El m´ etodo de reconstrucci´ on algebraica (ART)

In three grade I tumours no genetic changes could be found. The mean number of genetic changes in grade I tumours was 5.4 (range 0-14). Only four regions of change were commonly seen in greater than 25% of tumours - gains of Iq (70%), 16p (45%) and 8q (30%) and loss of 16q (65%). Overall gains were seen as frequently as losses. Unambiguous amplification (ratio >1.4) was seen in 12 tumours at only 6 different sites; 16p (7 cases), 8q (6 cases), 17ql2 (2 cases) and lp32-33, 20q and 1 Iq (1 case each). Two regions were unaffected by either gain or loss, chromosome 15 and the short arm of chromosome 12. Chromosome arms Iq, 8q and 16p were always gained, while chromosome arms 6q, 16q and 18q were always lost. The changes seen in specific chromosomes will now be discussed.

Chromosome 1

Four tumours showed loss of the short arm of chromosome 1 (T880, T1081, T1145 and T1401). T880 showed loss of the whole arm, while tumour T1145 showed loss of lpter-lp32. Tumours T1081 and T1401 both showed loss of band lp22. Four tumours showed gain of the short arm o f chromosome 1, with tumours T1440, T1443, and T843 all gaining lpter-lp35. No tumours showed loss of the long arm of chromosome 1. 28 tumours showed gain o f the long arm, with 19 tumours showing gain of the entire arm. This will be discussed in more detail later on.

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Figure 3-1. Ideogram showing genomic gains and losses in IDC.

T o p p anel 40 g rad e I tu m o u rs, b o tto m panel 50 g rad e III tu m o u rs. E ach bar represents a single tum our, bars to the right o f the chrom osom al ideogram s represent gains and bars to the left represent losses. T hree grade I tu m ours show ed no genetic changes so are not represented.

116 i . ” 0 ■20 O -60 n=40 p arm q arm n=50

Figure 3-2. Frequency of chromosomal aberrations in IDC.

Chromosomal aberrations in grade I breast carcinomas (top graph). Each bar on the x-axis represents either the short arm (black bar) or long arm (hatched bar) of each chromosome. The size of the bar represents the percentage of tumours showing that particular aberration. Gains are represented as positive changes and losses as negative changes. Chromosomal aberrations in grade III breast carcinomas are depicted in the same way (bottom graph). The difference between the top and bottom panels with respect to loss of the long arm of chromosome 16 is clearly apparent.

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Chromosome 2

No tumours showed gain of any region of chromosome 2. T1081 lost the entire chromosome, three other tumours all showed loss of regions on 2q.

Chromosome 3

A single tumour, T788 showed gain of 3p24-pl4 and 3q21-q26.1. T1272 lost the entire chromosome and T1440 showed loss of 3pter-p25, 3pl3-ql3.2 and 3q24- q26.1.

Chromosome 4

No tumours showed gain of any region on chromosome 4. Tumour T1272 lost 4pl5.3-pl5.1 and the entire long arm. Two other tumours each lost different regions from the long arm, 4q24-q26 and 4q27-qter.

Chromosome 5

A single tumour T953 showed gain of 5pl4-5q21. Three tumours showed loss of 5q with a minimal overlapping region of deletion at 5ql4-21, seen in all tumours.

Chromosome 6

No tumours showed gain o f any region on chromosome 6. Tumour T1108 showed loss of the entire chromosome. A further seven grade I tumours showed loss of 6q. Two minimal overlapping regions were seen at 6ql6 and 6q22. In two tumours, these bands were lost as discrete changes, tumour T455 lost 6ql6 and tumour T1022 lost 6q22.

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Tumour T1269 showed loss of the entire chromosome, while T92 gained the entire chromosome. Tumour T978 showed gain of the short arm together with loss of the long arm suggesting the formation in this tumour of an i(7p).

Chromosome 8

Six tumours (T1346, T1228, T1012, T1269, T843 and T1145) showed loss of the short arm of chromosome 8. All of these except for tumour T1228 also showed gain o f the entire long arm of chromosome 8, suggesting the formation o f i(8q). T1228 showed gain of 8q24.1-8qter. No tumours showed loss o f any region from the long arm.

Chromosome 9

Two tumours showed loss of 9pter-9p21 and two tumours showed gain of 9q32- qter.

Chromosome 10

A single tumour, (T953) showed loss of the entire chromosome. No other tumours showed any gains or losses from chromosome 10.

Chromosome 11

Five tumours showed loss o f genetic regions from the long arm o f chromosome 11. Tumours T1401 and T1285 showed loss of 1 lql4-qter, T798 showed loss of 1 lql4.2-qter and T1066 showed loss of 1 lq21-qter, together with loss of 1 Ipter- 1 lp l4 . T1012 showed loss of 1 Iql4-q22.2. Gain o f Ilq l2 -q l3 .2 was seen in a single tumour only.

Chromosome 12

Only two regions were affected in two different tumours. Tumour T1401 gained 12q23 and tumour T880 lost region 12q23-q24.2.

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Chromosome 13

Six tumours showed loss of chromosome 13, with a minimal region of deletion seen in five tumours at 13q21. Two tumours showed gain o f regions from 13q.

Chromosome 14

Two tumours showed loss of 14q24-qter. A single tumour, T889 showed gain of 14ql2-21.

Chromosome 15

No tumours showed any genetic aberrations involving chromosome 15.

Chromosome 16

26 tumours showed loss of the long arm of chromosome 16, of these 20 showed loss of the entire long arm. The minimal overlapping region o f deletion was 16q23-qter, seen in all tumours. 16 tumours showed gain o f the entire short arm and a further two tumours showed gain of 16pter-pl2 and 16pter-pl3.1. Loss of the short arm or gain of the long arm was never seen. This will be discussed in further detail later.

Chromosome 17

Two tumours showed gains of the entire short arm together with regions from the long arm o f chromosome 17. One tumour showed gain o f the entire long arm, and another tumour showed gain of 17q22-qter. A single tumour, T 1145 showed loss of 17pl2 and 17q23-qter.

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Gain of the entire short arm o f chromosome 18 was seen in a single tumour T843, and loss of the entire short arm was seen in tumour T953. Gain of the long arm of chromosome 18 was never seen. Loss of the long arm was seen in five tumours.

Chromosome 19

Loss of the entire chromosome was seen in tumour T953. Five tumours showed gain of the entire chromosome, T1272, T1346, T1440, T1443, and T843, while tumour T1401 showed gain only of the short arm and T1093 showed gain only of the long arm.

Chromosome 20

Loss of the short arm was never seen. Loss of 20ql3.2-qter was seen in a single tumour, T1145. Tumours T1188 and T1275 showed gain o f the entire chromosome 20, tumour T843 showed gain of only the short arm while tumours T1093, T1401 and T1108 showed gain of the entire long arm.

Chromosome 21

Tumours T1081 and T981 showed loss of 21q22 and tumour T842 showed gain of the entire chromosome 21.

Chromosome 22

Tumour T1401 showed gain of 22ql3. Three tumours showed loss of the entire chromosome, tumour T1275 showed loss of 22ql 1.2-ql2 while two tumours, T953 and T1012 showed loss of 22ql3.

Chromosome X

Tumour T1443 showed loss of the entire chromosome, gains were not seen in any tumour.

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Gains of the long arm o f chromosome 1 and loss o f the long arm o f chromosome 16 were not only common changes but they occurred together in 21 tumours and were the only changes in 4 tumours, Figure 4-1. Fifteen tumours showing gain of the long arm of chromosome 1 and loss of the long arm of chromosome 16, had a normal 16p copy number, while the remaining six tumours had gain o f the short arm of chromosome 16. A further nine tumours showed gain of Iq without 16q loss, and seven tumours showed loss o f 16q and gain o f 16p with a normal chromosome 1 copy number. An unexpected association was seen between am plification o f the long arm o f chromosome 8 and the short arm of chromosome 16. Thirteen tumours showed gain of the long arm o f chromosome 8, six o f these tumours showed gain of the short arm o f chromosome 16 and in five o f these tumours it was not simply gain o f the arm but high level amplification. Furthermore, all six tumours which showed gain o f 8q and 16p also showed loss of 8p and 16q. Interestingly, only two tumours in our study showed loss o f 17q, and both o f these also had the pattern o f high level amplification of 8q and 16p and loss of 8p and 16q. Also, interestingly tumours which showed a large number of genetic changes (10-14) tended to have a normal Ip copy number and loss of 16q.