PROTOCOLOS DE REDES DE INFORMACIÓN

CAPÍTULO 1. MARCO TEÓRICO

1.4 PROTOCOLOS DE REDES DE INFORMACIÓN

of age

100

90 =

6 0 -

Q-

5 0 -

^ < 3 years

^ > 3 years

30

20 Survival (months)

Figure 5.1 Association of survival with age. Patients aged 3 years or less survived significantly longer than those patients older than 3 years (Log- rank test, P = 0.0496)

available, three had LOH (0 - 0.5 ratio) and eleven had LOH/imbalance (0 - 0.75) at D9S170. Length of survival was not asociated with loss at this locus for either the 0 - 0.5 ratio (p=0.67 Log Rank Test) or the 0 - 0.75 ratio (p=0.82 Log Rank Test).

The LOH data was also analysed to assess whether there was a relationship between LOH and age <3 years versus age >3 years. With each marker there was no association with age at either the 0 - 0.5 ratio or the 0 - 0.75 ratio (see Table 5.2, page 153, for p values).

Chromosome lOq

Of twenty three patients for whom clinical follow up and LOH data was available, four had LOH at one or more loci (ratio 0 - 0.5) and ten had LOH/imbalance at one or more loci (ratio 0 - 0.75). LOH lOq was not associated with survival in this group of patients (p=0.69. Log Rank Test).

The association of survival and LOH at each marker locus was assessed individually. Of twenty one patients for whom data was available, two had LOH (0 - 0.5 ratio) and nine had LOH/imbalance (0 - 0.75) at D10S581. Length of survival was not asociated with loss at this locus for either the 0 - 0.5 ratio (p=0.64 Log Rank Test) or the 0 - 0.75 ratio (p=0.69 Log Rank Test). Of twenty one patients for whom data was available, two had LOH (0 - 0.5 ratio) and five had LOH/imbalance (0 - 0.75) at D10S540. Length of survival was not associated with loss at this locus for either the 0 - 0.5 ratio (p=0.63 Log Rank Test) or the 0 - 0.75 ratio (p=0.48 Log Rank Test).

Chromosome 12q

Of twenty three patients for whom clinical follow up and LOH data was available, eleven had LOH at one or more loci (ratio 0 - 0.5) and twenty two had LOH/imbalance at one or more loci (ratio 0 - 0.75). LOH 12q was not associated with survival in this group of patients (p=0.96, Log Rank Test).

The association of survival and LOH at each marker locus was assessed individually. Of twenty one patients for whom data was available, three had LOH ( 0 - 0 . 5 ratio) and eleven had LOH/imbalance (0 - 0.75) at D12S327. Length of survival was not asociated with loss at this locus for either the 0 - 0.5 ratio (p=0.35 Log Rank Test) or the 0 - 0.75 ratio (p=0.69 Log Rank Test). Of twenty two patients for whom data was available, one had LOH (0 - 0.5 ratio) and nine had LOH/imbalance (0 - 0.75) at D12S360. Length of survival was not asociated with loss at this locus for either the 0 - 0.5 ratio (p=0.59 Log Rank Test) or the 0 - 0.75 ratio (p=0.31 Log Rank Test). Of eleven patients for whom data was available, four had LOH (0 - 0.5 ratio) and six had LOH/imbalance (0 - 0.75) at D12S330. Length of survival was not asociated with loss at this locus for either the 0 - 0.5 ratio (p=0.53 Log Rank Test) or the 0 - 0.75 ratio (p=0.24 Log Rank Test). Of fourteen patients for whom data was available, four had LOH (0 - 0.5 ratio) and nine had LOH/imbalance (0 - 0.75) at D12S366. Length of survival was not asociated with loss at this locus for either the 0 - 0.5 ratio (p=0.44 Log Rank Test) or the 0 - 0.75 ratio (p=0.96 Log Rank Test). Of twenty three patients for whom data was available, three had LOH (0 - 0.5 ratio) and eleven had LOH/imbalance (0 - 0.75) at D12S342. Length of survival was not asociated with loss at this locus for either the 0 - 0.5 ratio (p=0.21 Log Rank Test) or the 0 - 0.75 ratio (p=0.48 Log Rank Test).

Chromosome 16q

Of twenty three patients for whom clinical follow up and LOH data was available, eleven had LOH at one or more loci (ratio 0-0.5) and eighteen had LOH/imbalance at one or more loci (ratio 0 - 0.75). LOH 16q was not associated with survival in this group of patients (p=0.13. Log Rank Test).

The association of survival and LOH at each marker locus was assessed individually. Of twenty one patients for whom data was available, three had LOH (0 - 0.5 ratio) and thirteen had LOH/imbalance (0 - 0.75) at D16S409. Length of survival was not asociated with loss at this locus for either the 0 - 0.5 ratio (p=0.12. Log Rank Test) or the 0 - 0.75 ratio (p=0.66 Log Rank Test). Of twenty one patients for whom data was available, two had LOH (0 - 0.5 ratio) and seven had LOH/imbalance (0 - 0.75) at D16S416. Length of survival was not asociated with loss at this locus for either the 0 - 0.5 ratio (p=0.58 Log Rank Test) or the 0 - 0.75 ratio (p=0.42 Log Rank Test). Of twenty three patients for whom data was available, five had LOH (0 - 0.5 ratio) and twelve had LOH/imbalance (0 - 0.75) at D16S512. Length of survival was not asociated with loss at this locus for the 0 - 0.5 ratio (p=0.54 Log Rank Test) but it was significantly associated with loss at the 0 - 0.75 ratio (p=0.01 Log Rank Test). Of twelve patients for whom data was available, three had LOH (0 - 0.5 ratio) and five had LOH/imbalance (0 - 0.75) at D16S516. Length of survival was not asociated with loss at this locus for either the 0 - 0,5 ratio (p=0.33 Log Rank Test) or the 0 - 0.75 ratio (p= 0.46 Log Rank Test). Figures 5.2 and 5.3 (pages 157 and 158 ) show summaries of the data for the chromosome 16q markers.

The LOH data was also analysed to assess whether there was a relationship between LOH and age <3 years versus age >3 years. With each marker there was no association with age at either the 0 - 0.5 ratio or the 0- 0.7 5 ratio (see Table 5.5 page 154, for p values).

Chromosome 17p

Of twenty three patients for whom clinical follow up and LOH data was available, all had LOH at one or more loci (ratio 0 - 0.5) and all had LOH/imbalance at one or more loci (ratio 0 - 0.75). As the extent of LOH seen is so frequent and so widespread a statistical analysis assessing association with overall survival not been performed.

Since many markers were used in the microsatelhte analysis of chromosome 17p, the association of LOH and LOH/allehc imbalance on survival was assessed at only four markers. These were the D17S720, D17S799, D17S798 and TP53 loci. Of twenty three patients for whom data was available, twelve had LOH ( 0 - 0 . 5 ratio) and seventeen had LOH/imbalance (0 - 0.75) at D17S720. Length of survival was not asociated with loss at this locus for either the 0 - 0.5 ratio (p=0.27 Log Rank Test) or the 0 - 0.75 ratio (p=0.35 Log Rank Test). Of twenty one patients for whom data was available, seven had LOH (0 - 0.5 ratio) and sixteen had LOH/imbalance (0 - 0.75) at D17S799. Length of survival was not asociated with loss at this locus for either the 0 - 0.5 ratio (p=0.31 Log Rank Test) or the 0 - 0.75 ratio (p=0.93 Log Rank Test). Of twenty three patients for whom data was available, eight had LOH (0 - 0.5 ratio) and fifteen had LOH/imbalance (0 - 0.75) at D17S798. Length of survival was not asociated with loss at this locus for either the 0 - 0.5 ratio (p=0.32 Log Rank Test) or the 0 - 0.75 ratio (p=0.78 Log Rank Test). Of eighteen patients for whom data was available, three had LOH (0 - 0.5 ratio) and five had

LOH/imbalance (0 - 0.75) at TP53. Length of survival was not asociated with loss at this locus for either the 0 - 0.5 ratio (p=0.97 Log Rank Test) or the 0 - 0.75 ratio (p= 0.59 Log Rank Test).

Chromosome 22q

Of twenty three patients for whom clinical follow up and LOH data was available, all had LOH at one or more loci (ratio 0 - 0.5) and all had LOH/imbalance at one or more loci (ratio 0 - 0.75). LOH 22q was not associated with survival in this group of patients (p=0.91. Log Rank Test).

The association of survival and LOH at each marker locus was assessed individually. Of twenty one patients for whom data was available, seven had LOH (0 - 0.5 ratio) and eleven had LOH/imbalance (0 - 0.75) at F8VWFP. Length of survival was not asociated with loss at this locus for either the 0 - 0.5 ratio (p=0.37 Log Rank Test) or the 0 - 0.75 ratio (p=0.59 Log Rank Test). Of twenty one patients for whom data was available, two had LOH (0 - 0.5 ratio) and eight had LOH/imbalance (0 - 0.75) at D22S301. Length of survival was not asociated with loss at this locus for either the 0 - 0.5 ratio (p=0.41 Log Rank Test) or the 0 - 0.75 ratio (p=0.45 Log Rank Test). Of eighteen patients for whom data was available, two had LOH (0 - 0.5 ratio) and nine had LOH/imbalance (0 - 0.75) at D22S294. Length of survival was not asociated with loss at this locus for either the 0 - 0.5 ratio (p=0.16 Log Rank Test) or the 0 - 0.75 ratio (p=0.28 Log Rank Test).

The LOH data was also analysed to assess whether there was a relationship between LOH and age <3 years versus age >3 years. With 2 markers there was no association with age at either the 0 - 0.5 ratio or the 0 - 0.75 ratio (see Tables 5.7, page 155 for p values), but with D22S301 there was an association between >3 years of age and a lower frequency of LOH (p=0.03 Log Rank Test).

MIN and survival

Only two out of the twenty seven tumours analysed showed MIN. Each of these tumours, IN2659 and IN2697 showed changes in electophoretic mobility, or band shifts, at two independent loci on chromosome 17p. A log rank test was performed and the presence of MIN was not associated with length of survival.

Correlation of length of survival with losses and gains determined hy CGH

There was clinical follow up on thirteen of the fifteen patients whose tumours were analysed by CGH. The most frequent CNAs in this study were loss on 9q, lOq, 12q, 16q, 17p and 22 and gain on 4q, 5q, 6q and 9p. With the exception of loss on 16q, there was no correlation between presence of any of these CNAs and length of survival. However, patients whose tumours had loss of 16q survived significantly longer than those with no loss (p=0.01). This is shown in Figure 5.4, page 159, along with a summary of the microsatellite analysis 16q v survival data for comparative purposes.

Table 5.2. p values denoting the association between LOH at each chromosome 9 marker and age. With each marker there was no association with age at either the 0 - 0.5 ratio or the 0 -0 .7 5 ratio

Markers Association with LO H

(0-0.5 ratio) Association with LO H (0-0.75 ratio) D9S166 p = 0.66 p = 0.18 D9S287 p = 1.00 p = 0.65 D9S170 p = 0.60 p = 1.00

Table 5.3. p values denoting the association between LOH at each chromosome 10 marker and age. With each marker there was no association with age at either the 0 - 0 . 5 ratio or the 0 - 0.75 ratio. D10S580 was not assessed as the patient number was too small.

Markers Association with LOH

(0-0.5 ratio)

Association with LOH (0-0.75 ratio)

D10S581 p = 1.00 p = 0.67

Table 5.4. p values denoting the association between LOH at each chromosome 12

marker and age. With each marker there was no association with age at either the 0 - 0 . 5 ratio or the 0 - 0 . 7 5 ratio.

Markers Association with LO H

(0-0.5 ratio) Association with LO H (0-0.75 ratio) D12S327 p = 0.52 p = 0.38 D12S360 p = 1.00 p = 0.65 D12S330 p = 1.00 p = 1.00 D12S342 p = 0.54 p = 0.68 D12S366 p = 1.00 p = 1.00

Table 5 .5 . p values denoting the association between LOH at each chromosome 16 marker and age. With each marker there was no association with age at either the 0 - 0 . 5 ratio or the 0 - 0.75 ratio.

Markers Association with LO H

(0-0.5 ratio) Association with L O H (0-0.75 ratio) D16S409 p = 1.00 p = 1.00 D16S416 p = 1.00 p = 0.35 D16S512 p = 1.00 p = 0.40 D16S516 p = 1.00 p = 1.00

Table 5.6. p values denoting the association between LOH at each chromosome 17 marker and age. With each marker there was no association with age at either the 0 - 0 . 5 ratio or the 0 - 0.75 ratio.

Markers Association with LOH

(0-0.5 ratio)

Association with LOH (0-0.75 ratio)

D17S720 p = 0.11 p = 1.00

D17S799 p = 0.17 p = 1.00

D17S798 p = 1.00 p = 0.66

TP53 p = 1.00 p = 0.60

Table 5.7. p values denoting the association between LOH at each chromosome 22 marker and age. With two markers there was no association with age at either the 0 - 0 . 5 ratio or the 0 - 0.75 ratio. However, at the D22S301 locus LOH was significantly associated with age.

Markers Association with LOH

(0-0.5 ratio)

Association with LOH (0-0.75 ratio)

F8VWFP p = 0.12 p = 0.24

D22S301 p = 0.15 p = 0.03

Table 5.8 p values denoting the association between consistent losses by CGH and age (Fisher’s exact test). There was no association between any chromosomal loss and age.

CG H loss p value 17p 1.00 lOp 0.61 9p 0.14 12q 1.00 16q 0.61 22 0.64

Table 5.9 p values denoting the association between consistent gains by CGH and age (Fisher’s exact test). There was no association between any chromosomal gain and age.

CG H gain p value

4 1.00

5 0.24

6 0.33

A 1UU- 9 0 8 0 ■ 7 0 - 6 0 - & 5 0 - s 4 0 - 3 0 - 2 0 - 1 0 - Loss of D16S409 ■D16S409 Yes (a) ■D16S409 No (a) 0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 1 0 0 Survival (months) B 1 0 0 9 0 8 0 I 7 0 c 6 0 s. 5 0 o 4 0 5S 3 0 2 0 10 0 Loss of D16S409 ■D16S409 Yes (b) -D16S409 No (b) 0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 1 0 0 Survival (months)

Loss ofD16S416 Loss ofD16S416

1 0 0 9 0 £ 8 07 0 1 6 0 Q . 5 0 • 5 4 0 3 0 2 0 1 0 ° 0 ■D16S416 Yes (a) -D16S416 No (a) 10 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 1 0 0 Survival (months) —L-D 16S416 Y es(b) D16S416 No (b) 0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 1 0 0 Survival (months)

Figure 5.2 Association between LOH 16q and survival. Loss of D16S409, at a ratio of 0 - 0.5 is shown in panel A and a ratio of 0 - 0.75 is shown in panel B. Loss of D16S416, at a ratio of 0 - 0.5 is shown in panel C and a ratio of 0 - 0.75 is shown in panel D. There appeared to be no association between loss of these markers and survival at either ratio (Log-rank test, p = 0.22. 0.54. 0.29 and 0.67 respectively)

Loss ofD16S512 B Loss of D16S512

—^ 0 1 6 8 5 1 2 Yes (a) - ^ 0 1 6 3 5 1 2 No (a) 0 10 2 0 30 4 0 50 6 0 7 0 80 90 100 Survival (months) 100 c 70 B 60 S. 50 O _{—<— 0163512 Yes (b)} —‘— 0163512 No(b) Survival (months) 100 90 80 70 - 60 50 40 30 20 10 0, Loss of D16S516 -0 1 6 3 5 1 6 Yes (a) ■0163516 No (a) 10 2 0 30 4 0 50 6 0 70 80 9 0 100 Survival (months) D Loss of D16S516 —‘— 0163516 Yes (b) - ^ 0 1 6 3 5 1 6 No (b) 10 2 0 30 4 0 50 6 0 70 8 0 9 0 100 Survival (months)

Figure 5.3 Association between LOH 16q and survival. Loss of D16S512, at a ratio of 0 - 0.5 is shown in panel A and a ratio of 0 - 0.75 is shown in panel B. Loss of D16S516, at a ratio of 0 - 0.5 is shown in panel C and a ratio of 0 - 0.75 is shown in panel D. There appeared to be no association between loss of D16S512 and survival at a ratio of 0 - 0.5 (Log-rank test, p = 0.54 although at a ratio of 0 - 0.7 there was a significant association between loss of this marker and survival (p = 0.01). There was no significant

association between loss of D16S516 and survival at either ratio (p = 0.47 and 0.8).

16q loss by CGH

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