e t h e r t h e s e m o r p h o l o g i c a l a b n o r m a l i t i e s were reflected i n a n y l o s s e s i n t h i s region of t h e g e n o m e , we c o m p a r e d t h e r e s t r i c t i o n f r a g m e n t l e n g t h p o l y m o r p h l s m of DNA e x t r a c t e d from b o t h n o r m a l a n d t u m o r t i s s u e of the s a m e i n d i v i d u a l . Seven r a n d o m p r o b e s f r o m t h e I p d i s t a l r e g i o n w e r e u s e d for t h i s assessment. Of t h e s m h e p a t o c e l l u l a r c a r c i n o m a p a t i e n t s w h o e x h i b i t e d h e t e r o z y g o s i t y w i t h i n t h l s region, five s h o w e d a l o s s of h e t e r o z y g o s t t y w i t h i n t h e t u m o r t i s s u e ; n o l o s s of h e t e r o z y g o s l t y w a s d e t e c t e d i n t h e t u m o r t i s s u e of t h e t w o i n f o r m a t i v e hepatoblastoma patients analyzed. This finding indicates that g e n e t i c m a t e r i a l f r o m c h r o m o s o m e Ip is d e l e t e d in h e p a t o c e H u l a r carcinomas. Thus, through this combined cytogenetic and m o l e c u l a r a p p r o a c h w e h a v e d e t e r m i n e d t h a t c h r o m o s o m e I p is p r e f e r e n t i a l l y r ~ a r r a n g e d in h u m a n h e p a l o m a s . E v e n t h o u g h the n u m b e r of c o m p l e t e or p a r t i a l copies of c h r o m s o m e I i n c r e a s e s in t h o s e t u m o r c e l l s we h a v e e x a m i n e d , t h e r e is. n o n e t h e l e s s , a l o s s of g e n e t i c m a t e r i a l f r o m c h r o m o s o m e I in v a r i o u s h e p a t o c e l l u l a r c a r c i n o m a s . T h e s e r e s u l t s s u g g e s t the p o s s i b i l i t y of a c h r o m o s o m e I p e n c o d e d t u m o r s u p p r e s s o r gene t h a t affects t h e p a r e n c h y m a l hepatocyle.
15
105
1"7
THE CANCER CHROMOSOME REGISTRY - SOLID TUMORS Felix Mitclman, Department of Clinical Genetics, University of Lund, Lund, Sweden
Clonal chromosome abnormalities identifiedby banding techniqueshave been reported in 2 955 solidtumors, compnsing 21% of the totaldam base. The distribution according to tumor site is presented below. P~t~ory
~
Nleo~a=~nx L=rynx
F~ad~ emit
II
Phmm
16 toa "/'3
D~Imave~ M~m
II
Modmmm~m
6
Over Ul=rg=, ¢~11~l ~ , ¢ln'~= Viii MaJe m
Salw.r~ I,.nd Liver P~ncr.io
0¢~s~6~ S~J¢.~
163 $
5
Smili iami~m
It 19 3
Large :ma,m m ~
1445
Utimu~ trms
)GdaIv
346
~_~_-_e
9"/
Bfmm ~x.
fcm~
B~mm.nm~.
98 2
oq~m
T~
9t
~
19
Peme
8
F~Jocrum ~]uem P ~ ~ Tlil~m~li
I t33 39
~llymlm
2
N~s, m m ~ m ~ m C ~ m s 0 r.~.--.~.dsym-m
P ~
~
Skalml. ~o4~tim~, *=.,* *~-. Sk~evm. toA t ~ l e
~
U~mm~
~ I6
37 373
115
U ~ k P --= ma
16
185, 17| lO I
m~a
22 17
GENETIC INSTABILITY (GD: BIOLOGIC RELEVANCE IN 185 BONE AND SOFT TISSUE (B&ST) TUMORS. Fletcher JA, Corson JM, Kozakewich HP, Morton CC. Dept of Pathology, Harvard Medical School, Boston, MA Many B&ST tumors contain nonclonal chromosome aberrations which arc presumed to result from defects in DNA replication, division, and/or repair. A consequence of this genetic heterogeneity, or GI, may be accelerated acquisition of adverse biologic features. We prospectively evaluated GI in consecutive, successfully cultured, benign (n ffi 54) and malignant (n = 131) B&ST tumors. GI was assessed using a grading system (Cancer Res 1990; 50:4092-4097) in which grades I, II, III, and IV, denoted tumors having unique, nonclonal, aberrations in 0-10%, 11-49%, 50-90%, and > 90%, of metaphases, respectively. Virtually all benign tumors were GI grade I (n -- 49), whereas malignant tumors were grade I (n = 30), grade II (n = 24), grade III (n = 24), and grade IV (n = 53). Certain malignant tumors, e.g. malignant fibrous histiocytomas and malignant schwannomas, were always GI grade IV; others, e.g. Ewing's sarcomas, were always GI grade I. Preliminary clinical correlation suggested that tumors with low-grade GI enlarged more rapidly than tumors with similar in vivo mitoticactivityand high-grade GI. This observation indicates thathigh-grade GI might retard tumor growth in the short term due to lethalcellulargenetic events. Our findingsindicatethathigh-grade GI is not an inevitable consequence of malignant transformation. High-grade GI might be essentialto progression in certainmalignant tumors, but unnecessary, and perhaps counterproductive to growth, in others.
Is KARYOTYPE AN INDEPENDENT PROGNOSTIC INDICATOR IN BLADDER CANCER?
VR Babu, 8 Tllley, A WIktor, T ~'umh~ler and 8J IVUles. Medical Genetics and Birth D e f ~ s C.,4KWW, D ~ m 4 m ~ of L.}fo~y ~ Bio~atiatlcs, Henry Ford Hospital, O~rcll, MJchigen. Tr~,s~on~ cedl c..wcmoma of the bladder (TCCB) is a hme¢ogeneous disease anti currer~y thece w'e no ratable prognostic InOic,ators Ka~otype has been prove1 to be an Inclepenclen¢ prognos~c indicmor in hemmc~ogJc malignancies. We concluaeO• mx yew cytogec~mc atuay witch comprised a to~al of 170 new4y dia0noesO pe~ects v~tll TCCB. The study des4gn consJsted of 1] chromosome ~ of pnmacy ~. w ~ as reourre41 tumocs 2) statistical testing for s) esloOatloct ~ ka~olype, chromosome mmkers and tumo," grade and stage b) ¢ocraation 10e~vNn kmyolype, chromosome ma~kers and c.J=n~c..~Cutcorne - rK:utreoc, e, progress=on and uitim~e survival. A complexity system akin to the one used for I~mlMolog=c rnalJgnanaes was used to c...lassJty the patier~s i,e.. r~'mal - no changes; ..mp~e - 1 change; com~ex - 2-5 changes: ve~ complex - > 5 changes Lo~-Rank tests for unNa/iate analys~s and Cox. Regression nl~;Jei8 for multivariate analys~s w~e used foe statistical testing. The median f~low-up was 1.5 years. Reflecting the c~n~cal hete~ogenedy, sevsral chromosome ma~kecs were idantnf~ed. Most of the c . J ' v o ~ : x ~ changes were un~8/snced w~th deletions predon~nsting the dup41c~ions. Majority of the common ove¢lapping regions of demt=ons coinode with the location of known Or putative tumor suppressor genes. FOur rK:urrtn 0 trm~KxT,~ns were observed. C~ede and stage i t the tumor srlowe~ atrorlO es,sooation wdh c'ylogsn~ic complexity of the tumor (p < 0.001). Low grade, nonlnvesa~ tumors tend to ~ norm= Or rumple ka~otype~ whereas high grade, Inva=ve tumors tend to have comglex or ve~/ complex km'yoCyp~m. A ~ ct~omosome mark.s, l i d 5p, del 6¢1, trisomy 20. de~ 2q, de~ ~1, dsl tp, din ~ snowecI strong essoc~ation (p < 0.005). V~th resDe,~ to c~i~c~ outcom~ the following correlations wine ohse~n~d. Patients w~th a) trtsomy 7 t ~ to ~ less recurrertce (p <0.03); b) I'~ghe¢ complexity kafyo~ypes tend to p r o g r ~ wlth recurrence (p < 0.02'); c) no~mal karyotype tend to n i l c / ' ~ e grade Or stage w~th re¢.urranc@ (p < 0.05); d) iso 5p, del lp and tnsomy lS h a w • poo¢ sup~vaL Thu~k OUt results strongly in~cate that s~r~laf to I~er~MIe~o~c rnalignandes, klu~fotype is an inclepeoclent prognoshc indicato¢ In 10laddie cancer and therefore, r~g~ be usef~ in the management cf bladd~ cancer pa~ents.
18
ABNORMALrrIES OF CHROMOSOME I AND LOSS OF H~-I~ROZYGOSITY l i p DISTALI IN PRIMARY HEPATOCELLULAR CARCINOM A. D a m e l a S i m o n . A n d r e a s W e i t h ' , a n d B a r b a r a B. Knowles. The W l s t a r i n s t i t u t e . P h i l a d e l p h i a . PA a n d " R e s e a r c h I n s t i t u t e for M o l e c u l a r Pathology. Vienna. Austria. C y t o g e n e t i c a n a l y s i s of m e t a p h a s e c h r o m o s o m e s , o b t a i n e d d i r e c t l y from a s i n g l e b l o p m e d h e p a t o c e l l u l a r c a r c i n o m a a n d from e i g h t cell Lines d e r i v e d f r o m s e p a r a t e h u m a n p r m m r y liver t u m o r s revealed many different chromosomal abnormalities. However. c h r o m o s o m e I w a s t h e o n l y c h r o m o s o m e c o n s i s t e n t l y f o u n d to be a b n o r m a l m e a c h c a s e . D e l e t i o n s a n d / o r t r a n s l o c a t i o r m w e r e the m o s t c o m m o n c h r o m o s o m e I a b n o r m a l i t i e s d e t e c t e d ; e i g h t of t h e 15 IdentLfied b r e a k p o i n t s w e r e in fragile s i t e [FS} r e g i o n s . The m o s t f r e q u e n t b r e a k - p o i n t s were located at I p 2 1 - p22 In all c a s e s p s e u d o t r l s o m y to p s e u d o h e x a s o m y of c h r o m o s o m e i w a s f o u n d w i t h i n t h e h y p e r d i p l o i d to h y p o t e t r a p l o l d cell. T h e s e r e s u l t s s e r v e d to f o c u s o u r m o l e c u l a r s t u d i e s to t h e d i s t a l r e g i o n of c h r o m o s o m e Ip. To d e t e r m i n e w h e t h e r t h e s e m o r p h o l o g i c a l a b n o r m a l i t i e s were reflected i n a n y l o s s e s i n t h i s region of t h e g e n o m e , we c o m p a r e d t h e r e s t r i c t i o n f r a g m e n t l e n g t h p o l y m o r p h l s m of DNA e x t r a c t e d from b o t h n o r m a l a n d t u m o r t i s s u e of the s a m e i n d i v i d u a l . Seven r a n d o m p r o b e s f r o m t h e I p d i s t a l r e g i o n w e r e u s e d for t h i s assessment. Of t h e s m h e p a t o c e l l u l a r c a r c i n o m a p a t i e n t s w h o e x h i b i t e d h e t e r o z y g o s i t y w i t h i n t h l s region, five s h o w e d a l o s s of h e t e r o z y g o s t t y w i t h i n t h e t u m o r t i s s u e ; n o l o s s of h e t e r o z y g o s l t y w a s d e t e c t e d i n t h e t u m o r t i s s u e of t h e t w o i n f o r m a t i v e hepatoblastoma patients analyzed. This finding indicates that g e n e t i c m a t e r i a l f r o m c h r o m o s o m e Ip is d e l e t e d in h e p a t o c e H u l a r carcinomas. Thus, through this combined cytogenetic and m o l e c u l a r a p p r o a c h w e h a v e d e t e r m i n e d t h a t c h r o m o s o m e I p is p r e f e r e n t i a l l y r ~ a r r a n g e d in h u m a n h e p a l o m a s . E v e n t h o u g h the n u m b e r of c o m p l e t e or p a r t i a l copies of c h r o m s o m e I i n c r e a s e s in t h o s e t u m o r c e l l s we h a v e e x a m i n e d , t h e r e is. n o n e t h e l e s s , a l o s s of g e n e t i c m a t e r i a l f r o m c h r o m o s o m e I in v a r i o u s h e p a t o c e l l u l a r c a r c i n o m a s . T h e s e r e s u l t s s u g g e s t the p o s s i b i l i t y of a c h r o m o s o m e I p e n c o d e d t u m o r s u p p r e s s o r gene t h a t affects t h e p a r e n c h y m a l hepatocyle.