Supplementary Data for Monti, et al.

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1 Supplementary Data for Monti, et al. Supplementary Figure S1 Legend to Supplementary Figure S1 Tumor spectrum associated with germline p53 alleles (restricted to the 7 most frequent tissue targets). Structural regions within the DNA binding domain are indicated based on a previously adopted classification (20): N-ter for N-terminus and C-ter for C-terminus containing the tetramerization domain (tet). The distribution of PD and SD missense mutant alleles in the structural groups is reported. PD and SD alleles are distributed in all structural regions of the DNA binding domains with somewhat different frequencies. 1

2 Supplementary Table S1A: Summary of available data retrieved from IARC database for SD alleles. Codon WT Mutant functional N. Families Individuals tumors n of generations ALL NA nofh FH LFL LFS 132 Lys Glu Met Arg ;2 138 Ala Pro Cys Tyr ;3 151 Pro Ser Pro Thr n.a. 152 Pro Leu ;2;3;3;5;4 154 Gly Val Thr Asn Arg Gly Ile Asn Tyr Cys Arg Gly Arg His ;3;3;4;3;4;2;2 ;3;3;4;1;3;na 193 His Arg ) 197 Val Glu ) 213 Arg Gln Tyr Cys ;3;2 220 Tyr Ser Tyr Cys ;2 236 Tyr Cys Met Ile Cys Ser Ser Phe Ser Thr Cys Tyr ;1;4 245 Gly Asp Gly Cys Gly Val Arg Gln ;2;3;na;1;2;2; 2;2;2;2;2 248 Arg Trp ;2;3;2;3;3;3;2 ;2;2 257 Leu Gln Glu Lys Leu Pro Arg Cys ;2;3;3;3;2;2;2 273 Arg Gly Arg His ;2;1;1;1;4;2;1 ;3;3;2 273 Arg Leu Cys Tyr ;5 277 Cys Tyr Pro Leu Pro Ser Arg Lys Asp Val Arg Trp ;2;3;2;3;2;2 283 Arg His Glu Ala Lys Met Leu Pro ;1 Total Notes 2

3 Supplementary Table S1B: Summary of available data retrieved from IARC database for PD alleles. Codon WT Mutant functional N. Families Individuals tumors n of generations ALL NA nofh FH LFL LFS 82 Pro Leu Val Ile ) 105 Gly Cys Ser Arg Met Thr ;3;4 138 Ala Ser Gln Leu ) 156 Arg His Arg His ;3;5 167 Gln Lys Arg Gly Glu Lys Arg Cys Arg His Arg Leu ) 189 Ala Val Arg Pro Pro Ser His Asp ) 235 Asn Asp Asn Ser ;1;4 238 Cys Tyr Gly Ser ;3;2;3;3;2;2;1 ;3;3 246 Met Val Ile Met Thr Ile Arg Gln ;3 271 Glu Val Val Leu Arg Ser ) 282 Arg Gln Glu Gln Arg His Lys Ile Gly Trp Arg Pro Gly Val ) 337 Arg Cys ;2;3 365 His Tyr na 3) 366 Ser Ala ) Total Notes Legend to Supplementary Tables S1A and S1B. The dataset was limited to the seven most frequent tumor types: soft tissue sarcomas and osteosarcomas, breast cancer, brain tumors, haematopoietic tumors (leukaemia + lymphoma), adrenocortical carcinoma and bronchus/lung cancer. These account for ~72% of the reported cases. The remaining data were highly heterogeneous with very few observed cases in more than 20 different tumor types examined. This restriction on tissue targets excluded two partial function p53 3

4 alleles (N210Y, S227T) from consideration as they are associated with only 5 rare tumors. We have also excluded from the analyses individuals with inherited R337H, a unique PD p53 allele rather frequent in the Brazilian population, that appears to predispose only to paediatric adrenocortical carcinomas. The tables present the families with a given allele, the clinical classification (NA, nofh, FH, LFL, LFS), the individuals studied and reported in the IARC database, the total N of tumors with SD (Table 1A) and PD (Table 1B) alleles and the number of generations reported in the IARC database. When multiple families had the same mutant allele, we reported the n of generations for each family ordered by clinical classification (NA, nofh, FH, LFK, LFS) and, within each clinical classification, by family ID 1 ). In some cases information was not available (na). Notes: 1) data is limited to only one individual of a clinically defined cancer prone family because family members were not available for molecular testing. 2) at least two individuals and two generations were studied, but only 1 individual and 1 tumor are considered in our analyses because of the described restriction on tissue types. 3) de novo germline mutation (or suspected de novo mutation). Families #194 and #64 1 show multiple p53 mutations; the former was excluded from the analysis since functional classification was impossible, while the latter is a SD allele and was included, but duplicated entries were removed. A summary functional for each of the tested alleles on 8 REs (or 3 REs) is indicated: a value of 8 (or 3) indicates that a mutant allele exhibited >25% of wild type p53 activity toward every RE. We defined as SD a mutant exhibiting <25% of wild-type activity towards all 8 REs. PD alleles are mutants that showed >25% of wild type activity toward at least one reporter (see Materials and Methods). 1 see 4

5 Supplementary Table S2A. Summary of functional subgroups of PD alleles based on. Score n Alleles n Families n Individuals n Tumors > Numbers of families, individuals, and tumors carrying germline PD alleles with a specific functional (see legend to supplementary Tables 1A and B for definition). Supplementary Table S2B: Impact of different functional subgroups of p53 mutant alleles on severity of cancer risk. Distribution of clinical classes. PD* PD =1 PD >2RE PD=8 SD* Functional Class: >1 1 >2 8 0 p53 alleles Clinical Classes Families n % n % n % n % n % Not Available 2 3,4% 0 0,0% 2 5,4% 1 6,3% 5 4,2% nofh 8 13,8% 3 14,3% 5 13,5% 2 12,5% 19 16,0% FH 18 31,0% 5 23,8% 13 35,1% 8 50,0% 15 12,6% LFL 17 29,3% 6 28,6% 11 29,7% 3 18,8% 29 24,4% LFS 13 22,4% 7 33,3% 6 16,2% 2 12,5% 51 42,9% Total N families ,0% ,0% ,0% ,0% ,0% * the data from Table 1A are reported here for comparison A significantly lower percentage of FH families carried SD alleles than carried PD alleles of higher functionality (PD* vs SD: p=0.0067; PD>2 vs SD: p=0.0032; PD=8 vs SD: p=0.0012; Fisher s exact test). The percentage of FH families that carried SD and PD=1 alleles did not differ significantly. A significantly higher percentage of LFS families carried SD alleles than carried PD alleles of higher functionality (PD* vs SD: p=0.008; PD>2 vs SD: p=0.0033; PD=8 vs SD: p=0.0272; 5

6 Fisher s exact test). The percentage of LFS families that carried SD and PD=1 alleles did not differ significantly. Supplementary Table S2C. Impact of different functional grouping of p53 mutant alleles on severity of cancer risk. Multiple tumors. Functional Class: PD* PD=1 PD>2 PD=8 SD* Number of: n % n % n % n % n % Families Families where at least one individual has 19 33% 6 29% 13 35% 4 25% 66 55% multiple tumors * the data from Table 1A are reported here for comparison Families where at least one individual had multiple tumors more commonly carried SD than PD alleles (PD* vs SD: p=0.0062; PD=1 vs SD: p= ; PD>2 vs SD: p= ; PD=8 vs SD: p=0.0316; Fisher s exact test). 6

7 Supplementary Table S3: Germline p53 functionality and occurrence of multiple tumors (restricted to confirmed carriers). Functional Class: PD SD O-SD PD for REs SD for REs Number of: Alleles Tumors Families Families where at least one individual has multiple tumors Individuals Individuals with multiple tumors Families where at least one individual had multiple tumors more commonly carried SD than PD alleles (p=0.002) and more commonly carried SD alleles for REs than PD alleles for REs (p=0.04) (Fisher s exact test). Comparisons between O-SD and either PD (p=0.18) or SD (p=0.12) were not statistically significant. 2 Individuals with multiple tumors more commonly carried SD than PD or O-SD alleles (p= and 0.02, respectively) and more commonly carried SD alleles for REs than PD alleles for REs (p=0.03) [Within-Cluster Resampling test (24)]. The comparison between PD and O- SD alleles (p=0.25). was not statistically significant. 7

11 questions for a total of 120 points

Your Name: BYS 201, Final Exam, May 3, 2010 11 questions for a total of 120 points 1. 25 points Take a close look at these tables of amino acids. Some of them are hydrophilic, some hydrophobic, some positive