Breast Cancer Res Treat DOI 10.1007/s10549-007-9608-6
EPIDEMIOLOGY
Germline TP53 mutations in BRCA1 and BRCA2 mutationnegative French Canadian breast cancer families Suzanna L. Arcand Æ Christine M. Maugard Æ Parviz Ghadirian Æ Andre´ Robidoux Æ Chantal Perret Æ Phil Zhang Æ Eve Fafard Æ Anne-Marie Mes-Masson Æ William D. Foulkes Æ Diane Provencher Æ Steven A. Narod Æ Patricia N. Tonin
Received: 20 April 2007 / Accepted: 23 April 2007 Springer Science+Business Media B.V. 2007
Abstract About 40% of French Canadian breast and/or ovarian cancer families harbor germline BRCA1 or BRCA1 mutations where common mutations account for about 84% of all mutations identified in cancer families. Within a series of BRCA1 and BRCA2 mutation-negative families, a germline TP53 13398 G>A (Arg213Gln) mutation was identified, which was selected for mutation analysis in this gene because of a family history consistent with Li–Fraumeni syndrome (LFS). Given the founder effects in this population, the 13398 G>A mutation was screened in series of 52 BRCA1 and BRCA2 mutationnegative cancer families, and a mutation-positive family was identified. However, pedigree inspection and
expansion of mutation-positive families with the same mutation revealed that they were closely related to each other. To further characterize the contribution of TP53 in cancer families, mutation analysis was performed in the remaining BRCA1 and BRCA2 mutation-negative cancer families. Thirty sequence variants were identified, the majority of which occur in intronic sequences and are not predicted to affect the functionality of TP53. However, the 14538 G>A (Arg290His) mutation was identified in a family which did not exhibit features consistent with LFS or Li–Fraumeni-like (LFL) syndrome. Neither of the TP53 mutations was detected in 381 French Canadian women with breast cancer diagnosed before 50 years of age not
S. L. Arcand W. D. Foulkes D. Provencher P. N. Tonin The Research Institute of the McGill University Health Centre, Montreal, QC, Canada
P. Zhang S. A. Narod Women’s College Research Institute, Women’s College Hospital and University of Toronto, Toronto, ON, Canada
C. M. Maugard Service de Me´decine Ge´nique, Centre Hospitalier de l’Universite´ de Montre´al (CHUM), Montreal, QC, Canada C. M. Maugard A.-M. Mes-Masson De´partement de me´decine, Universite´ de Montre´al, Montreal, QC, Canada P. Ghadirian E. Fafard Epidemiology Research Unit, Research Centre, CHUM—HoˆtelDieu, Montreal, QC, Canada A. Robidoux Department of Surgery, CHUM—Hoˆtel-Dieu, Montreal, QC, Canada C. Perret A.-M. Mes-Masson D. Provencher Centre de Recherche du Centre Hospitalier de l’Universite´ de Montre´al/Institut du Cancer de Montre´al, Hoˆpital Notre-Dame, Montreal, QC, Canada
W. D. Foulkes P. N. Tonin Program in Cancer Genetics, Departments of Oncology and Human Genetics, McGill University, Montreal, QC, Canada W. D. Foulkes Department of Medical Genetics, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, QC, Canada W. D. Foulkes P. N. Tonin Departments of Medicine and Human Genetics, McGill University, Montreal, QC, Canada D. Provencher De´partement d’obste´trique gyne´cologie, Division de gyne´cologie oncologique, Universite´ de Montre´al, Montreal, QC, Canada P. N. Tonin (&) Medical Genetics, Montreal General Hospital, Room L10-120, Montreal, QC, Canada H3G 1A4 e-mail:
[email protected]
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selected for family history of cancer. In all, germline TP53 mutations were identified in two of 52 (3.8%) cancer families, suggesting that TP53 is not a major contributor to BRCA1 and BRCA2 mutation-negative breast and/or ovarian cancer families of French Canadian descent. Keywords TP53 BRCA1 BRCA2 Breast cancer French Canadian Founder effects
Introduction Approximately 40% of French Canadian families from the Province of Quebec containing at least three cases of female breast cancer (diagnosed A mutations identified in the French Canadian breast cancer families. Genomic DNA was extracted from peripheral lymphocytes. Mutation analysis was performed using the tetra-primer Amplification Refractory Mutation System (ARMS) PCR method as described previously [33].
Results Frequency of TP53:13398 G>A mutation
TP53 mutation analyses DNA was extracted from peripheral blood lymphocytes. Polymerase chain reaction (PCR) was used to amplify the domain regions and flanking splice sites of exons 2–11 of TP53, using primer sets and conditions described in Table 2. PCR was performed in a 25 ll volume containing 200 ng of genomic DNA; 1· PCR buffer (Invitrogen, Burlington, Canada); 5 nmol each dCTP, dGTP, dTTP, and dATP; 1.5 mM MgCl2; 15 pmol of each primer; and 1 U of Taq polymerase (Invitrogen). The PCR conditions were 3 min at 95C, 35 cycles of 94C for 30 s, appropriate annealing temperature (Table 2) for 30 s
The TP53:13398 G>A mutation (Table 3) was initially identified in a women diagnosed with breast cancer at age 41 from Family 1444. This individual was tested for mutations in TP53 because of close relatives with very young age of diagnoses of brain tumors and an adrenal cortical carcinoma, which are features consistent with LFS (Fig. 1). The index case was previously tested and found negative for BRCA1 and BRCA2 mutations as part of a study of French Canadian HBC families [3]. Notable are the six breast cancer cases in first- and second-degree relatives of the index case, which include four cases diagnosed at A mutation was determined by screening HBC and HBOC families previously tested negative for BRCA1 and BRCA2 mutations (Table 1). The analysis of index cases of 52 families identified only one carrier of this mutation. The mutation carrier, identified in Family 1039 (Fig. 1), was diagnosed with bilateral breast cancer at age 38. DNA was not available from other cases in this family and thus the carrier status of other individuals in this family is not known. Notable is that the features of this family are not consistent with those found in either LFS or LFL families. The 13398 G>A mutation was not detected in 381 French Canadian women diagnosed with breast cancer before the age of 50 years not selected for family history of cancer. Mutation analysis of TP53 The identification of germline TP53 mutation in HBC family prompted a mutation analysis of the domain regions and splice sites of this gene in the remaining HBC and HBOC families tested negative for BRCA1 and BRCA2 mutations (Table 1). This mutation analysis identified 30 sequence variants (Table 3). The majority of variants occur within intronic sequences, are predicted to have no effect on the functionality of TP53, and have been classified as polymorphisms in the IARC TP53 Mutation Database (www-p53.iarc.fr) and/or the Single Nucleotide Polymorphism (SNP) Database (www.ncbi.nlm.nih.gov/projects/ SNP/). Although the genotype and allele frequencies of these variants in the French Canadian population are not known, those exhibited by the index cases are comparable
123
F: 5¢-tgcttgccacaggtctccc-3¢ R: 5¢-tatggaagaaatcggtaagag-3¢
F: 5¢-ttgatttgaattcccgttg-3¢
55
R: 5¢-aacccttaactgcaagaaca-3¢
to frequencies reported in the SNP Database and/or the Cancer Genome Anatomy Project SNP500Cancer Database (snp500cancer.nci.nih.gov) (Table 3). Of the four variants predicted to affect the encoded product due to a missense mutation, only the 14538 G>A sequence variation resulting in the Arg290His amino acid substitution has previously been classified as a mutation in the IARC TP53 Database. This mutation was identified in an index case diagnosed with breast cancer at age 44 years in Family 875 (Fig. 1). Although there were multiple cases of cancer reported in this family, the features are not consistent with those seen in LFS or LFL families. Notable is that this mutation was not detected in a maternal aunt diagnosed with breast cancer at age 61 and colon cancer at age 81. DNA was not available from other family members and thus the carrier status of the other cancer cases in this family is not known. The 14538 G>A mutation was also not detected in 381 French Canadian women diagnosed with breast before the age of 50 years not selected for family history of cancer.
Discussion Germline mutations in TP53 were identified in two of 52 (3.8%) BRCA1 and BRCA2 mutation-negative families of French Canadian descent. The frequency of mutation-positive families identified in our study is consistent with independent reports suggesting that germline TP53 mutations are rare in multiple case breast cancer families, possibly accounting for C
Polymorphism IVS4+101 A>T
Polymorphism IVS4– 67 G>C
Mutation
14181 14201 14538 14766
Polymorphism IVS7+72 C>T
Polymorphism IVS7+92 T>G
Ex8–51 G>A
Mutation
Polymorphism IVS9+12 T>C
17536 17699 17708
Polymorphism IVS10+21 A>C
Polymorphism IVS10+30 A>T
17480
Polymorphism IVS9–92 T>A
Polymorphism IVS9–36 A>T
17479
Polymorphism IVS9–93 A>T
17466
14168
Polymorphism IVS7+59 G>T
IVS9–106 G>C
13964
Polymorphism IVS6–36 G>C
17465
13494
Polymorphism IVS6+62 G>A
1VS9–107 C>G
13399 13477
Polymorphism Ex6–34 A>G IVS6+45 G>A
Ex6–35 G>A
11992
Polymorphism Ex4+12 G>A
11827
Polymorphism IVS2+37 G>C
Polymorphism IV3–29 C>A
11654
Polymorphism IVS1–35 C>T 11875
11621
Polymorphism IVS1– 68 C>T
11951
11616
IVS1–73 C>T
Polymorphism IVS3+24 insACCTGG AGGGCTGGGG
11615
Polymorphism IVSI–74 C>G
Polymorphism IVS2–31 insC
11577
Polymorphism IVS1– 112 G>A
–
–
–
–
–
–
–
Codon change
A>T
A>C
A>T
T>A
A>T
G>C
C>G
T>C
G>A
T>G
C>T
G>T
G>C
G>A
A>G G>A
G>A
G>C
A>T
G>C
G>A
C>A
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
CGC>CAC 290
–
–
–
–
–
CGA>CGG 213 – –
CGA>CAA 213
–
–
CGC>CCC 72
–
–
–
–
–
–
–
–
Arg>His
–
–
–
–
–
Arg>Arg –
Arg>Gln
–
–
Arg>Pro
Pro>Pro
–
–
–
–
–
–
–
–
–
Codon Amino acid change
CCG>CCA 36
–
insACCTGGA – GGGCTGGGG
insC
G>C
C>T
C>T
C>T
C>G
G>A
Nucleotideb Base change
Classificationa Genomic location and variant
Table 3 TP53 sequence variations identified in French Canadian HBC and HBOC cancer families
Intronic
Intronic
Intronic
Intronic
Intronic
Intronic
Intronic
Intronic
Missense
Intronic
Intronic
Intronic
Intronic
Intronic
Silent Intronic
Missense
Intronic
Intronic
45
0
22
0
0
0
0
rs1800370
33
47 48
51
0
0
0
50
0
0
0
0
0
0
47
rs17880847 47
rs2856755
rs2856754
rs2543550
rs2856921
rs1800899
rs12951053 41
rs12947788 41
rs1642786
rs17880604 46
rs1625895
rs1800372
rs2856920
rs1794286
26
46
rs17883323 45
rs17878362 36
rs2307496
rs1642785
rs2543548
rs2543547
rs2543546
rs8079544
1
0
0
0
0
0
0
2
1
7
7
0
2
15
2 1
1
0
0
23
2
2
15
0
23
0
0
0
0
2
0
96
96
96
96
96
96
0
0
0
0
96
0
1
0 0
0
96
96
3
0
1
1
96
3
96
96
96
96
1
4
95
0
0
0
0
0
0
96
98.0 2.0 99.0 1.0
7 7
92.7 7.3
1
102 98
96
100.0 96
100.0 96
100.0 96
100.0 96
100.0 96
99.0 1.0
96 0.0
96 0.0
96 0.0
96 0.0
96 0.0
96 96
100.0 96
98.0 2.0
99.0 1.0
92.7 7.3
96 0.0
2
96
98 100.0 96
97.9 2.1 96 0.0
2
98 98
104
100.0 96
17 82.7 17.3
2 1
104
96
96
100.0 96 99.0 1.0
96 0.0
96 0.0
101 1
89
89
0
94
81
96 97
97.9 2.1
95.8 4.2 29 72.1 27.9
2
4
104
100.0 96
17 83.7 16.3
96 0.0
96
100.0 96
100.0 96
100.0 96
29 69.8 30.2
96 0.0
96 0.0
96 0.0
96
–
+
+
+
–
–
–
–
–
+
+
+
+
+
+ –
–
–
+
+
+
+
–
+
+
+
+
–
+
+
CHR Known allele no. frequenciesa
100.0 96
95.8 4.2
96 0.0
103 1
0
0
75
94
92
87
0
67
0
0
0
0
92
SNP Genotypes Allele frequency designationa AA AB BB A B A% B%
Missense rs1042522
Silent
Intronic
Intronic
Intronic
Intronic
Intronic
Intronic
Intronic
Intronic
Intronic
Effect
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Nucleotide position based on X54156
Fig. 1 Pedigrees of TP53 mutation-positive families. Cancer type or site [adrenocorticol carcinoma (ACC), bladder (Bla), brain (Bt), breast (Br), cervical (Cx), colon (Co), kidney (Ki), liver (Li), lung (Lu) pancreatic (Pan), skin (Sk)] and age of diagnosis are shown or age of death (d) along with TP53 mutation carrier status. The index case initially tested for TP53 mutation is shown with an arrow
b
a Classification, SNP designation, and allele frequencies are based on information from the IARC TP53 Mutation database (www-p53.iarc.fr), the Single Nucleotide Polymorphism Database (www.ncbi.nlm.nih.gov/projects/SNP/) and the Cancer Genome Anatomy Project SNP500Cancer Database (snp500cancer.nci.nih.gov). Allele frequencies were compared with those reported for European (Caucausian) populations when possible
+ 0 96 0.0 100.0 96 96 0 0 rs1042526 Noncoding [3¢ UTR] – – – 18717 Polymorphism Exl1+119 T>A
123
T>A
Nucleotideb Base change Classificationa Genomic location and variant
Table 3 continued
Codon change
Codon Amino acid change
Effect
SNP Genotypes Allele frequency designationa AA AB BB A B A% B%
CHR no.
Known allele frequenciesa
Breast Cancer Res Treat
identification of two 13398 G>A mutation-positive families is not attributable to recurrent mutations in this founder population as subsequent pedigree expansion revealed that the index cases of the two independently ascertained families are cousins (Fig. 1). The 13398 G>A (Arg213Gln) and 14538 G>A (Arg290His) mutations are both missense mutations and would affect the amino acid composition of the non-DNA-binding loops in the beta-sheet scaffold of the p53 DNA binding domain (www-p53.iarc.fr). Both mutations have been reported in the IARC TP53 Mutation Database occurring as both somatic and germline events. However, based on various prediction tools for amino acid substitutions, the IARC TP53 Mutation Database has classified the 13398 G>A nucleotide substitution as a deleterious mutation and the 14538 G>A nucleotide substitution as a neutral change. Notable is that the 13398 G>A mutation appears to segregate with affected cases in Family 1444 which contained features consistent with LFS, such as the pediatric cases of adrenocortical carcinoma and brain tumors occurring in first- and second-degree relatives of the index case (Fig. 1). The mutated allele was maternally transmitted, and it was through pedigree expansion of this maternal branch of the family that the index case was linked to another who carried of the same mutation, but was ascertained independently from Family 1039 (Fig. 1). The number and age range of the breast cancer cases with diagnosis before age 55 years in Family 1444 overlap familial cases of breast cancer found to harbor either BRCA1 and BRCA2 germline mutations ascertained from the French Canadian population of Quebec [1–3]. However, the mother of the index case was diagnosed with basal cell carcinoma at age 66 years, followed by diagnoses of breast and pancreatic cancers at age 69. The late age of diagnosis of cancers in this mutation carrier is interesting in light of younger ages of diagnoses of cancer and severity of disease in her children and grandchildren. Her sister was also diagnosed with similar late age of onset cancers, a breast cancer at age 74 and a pancreatic carcinoma at age 75. The two other sisters who were both diagnosed with breast cancer at age 53 years. Recently, it was suggested that the 13398 G>A mutation confers susceptibility to late age of onset cancers by the genetic analysis of a large kindred with multiple and varied adult onset cancers [38]. However, in Family 1444, the family history of cancer, carrier status of tested cases, and probable cases of pediatric cancers in two other branches of the family, would imply that this mutant allele
Breast Cancer Res Treat Family 1444 I 1 d. 56
2 d. 66
II 14 Sk 66 Br 69 Pan 69
13
-
3
4 Br 53 Li 76 d. 76
8 Br 74 Pan 75 d. 76
11
12 Br 53 d. 56
15
5
6
9 d. 45
10
+
III
4 25 Br 43 d. 45
24
28
27 Br 41
-
26
16 BiBr 38
19 ACC ?
18
17
20
21
22
23 Bt 1 d. 1
+
IV 29 Bt 12
30
33 ACC 9
32
31 Bt 6 d. 9
+
Family 1039 I 1
2
II 4 Br 53
3 Lu Leu
5 Br 53
6
3
6
7
3
III 8 Cx 49
9
10 BiBr 38
11
12
+ Family 875 I 1 d. 85
2 Br 68 d. 75
II
2 9
10
3 Br 61 Co 81 d. 83
4 d. 28
5 Br 62
8 Bla 65 Psu 73 d. 74
11 d. 11
12 Pan 74 d. 74
13 Lu 65 Pan 68 d. 69
14 Kd 66 d. 66
15
16
6
7
III 21 Bla 33 d. 38
20 Br 44
19
+
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is highly penetrant warranting clinical surveillance for family members. The significance of 14538 G>A mutation is less certain. Family 875 does not exhibit features consistent with LFS or LFL (Fig. 1). Interestingly, Canada was reported as the country of origin for the two 14538 G>A mutation-positive families noted in the IARC TP53 Mutation Database. Based on the reference citation in the database, both mutation-positive families were initially described by Quesnel et al. [39]. A review of the reported pedigrees [39], shows that the 14538 G>A mutation carrier probands are associated with an LFS and LFL families. The proband in the LFS family was diagnosed with a soft tissue sarcoma at age two and then a brain tumor at age 10. However, one of these probands also carried two other TP53 variants, which affected codons 156 (CGC>CAC, Arg156His) and 267 (CGG>CAG, Arg267Gln). Genotyping analysis indicated that the index case inherited the compound mutation from the mother who was affected with bilateral breast cancer (at ages 35 and 43 years), whereas the father who carried and transmitted the 14538 G>A allele was unaffected with cancer. Although both codon 156 and 267 mutations would affect the p53 DNA binding domain, only the codon 267 mutation is classified as deleterious in the IARC TP53 Mutation Database. However, various in vitro assays assessing the functionality of the TP53 variants suggest that all variants exhibited partial or complete loss of wild-type p53 function, where the 14538 G>A alteration exhibited the least detrimental effects overall in comparison to the other mutations alone or combined [39]. Neither parent of the 14538 G>A mutation carrier proband in the LFL family reported a personal history of cancer, although a paternal grandfather was diagnosed with a brain tumor at age 40 years and a paternal cousin was diagnosed with a rhabdomyosarcoma at 4 years of age (with both parents also unaffected with cancer) [39]. Although other members of this family were not tested for carrier status, the family history would imply incomplete penetrance. This is also suggested by the family history and carrier status in the 14538 G>A mutation-positive family identified in our study. The 14538 G>A mutation-positive index case in Family 875 did not exhibit features consistent with LFS or LFL. Moreover, the one other cancer case available for testing (a maternal aunt with breast cancer at 61 and colon cancer at 81) tested negative for this mutation (Fig. 1). However, it is not known if this mutant allele was transmitted from the maternal branch of the family, which had cancer cases, or the paternal branch where the family history of cancer is unknown, as DNA is not available from the parents of the index test in this family. The low frequency of germline TP53 mutations in HBC and HBOC families of French Canadian descent would suggest that routine screening for TP53 mutations in
123
BRCA1 and BRCA2 mutation-negative families is not warranted. The observation that the TP53 mutations were not found in a series of 381 invasive breast cancer cases diagnosed before age 50 years would suggest that these variants are not present in excess in this founder population and thus screening for these mutations is also not warranted. However, during the course of this study independent reports appeared showing that germline mutations in novel candidate breast cancer susceptibility genes ATR [40] and PALB2 [41] were not identified in French Canadian HBC and HBOC families previously tested negative for BRCA1 and BRCA2 mutations. Although germline PALB2 mutations have been reported in breast cancer families [42], this gene appears not to be a major contributor to HBC in the French Canadian cancer families [41]. The identification of germline TP53 mutations in HBC families is disconcerting. Careful monitoring of such families could over time reveal features consistent with those found in LFS or LFL families, as demonstrated with families 1444 and 1039. The clinical significance of the 13398 G>A mutation is evident in the family history of cancer in Family 1444 and monitoring of family members is warranted. Less certain is the significance of 14538 G>A mutation classified as neutral by the IARC TP53 Database and identified in a site-specific breast cancer family, but found independently to occur in a LFS family. It is not clear if this mutation segregates with cancer in both independently ascertained families. Although both independently ascertained families with this mutation were identified in Canada, the familial relationship is unknown. Given the founder effects in the French Canadian population it would be interesting to determine if the carriers of the 14538 G>A mutation are identical-by-descent. Further characterization the TP53 14538 G>A mutation is warranted in light of the association of affected carriers with cancer families featuring different cancer types. Acknowledgments With thank Marise Roy, Ste´phanie Lepage, Manon Deladurantaye, and Myriam Costa for technical support. C.M.M. is a recipient of a chercheur-boursier Fonds de la recherche en sante´ du Que´bec (F.R.S.Q.). This work was supported by grants from the Cancer Research Society Inc., to P.N.T., and the Banque de tissus et de donne´es of the Re´seau de recherche sur le cancer of the F.R.S.Q. to W.D.F., P.G, C.M.M., A.M. M.-M., D.M.P., and P.N.T.
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