Table 1.
Effect of different functional subsets of p53 mutant alleles on severity of cancer risk
| (A) Alleles classified with respect to transactivation of all target genes | |||||
|---|---|---|---|---|---|
| Functional class
|
PD
|
SD
|
O-SD
|
||
| No. of p53 alleles
|
40* |
49
|
52
|
||
| Clinical classes | Families† | ||||
| Not available‡ | 2 (3.4) | 5 (4.2) | 1 (1.5) | ||
| noFH‡ | 8 (13.8) | 19 (16.0) | 9 (13.2) | ||
| FH§ | 18 (31.0) | 15 (12.6) | 9 (13.2) | ||
| LFL‡ | 17 (29.3) | 29 (24.4) | 20 (29.4) | ||
| LFS|| | 13 (22.4) | 51 (42.9) | 29 (42.6) | ||
| Total no. of families | 58 (100) | 119 (100) | 68 (100) | ||
| Clinical classes | Individuals† | ||||
|
| |||||
| Not available | 2 (1.2) | 5 (1.6) | 1 (0.4) | ||
| noFH | 8 (4.6) | 19 (6.2) | 9 (3.5) | ||
| FH | 31 (17.9) | 35 (11.4) | 19 (7.4) | ||
| LFL | 60 (34.7) | 80 (26.0) | 76 (29.6) | ||
| LFS | 72 (41.6) | 169 (54.9) | 152 (59.1) | ||
| Total no. of individuals | 173 (100) | 308 (100) | 257 (100) | ||
| Clinical classes | Tumors† | ||||
|
| |||||
| Not available | 4 (2.0) | 8 (1.9) | 1 (0.3) | ||
| noFH | 10 (5.1) | 33 (8.0) | 16 (5.1) | ||
| FH | 37 (18.6) | 41 (9.9) | 20 (6.3) | ||
| LFL | 70 (35.2) | 110 (26.5) | 89 (28.3) | ||
| LFS | 78 (39.2) | 223 (53.7) | 189 (60.0) | ||
| Total no. of tumors | 199 (100) | 415 (100) | 315 (100) | ||
| (B) Alleles classified with respect to transactivation of apoptotic genes only | |||||
|
| |||||
| Functional class | PD for apoptotic REs | SD for apoptotic REs | |||
|
| |||||
| No. of p53 alleles | 32 | 57 | |||
|
| |||||
| Clinical classes | Families¶ | ||||
|
| |||||
| Not available** | 2 (5.4) | 5 (3.6) | |||
| noFH** | 7 (18.9) | 20 (14.3) | |||
| FH†† | 13 (35.1) | 20 (14.3) | |||
| LFL** | 11 (29.7) | 35 (25.0) | |||
| LFS‡‡ | 4 (10.8) | 60 (42.9) | |||
| Total no. | 37 (100) | 140 (100) | |||
| Clinical classes | Individuals¶ | ||||
|
| |||||
| Not available | 2 (2.5) | 5 (1.3) | |||
| noFH | 7 (8.6) | 20 (5.0) | |||
| FH | 23 (28.4) | 43 (10.8) | |||
| LFL | 39 (48.1) | 101 (25.2) | |||
| LFS | 10 (12.3) | 231 (57.8) | |||
| Total no. | 81 (100) | 400 (100) | |||
| Clinical classes | Tumors¶ | ||||
|
| |||||
| Not available | 4 (4.1) | 8 (1.6) | |||
| noFH | 9 (9.2) | 34 (6.6) | |||
| FH | 27 (27.6) | 51 (9.9) | |||
| LFL | 47 (48.0) | 133 (25.8) | |||
| LFS | 11 (11.2) | 290 (56.2) | |||
| Total no. | 98 (100) | 516 (100) | |||
| (C) Risk of multiple tumors | |||||
|
| |||||
| Functional class (no.) | PD | SD | O-SD | PDa§§ | SDa§§ |
|
| |||||
| Families | 58 | 119 | 68 | 37 | 140 |
| Families in which at least one individual has multiple tumors|| || | 19 | 66 | 28 | 12 | 73 |
| Individuals | 173 | 308 | 257 | 81 | 400 |
| Individuals with multiple tumors¶¶ | 20 | 84 | 45 | 13 | 91 |
Of the 43 PD alleles, three were excluded because they were associated with only five rare tumors (N210Y, S227T) or seemed to predispose only to pediatric adrenocortical carcinomas (R337H).
Numbers (and percentages) of families, individuals, and tumors carrying germ line PD, SD, and O-SD p53 alleles. Rounding off may prevent percentages from summing exactly to a value of 1. Clinical class is a characteristic of families in that the class definition may depend in part on the number of affected family members and every affected individual in a family is assigned the same clinical class. Consequently, families are the appropriate units for statistical analyses of how the distribution of the clinical classes may depend on mutation functional class. We report P values only for analyses based on families, but display the distributions for individuals and for tumors for completeness.
Percentage of families in clinical classes NA, noFH, and LFL did not differ significantly among those carrying PD, SD, or O-SD alleles (all P ≥ 0.42).
A significantly higher percentage of FH families carried PD alleles than carried SD or O-SD alleles (P = 0.007 versus SD; P = 0.02 versus O-SD; Fisher’s exact test) but the percentage of FH families that carried SD and O-SD alleles did not differ significantly (P =1.0).
A significantly lower percentage of LFS families carried PD alleles than carried SD or O-SD alleles (P = 0.009 versus SD; P = 0.03 versus O-SD; Fisher’s exact test) but the percentage of LFS families that carried SD and O-SD alleles do not differ significantly (P = 1.0).
Numbers (and percentage) of families, individuals, and tumors carrying germ line PD and SD p53 alleles. Rounding off may result in percentages not summing precisely to a value of 1. Clinical class is a characteristic of families in that the class definition may depend in part on the number of affected family members and every affected individual in a family is assigned the same clinical class. Consequently, families are the appropriate units for statistical analysis of how the distribution of the clinical classes may depend on mutation functional class. We report P values only for analyses based on families, but display the distributions for individuals and for tumors for completeness.
Percentage of families in clinical classes NA, noFH, and LFL did not differ significantly between those carrying PD alleles for apoptotic REs and those carrying SD alleles for apoptotic REs (all P ≥ 0.61).
A significantly higher percentage of FH families carried PD alleles for apoptotic REs than carried SD alleles for apoptotic REs (P = 0.008).
A significantly lower percentage of LFS families carried PD alleles for apoptotic REs than carried SD alleles for apoptotic REs (P = 0.0003).
PD or SD alleles for apoptotic REs.
Families in which at least one individual had multiple tumors more commonly carried SD than PD alleles (P = 0.007) and more commonly carried SD alleles for apoptotic REs than PD alleles for apoptotic REs (P = 0.05; Fisher’s exact test). Comparisons between O-SD and either PD (P = 0.36) or SD (P = 0.07) were not statistically significant.
Individuals with multiple tumors more commonly carried SD than PD or O-SD alleles (P = 0.002 and 0.0004, respectively; within-cluster resampling test; ref. 24). The comparisons between PD and O-SD alleles (P = 0.89) and between SD alleles for apoptotic REs and PD alleles for apoptotic REs (P = 0.12) were not statistically significant.