Chromosome Changes in 43 Carcinomas of the Cervix Uteri Niels B. Atkin, Marion C. Baker, and Margaret F. Fox

ABSTRACT: A summary of the chromosome changes in 43 carcinomas of the cervix studied by a direct technique showed that the most common anomaly was a small metacentric [in 77%, often in two copies: an i(Sp) or possibly an i(4p)]. Others commonly involved in structural changes were: chromosome 1 (60%; most commonly an i( l q), l p - , or translocation of part of l q onto another chromosome); chromosome 17 (47"/0; translocations onto the short arm or long-arm isochromosomes), chromosome 11 (37%; translocations onto the short arm); chromosome 3 (26%; including 3 p - and 3 1 - ) ; and chromosomes 2. 6, and 9 (each in 19%). Considering the four most frequent categories of markers--small metacentrics and markers derived from chromosomes 1, 17, and 11, none of which is specific for cervical carcinoma--almost any combination of these four might be present in a tumor (and at least one was present in all tumors) so that they were not mutually exclusive. Estimates of the average numbers of normal chromosomes based on representative karyotypes from 35 of the tumors showed that three chromosomes in particular were underrepresented (chromosomes 4, 11. and 14; 72-73% of the expected values), while chromosomes 3~ 19. and 20 were those most highly represented (99-103%).

INTRODUCTION C a r c i n o m a of t h e c e r v i x is o n e of t h e m a j o r f o r m s of c a n c e r i n w o m e n , yet t h e r e h a v e b e e n o n l y a f e w s t u d i e s of t h e c h r o m o s o m e s u s i n g b a n d i n g t e c h n i q u e s . T h e d e t a i l e d c h r o m o s o m e c h a n g e s s e e n i n 19 t u m o r s s t u d i e d i n t h i s l a b o r a t o r y h a v e p r e v i o u s l y b e e n d e s c r i b e d [1, 2]. Here, w e s u m m a r i z e o u r f i n d i n g s o n t h e s e a n d 24 a d d i t i o n a l t u m o r s , c o m p r i s i n g 16 n e w c a s e s a n d e i g h t t h a t w e r e i n c l u d e d in a n e a r l i e r s t u d y o n c h r o m o s o m e 1 c h a n g e s [3], for w h i c h m o r e c o m p r e h e n s i v e d a t a are n o w a v a i l a b l e .

MATERIALS A N D METHODS T h e 43 t u m o r s d e s c r i b e d h e r e w e r e part of a series of 78 c o n s e c u t i v e t u m o r s s t u d i e d b y a d i r e c t m e t h o d [1]. Of t h e r e m a i n d e r , 21 w e r e d i s c a r d e d b e c a u s e of a lack of m e t a p h a s e s a n d 14 w e r e d i s c a r d e d b e c a u s e o n l y v e r y l i m i t e d c h r o m o s o m a l a n a l y s i s was possible. Of t h e 43 t u m o r s , 35 w e r e c o n s i d e r e d s u i t a b l e for d e t a i l e d a n a l y s i s i n c l u d i n g c h a r a c t e r i z a t i o n of m o s t or all of t h e m a r k e r c h r o m o s o m e s a n d d e t e r m i n a t i o n of t h e n u m e r i c a l c h a n g e s . T h e s e c o m p r i s e : all t h o s e in (1) a n d (2) e x c e p t case 8 i n (1); c a s e s 6, 12, 20, 24, a n d 26 in (3) (Table 1A); a n d 12 n e w cases (Table 1B). E i g h t of t h e cases

From the Department of Cancer Research, Mount Vernon Hospital, Northwood, Middlesex tfA6 2RN. U.K Address reprint requests to: Dr. N. B. Atkin, Department of Cancer Research. Mount Vernon Hospital, Northwood, Middlesex HA6 2RN, U.K. Received July 10, 1989; accepted July 13, 1989.

229 © 1990 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York. NY 10010

Cancer Genel Cytogenet 44:229 241 (1990) 0165 4608/90/$03.50

(12) [15) (181 {2)))

(24)

(25) (26)

2 3 4 5

6

7 8

39

2 3

56

43

Age (yr)

1

Case

73 63

66

55 64 60 34

53

Age (yr.)

Ill 11

1

Ill IV [ II

IV

Clinical stage

p P

1)~

p M P P~

p

A130 D8

D30

1)19 A108 D26

D25

Duration of follow-up {too)/'

lI lla

]I]

Clinical stage

p,

M

p

Degree of differentiation of t u m o r "

A18

A96

D22

Duration of follow-up /too.) b

49

47

46

7112 9/27

4/12

No. of metaphases analyzed/ counted

data from

for 12 p r e v i o u s l y

15,

unpublished

46,XX,+Ip-,4q~i(?5p),+7q-, 9, J], 1 4 , - 1 4 , + 16, + 1 6 , - 18, + rain 47,XX,+I[2q/. 5 , + ? 9 q + , 10,-11,- 14,17p+,+2mar 49,XX,deI{2)(q33),t(11 :?)(pl 1 or p15;?),der(15)t(1;15) ( q l l : p l l or p13).- 1 8 , + 1 9 , + 3 m a r

Representative karyolype

karyotypes

45,XXA(1;?)(q25;?)5 + 2 , - 4 , + i ( ? 5 p ) , + i ( ? 5 p ) , - 1 1 , - 11,+ der(11) t(11;14)(p11;q13),- 14,der(15)t(9;15)(q13;q26),- 17 4 8 , X X , + i ( l q ) , + i ( ? 5 q ) , + 9 p + , + 1 0 , 1 1 p + , - 1 5 , - 18 i[lp),i(?5p) {2 copies in s o m e m e t a p h a s e s ) l p - ,i(?5p) (2 copies),9p + ,1 l p + , d r a i n , d r a i n , m a r 7&XXXX, ~ 1, ~ 1 , + 2 , + 4 , + 5 , + i ( ? 5 p ) , ~ - i(?Sp), ~ 6, t 6, ~ 7, ÷ 8, + 9, + )2, + 12, 4 13, ~ 14, ~ 15, + 16, + 17, + 17, + 18, + 19, + 19, +20,+20,+2),+21,+22,+22, f mar 85,XXXX, + ) , + ) , + 1 . + i ( l q ) , + 2 , + 3 , + 3 , + 4 , + 4 , + 5 , + 5 , + 5 , i(?5p), ~-i(?5p),+6,+der(6)l{6:12}(p21;q13),+ 7,+ 7, + 8,+ 8, +8,+9,+10,+10. ~ 11. ~ 1 2 , + 1 2 , + 1 3 . + 1 4 , + 1 6 . + 17,+ 18, + 20, ~ 2 0 , + 2 1 , + 2 2 , + 2 2 l q - , i(?5p) ( 1 - 3 copies),i(17q) 96,XXXXX.+1,+2,+3,+3,+5,+ 5. + 6, + 6, ~ 7, ~ 8, t 9 , + 9 , + 1 0 , + 10,+ t o , + 1 2 , + 1 2 , + 1 2 , + 1 2 , + 1 3 , + 1 3 , + 1 4 , + 1 4 , + 1 5 , + 1 7 , + 1 8 , + 18, + 1 9 . + 2 0 , + 2 1 , + 2 2 , + 1 6 m a r

iVlodal k a r y o t y p e or clonal a b e r r a t i o n s identified

and representative

87-91 99-10/)

81 87

48 51 70 77-81

43-45

IVlodal chroIllOSOille no. or range

numbers,

Modal chronmsome number or range

Clinico-pathologic data, modal chromosome c a r c i n o m a s of t h e c e r v i x

(6)

1

T a b l e 1B

Case no. in (3)

Degree of differentiation of t u m o r "

Clinico-pathologic data, modal chromosome numbers, and representative karyolypes or limited chromosomal e i g h t c a r c i n o m a s of t h e c e r v i x i n c l u d e d in a n e a r l i e r s t u d y [3]

Case no.

Table 1A

t,o

46

82

11

12

~' f See Table lc.

53

10

5/17

87

D4

III

93

3/17

78-93

AIO

lb

3/20

80 91

6/30

A8

84

lla

-

5/19

81

2/8

2/6

84

A21

m ~

Ib

36

69

68

9/13 5/5

A19

D2

P

lb

43

64

52 61

Ill

D14"

P

111

63

64

D4 D9

M P

lla II

74 76

+21,+22 84,XXX, 1,+ lp +,+i(lq),+ 2 , + 2, + 2 , + 3 , + 4 , + 5 , + 6 , + 7, +7,+8,+8,+9,+9,+10, + 11,+11,+12, ~- t ( 1 3 c t 1 5 q ) , + 1 4 , + 1 4 , + 16, + 1 6 , + 1 6 p + , + 1 6 p + , + 1 7 , + 1 7 , + 1 7 , + 1 9 , + 2 0 , +20.~22,+4mar 8 5 , X X X , + 1, + d e l ( l ) ( q 1 1 1 , + del(l)((111), + 2, + 2 , + 2 , + 3, + 3, + 3,+ 3p-,+4,+ 5 , 6 q + , + 8 , + 8 , + 9 . + 9 , + 10, + d e r ( 1 1 ) t { 5 ; 1 1 ) ( q 1 1 ; p 1 5 ) , + 1 2 , + 1 2 , + 1 3 , 4 1 4 , + 14, + 16, + 1 7 , + 17, + 17, + 18, + 18, + 1 9 , + 20, + 20, + 21, + 2 1 , + 2 1 , + d e r [ 2 1 ) t ( 1 ; 2 1 ) { q 1 1 ; p 1 1 1 , + d e r ( 2 1 ] t ( l ; 2 1 ) ( q 1 1 ; p 11), + 22 8 5 , X X X X X , + 1 , + 2 , + 3q + , + i ( 7 5 t ) ) , + i ( ? 5 p ) , + 6 . + 6 , + 7 , + 8 , F 8, + 9, + 1 1 , + 1 1 , + 12, + 1 2 , + 1 2 , + 14, + 14, + t ( 1 4 q 1 4 q ) , + 15,+ 15,+ 16,+ 16,+17,+18, ÷ 18,+19,+20,+20,+20, +20, ~ 20,+21,+22 88,XXXX,+l, + i(1q),+i(1q),+2,+2,+3,+3, + 3p ,+3p , ~511 , + 5 t ) , + i ( ? S p ) , + i ( ? 5 p ) . ¢ 6 , + 6 , + 7 . + 7 . + 8 , + 8 , + 9 , + 10,+10,+11,+12,+ 13,+ 14,+14,+15, + 15,+16p+, +16p+, 17,+18.+19,+19,+20. + 20,+20,+21.+21, + 22. + m a r

52,XXX,+ 1,+ 3,+ i(?5p},+ i[6q),+ mar 6 1 , X X , + 1, + i(lq}, + 2 , + 2 , + 3, .~ i ( ? 5 p ) , + i ( 6 q ) , + i ( 6 q } , + 12, +15, ~ 18,+19,+19,~-20,+2(1 66,XXX,+1,+3, + i(75p},+6,+7,+8,+9,+10,+ 12,+ 13,+15, +17,+ i(17q},+19,+19,+19,+19, ~20,+21 69,XXX,+1,+1,+5,+i(?5p),+i(?5p),+6,+8, f9,+9,+10, + 1 1 , + 1 2 , + 1 3 , + 1 6 q - r , + 17, + 18, ~- 18, + 2(1, + 2 1 , + 3 1 n a t 8 3 , X X X , + 1 , + 1 , + 2, + 2, + 3 , + 3, + 3 , + 3 q , + 4 , + 4 , + 5 , + 5 , +6,+7,+7,+8,+8,+9,+10,+10,+11,+11,+12,+12, + 1 2 p + , + 1 3 , + 1 3 , + 1 6 , + 1 7 , + 1 , 7 p + , + 1 8 , + 1 9 , + 2 0 , + 21,

t'~

11

41

35 33

2

3 4

P P

P

P

D e g r e e of d i f f e r ( m t i a t i o n of l u n l o r ('

D5 D27

1)18

I)7/

D u r a t i o n of f o J h ) w - u p (mo.] b

r. Interslitial Cd~and on distal Im)g arm.

Adenoa(:anthonm.

' Died I)f (:ardiovascular disease.

d Adellocarcilloma of endonletrioid ~I[)[)(~,tF~IIIC(L

' Ad(~llOt:ar(;inolna.

r, A, alive; D, died.

" C, g()od; M, moderale: P. poor. Squan/¢ms (ell except where indicated.

IV [l

11

49

1

Clini(:al stage

Age (yr)

Case

50

78-8(1 A p p r o x . ~[)

48

A p p r o x . 76

Modal (:hromos(mm n t u n b e r or r a n g e

l p ~ (1 ~ , i('?5p) ( t w o (:ot)i(;s), 3q i('751)). 1 1 p + ( t w o c o p i e s )

(lw(~ c o p i e s )

M a r k e r c h r ( m / o s ( m m s iclenlific(I

i ( ? S p ) , i(17(t/

17p+

Table 1C Clinico-pathologic data, modal (:hromosome numbers, and limited chromosomal data for 4 previously unpublished carcinomas of the cervix

t'-,a

t'~

233

Chromosome Changes in Cervical Cancer

,~..... ~

~i ¸

i~;

~ ...... ~

:i,~i¸l

3 7

6

13

8

14

19

~ ~ = d

20

|" 9

15

10

11 ~ e

16

i

9

~

21

~ 17

22

12

18

X

Figure 1

Poorly differentiated adenocarcinoma (Case 3 in Table 1B]. 49 chromosomes. (a) der(15)t[1;15); (b) del(2)(q33); (c and d) markers probably derived from chromosome 8: (e) t(11;?); (f) 17p + (?not clonal); (g) unidentified minute.

were subjected to slightly less detailed analysis; although the origin of the markers could on the whole be determined with some confidence, there were a few chromosomes that could not be characterized. These cases were: case 8 in (1}; cases 15, 18, and 25 in (3) (Table 1A); and four new cases (Table 1C). At least five metaphases from each tumor were analyzed.

RESULTS Brief clinical and histologic data and representative karyotypes or clonal aberrations from the cases, other than those already described in detail [1, 2], are shown in Table 1. Karyotypes from three of the previously unreported tumors are illustrated in Figures 1-3.

Structural Chromosome Changes Table 2 shows the chromosomes that were most c o m m o n l y involved in structural changes in 43 tumors. The most frequent abnormality, a small metacentric that appears to be an i(4p) or i(5p), was seen in 77% of the tumors, often in two copies (Table 3). Chromosome 1 abnormalities were seen in 26 tumors (60%). These were most

234

A

1

a

2

6

i i

13

14

c

3

7

4

8

11

12

17

18

d

16

15

j 20

19

10

9

5

i

A

e

f

~

0 21

~ 22

" X

F i g u r e 2 Moderately differentiated squamous cell carcinoma (Case 4 in Table 1B}. 53 chrmnosomes. (a) ?rearranged c h r o m o s o m e 1 (not clonal; most metaphases had three normal chromosomes 1); (b) ?i(4p) or i(Sp); (c) i(6q); (d) 6 p - (not clonal); (e and f) unidentified.

Table 2

Chromosomes most frequently involved in structural changes in 43 carcinomas of the cervix

Chromosome

No. of tumors

i(4p) or i(5p) 1 17 11 3

33 26 20 16 11

(77%) (60%) (47%) (37%) (26%}

8

(19%)

8 8 5 4 4 1-3

(19%) (19%/ (12%) (9%) (9%) {2-7%)

2 6 9 4" 5" 15 7,8,12,13,14,16,19,21,22

" Excluding short-arm isochromosomes.

235

C h r o m o s o m e Changes in Cervical Cancer

Table 3

Incidence of tumors with 0, 1, and 2 small isochromosomes [?i(4p) or i(5p)] in relation to ploidy range

Number of small isochromosomes

Range of chromosome numbers 41-45

0

2

1

2

5

1

3

10

3

3

2

1

1

4

8

46-52

53-74

75-105

Total no. of tumors 10 19 14 43

often of one of three types, i(lq), l p - , or translocations of part of l q onto another chromosome. Thus, the changes c o m m o n l y resulted in short-arm loss and/or longarm d u p l i cat io n (Table 4). Chromosome 17 abnormalities, seen in 47% of the tumors, c o m m o n l y i n v o l v e d either the translocation of material onto the short arm, or were long arm isochromosomes; they resulted in loss of part or all of the short arm, as previously described [4]. Chromosome 11 markers were present in 37% of the tumors. These usually resulted from the translocation of material from another c h r o m o s o m e onto the short arm, thus resulting in the loss of part of the short arm. Chromosome 3 structural changes (26% of the tumors) involved either arm with about equal frequency. 3 q - and 3 p - c h r o m o s o m e s were present in four and three tumors, respectively. Chromosomes 2, 6, and 9 also showed evidence of n o n r an d o m involvement, with each present in markers in 19% of the tumors. With consideration to only the four chromosomes most often involved in structural changes, c h r o m o s o m e s 1, 5 (probably), 11, and 17, the markers derived from these c h r o m o s o m e s manifested in almost any possible combination in the tumors, and at least one such marker was present in every tumor (Table 5). No clear indication as to whether the presence or absence of these markers was of prognostic significance could be obtained, although suggested was that Stage I cases tended to have fewer markers than more advanced cases (Table 6). Although a significant relationship between markers derived from particular chromosomes and survival was similarly not appar-

Table 4

Incidence of different types of c h r o m o s o m e 1 markers (32 markers in 26 out of 43 tumors) Number of markers

Marker i(lq) lp lq+ lq lp+ lp+q+ i(lp) Translocation of part of lq onto a different chromosome: 3, 11 (2 tumors], 15, 17, 19, 21, and unidentified ° Including two lp Table 1B).

6 6 ~' 3 3 2 2 1 9"

(%) (19] (19] (9) (9) (6) (6) (3) (28)

and two der(21)t(1;21) chromosomes in Case 10 (see

3

a

A

iS iS i | i 1ii 2

iSt a i ; ; ~ | 8

9

4 s ~

A A c

p o o

7

• ~

16

6

be 4

15

21

14

20

13

19

4

Ill

10

A J

22

17

11

18

12

!A

5

"~ i i i

I:)

A

X

d; StS|

Figure 3 Poorly differentiated adenoacanthoma [Case 20 in (3]; Case 5 in Table 1C], 78 chromosomes, {a) t(:3p:?) (not cloilal): (b) two copies of [(4p] or i(5p]; (c) 7p+.

237

C h r o m o s o m e C h a n g e s in C e r v i c a l C a n c e r

Table

5

C o m b i n a t i o n s of m a r k e r s d e r i v e d f r o m c h r o m o s o m e s 1, 5 ( i n c l u d i n g s m a l l m e t a c e n t r i c s of w h i c h s o m e m a y , h o w e v e r , h a v e b e e n d e r i v e d f r o m 4p), 11, a n d 17 s e e n in 43 t u m o r s Chromosome

1

?5

11

17

+ + + +

+ + + -

+ + +

+ + +

-

+

+

+

2

+ + +

+ -

+ -

+

9 1 0

+

-

1

-

+

+

-

-

.

3 4 5 4

+

3

+

o

-

+

-

1

+

-

-

6

-

+

-

1

--

-

+

+ -

No. of tumors

.

.

3

.

0

43

ent, it w a s n o t e d that, of 36 c a s e s w h o h a d e i t h e r d i e d or s u r v i v e d for five years, six out of 11 (55%) w i t h o u t c h r o m o s o m e 1 m a r k e r s h a d s u r v i v e d c o m p a r e d w i t h n i n e out of 25 (36%) w i t h m a r k e r s .

Numerical

C h r o m o s o m e

Changes

T h i r t y - f i v e of t h e t u m o r s w e r e c o n s i d e r e d s u i t a b l e for t h e a s s e s s m e n t of n u m e r i c a l c h a n g e s . W i t h a r e p r e s e n t a t i v e k a r y o t y p e f r o m e a c h case, t h e average n u m b e r of e a c h of t h e n o r m a l c h r o m o s o m e s w a s c a l c u l a t e d a n d e x p r e s s e d as a p e r c e n t a g e of t h e e x p e c t e d n u m b e r (Table 7). C h r o m o s o m e s 4, 11, a n d 14 are p a r t i c u l a r l y u n d e r r e p r e s e n t e d w h i l e t h e t h r e e m o s t h i g h l y r e p r e s e n t e d c h r o m o s o m e s are 3, 19, a n d 20. T h e s e data also s u p p o r t e d e s t i m a t e s t h a t a n average 11.3% of t h e c h r o m o s o m e s in t h e

Table

6

R e l a t i o n s h i p b e t w e e n c l i n i c a l stage a n d w h e t h e r 1, 2, 3 or all of c h r o m o s o m e s 1, ?5, 11, a n d 17 are i n v o l v e d in m a r k e r c h r o m o s o m e s in 43 t u m o r s

No. of chromosomes involved

Stage I

II

III

IV

Total no. of tumors

1 2 3 4

5 3 4 0

5 3 7 2

1 6 3 1

0 2 1 0

11 14 15 3 43

238

N.B.

Table 7

A v e r a g e n u m b e r of n o r m a l c h r o m o s o m e s , e x p r e s s e d as a p e r c e n t a g e of the e x p e c t e d n u m b e r , in 35 t u m o r s

Chromosome

% of expected number

1 2 3 4 5 6 7 8 9 10 11 12

92.(I 91.9 99.1 72.0 83.8 87.3 91.6 97.1 92.1 88.4 73.2 97.7

1 ',3

85.2

14 15

73.4 81.8 93.9 87.3 83.3 100.0 103.2 83.3 86.4 94.5

16

17 18 19 20 21 22 X

A t k i n et al.

k a r y o t y p e s w e r e a b n o r m a l {e.g., there w e r e most c o m m o n l y five markers in a neard i p l o i d and eight in a n e a r t r i p l o i d tumor). T h e a b o v e data are based on findings on t u m o r s that i n c l u d e d s o m e that c o u l d not be f u l l y a n a l y z e d . Thus, the true i n c i d e n c e of the i n v o l v e m e n t of p a r t i c u l a r c h r o m o s o m e s in structural r e a r r a n g e m e n t s m a y be a little h i g h e r than has b e e n e s t i m a t e d . Variant m e t a p h a s e s w h o s e karyotypes u s u a l l y differed from the representative or " m o d a l " k a r y o t y p e w i t h respect to one or two n u m e r i c a l a n d / o r structural c h a n g e s w e r e fairly c o m m o n in m o s t tumors. D i p l o i d m e t a p h a s e s r e p r e s e n t i n g d i v i d ing n o r m a l cells present ill the t u m o r tissue w e r e u n c o m m o n (