Arabidopsis DUO POLLEN3 Is a Key Regulator of Male Germline Development and Embryogenesis
Germline TP53 mutations in BRCA1 and BRCA2 mutation-negative French Canadian breast cancer families
Transcript of Germline TP53 mutations in BRCA1 and BRCA2 mutation-negative French Canadian breast cancer families
EPIDEMIOLOGY
Germline TP53 mutations in BRCA1 and BRCA2 mutation-negative French Canadian breast cancer families
Suzanna L. Arcand Æ Christine M. Maugard Æ Parviz Ghadirian ÆAndre Robidoux Æ Chantal Perret Æ Phil Zhang Æ Eve Fafard ÆAnne-Marie Mes-Masson Æ William D. Foulkes Æ Diane Provencher ÆSteven 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 ef-
fects in this population, the 13398 G>A mutation was
screened in series of 52 BRCA1 and BRCA2 mutation-
negative 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
C. M. Maugard
Service de Medecine Genique, Centre Hospitalier de l’Universite
de Montreal (CHUM), Montreal, QC, Canada
C. M. Maugard � A.-M. Mes-Masson
Departement de medecine, Universite de Montreal, Montreal,
QC, Canada
P. Ghadirian � E. Fafard
Epidemiology Research Unit, Research Centre, CHUM—Hotel-
Dieu, Montreal, QC, Canada
A. Robidoux
Department of Surgery, CHUM—Hotel-Dieu, Montreal, QC,
Canada
C. Perret � A.-M. Mes-Masson � D. Provencher
Centre de Recherche du Centre Hospitalier de l’Universite de
Montreal/Institut du Cancer de Montreal, Hopital Notre-Dame,
Montreal, QC, Canada
P. Zhang � S. A. Narod
Women’s College Research Institute, Women’s College Hospital
and University of Toronto, Toronto, ON, 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
Departement d’obstetrique gynecologie, Division de gynecologie
oncologique, Universite de Montreal, Montreal, QC, Canada
P. N. Tonin (&)
Medical Genetics, Montreal General Hospital, Room L10-120,
Montreal, QC, Canada H3G 1A4
e-mail: [email protected]
123
Breast Cancer Res Treat
DOI 10.1007/s10549-007-9608-6
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 fe-
male breast cancer (diagnosed <65 years of age), ovarian
cancer, or male breast cancer have been shown to harbor
germline mutations in BRCA1 and BRCA2 [1–3]. Specific
BRCA1 and BRCA2 mutations have been found to recur in
French Canadian cancer families [2–5], and this has been
attributed to common founders in the Quebec population
[1, 6–10]. Mutation-negative families could be due to
unidentified BRCA1/BRCA2 mutations, chance clustering
of cancer cases or other genes conferring increased risk to
breast cancer [11].
Breast cancer has also been reported in Li–Fraumeni
Syndrome (LFS) families. LFS is a rare autosomal disorder
characterized by familial clustering of tumors, with a pre-
dominance of sarcomas, breast cancers, brain tumors and
adrenocortical carcinomas, diagnosed before the age of
45 years, where about 70% of families have been shown to
harbor germline mutations in TP53 [12–17]. Other cancers,
such as leukemia, lung cancer, skin melanoma, gastric
cancer, pancreatic cancer, and prostate cancer are also in
excess in some families; and rare cancers such as germ cell
tumors, choroid plexus papilloma, and Wilms tumor have
been reported [14, 18–20]. However, not all of the families
with germline TP53 mutations fulfill the definition of
classical LFS and Li–Fraumeni syndrome-like (LFL) has
been used to describe families which share some features
consistent with those described in LFS families [13, 16,
21]. LFS families are characterized by a proband with
sarcoma diagnosed <45 years of age; a first-degree relative
with any cancer diagnosed <45 years of age; and a first- or
second-degree relative in the same lineage diagnosed with
a sarcoma at any age or any cancer diagnosis occurring
<45 years of age [12]. Birch et al. [13] have defined LFL
families as a proband with any childhood cancer or sar-
coma, brain tumor or adrenal cortical tumor diagnosed
before 45 years of age and a first- or second-degree relative
with a typical LFS cancer (sarcoma, breast cancer, brain
tumor, adrenal cortical tumor or leukemia) at any age, and
a first- or second-degree relative with any cancer under the
age of 60 years [13]. Another definition of LFL is the
occurrence of two first- or second-degree relatives with
LFS-related malignancies at any age [22].
A feature in common with LFS and LFL families is the
presence of very young age of onset breast cancers, which
is a feature that overlaps hereditary breast cancer (HBC)
and breast-ovarian cancer (HBOC) families found to harbor
germline BRCA1 and BRCA2 mutations [23, 24]. The
frequency of TP53 germline mutations has been investi-
gated in multiple studies [25–32], suggesting that they
account for <1% of breast cancer families. However, the
contribution of TP53 to breast cancer in the French
Canadian population is not known. In the present study we
describe the frequency of a TP53 mutation, 13398 G>A
(Arg213Gln), identified in a family of French Canadian
descent originally selected for inclusion in a HBC study.
Given the strong founder effect in this population, we
determined the frequency of this mutation in a series of 52
independently ascertained HBC or HBOC families previ-
ously tested and found negative for BRCA1 and BRCA2
mutations. We also performed mutation analysis of all
domain regions and splice sites of TP53 in this series of
families and report on the deleterious mutation and variants
identified. The frequency of the deleterious mutations
identified was investigated in a series of breast cancer cases
diagnosed <50 years of age from French Canadian women
not selected for family history of breast cancer.
Materials and methods
Cancer families
TP53 mutation analysis was performed on index cases from
52 HBC and HBOC cancer families (Table 1). Each family
had at least three confirmed cases of female breast cancer
(diagnosed £ 65 years of age), epithelial ovarian cancer, or
male breast cancer. The affected individuals in each family
were first-, second- or third-degree relatives (occurring
within the same lineage) to the index case that was selected
for TP53 mutation analysis. Index cases reported grandpa-
rental French Canadian ancestry from Quebec, Canada.
Index cases from 42 of the 52 families were previously found
negative for BRCA1 and BRCA2 mutations by commercial
sequencing service (Myriad Genetics�, http://www.
myriad.com/index.php). Index cases from the remaining ten
families in the series analyzed for TP53 mutations were
found negative for sequence analysis of eight of the most
common BRCA1 (2953delGTAinsC, 3875delGTCT,
4446C>T, and 5221delTG) and BRCA2 (3398delAAAAG,
6085G>T, 7235G>A, and 8765delAG) mutations identified
in French Canadian cancer families that together account for
about 84% of the mutation-positive cases with a family
history exhibiting the inclusion criteria described above
Breast Cancer Res Treat
123
[1–3]. The families were ascertained through the Service de
Medecine Genique, Centre Hospitalier de l’Universite de
Montreal (CHUM) and the Hereditary Cancer Clinics of
McGill University in Montreal.
Breast cancer cases
The 381 female breast cancer cases tested for the pres-
ence of deleterious TP53 mutations were initially ascer-
tained as part of a hospital-based study of breast cancer
susceptibility among French Canadian women. The par-
ticipants were diagnosed with invasive breast cancer at or
under the age of 50 years at a single hospital at the Breast
Clinic of the CHUM—Hotel-Dieu Hospital, Montreal.
The participants were not selected for family history of
cancer, and were BRCA1 and BRCA2 mutation-negative.
The participants identified themselves to be of French
Canadian ancestry. The average age of diagnosis was
44 years (range 26–50 years). Within this series there
were 78 breast cancer cases diagnosed before age
40 years. None of the cases are known to be related to
each other.
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 con-
taining 200 ng of genomic DNA; 1· PCR buffer (Invi-
trogen, Burlington, Canada); 5 nmol each dCTP, dGTP,
dTTP, and dATP; 1.5 mM MgCl2; 15 pmol of each pri-
mer; and 1 U of Taq polymerase (Invitrogen). The PCR
conditions were 3 min at 95�C, 35 cycles of 94�C for
30 s, appropriate annealing temperature (Table 2) for 30 s
and 72�C for 30 s. The PCR products were sequenced
using the 3730XL DNA Analyzer system platform from
Applied Biosystems at the McGill University and Gen-
ome Quebec Innovation Center, Montreal, Canada (ge-
nomequebec.mcgill.ca). Sequence chromatograms were
compared with the TP53 reference sequence X54156 and
the TP53 genomic sequence represented in the UCSC
Genome Bioinformatics Human Genome Browser Gate-
way March 2006 hg 18 assembly (genome.ucsc.edu/cgi-
bin/hgGateway).
The 381 female breast cancer cases not selected for
family history of cancer were investigated for the presence
of the TP53 13398G>A and 14538G>A mutations identi-
fied in the French Canadian breast cancer families. Geno-
mic 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
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 rel-
atives of the index case, which include four cases diag-
nosed at <55 years of age. TP53 mutation analysis of
Table 1 Features of index cases
Syndrome Number of
families
Primary cancer of index case
Primary
site
Mean
age
Median
age
Age
range
Number with multiple
cancers
Cases with mulitiple Br
and/or Ov
Cases with other
cancers
HBC 34 Br 46.2 45.5 30–64 10 BiBr38 Br36Leu41
BiBr39–42 Br37Leu52
BiBr47 Br54Lu59Lar60
BiBr53–54 Br47Mel40
Bi59–66 Br60Sk62–64
HBOC 14 Br 48.6 38 38–64 3 Br38Per75
BiBr40–45
BiBr42–43
HBOC 4 Ov 40.3 37.5 33–42 1 Ov42Br45
Breast Cancer Res Treat
123
family members indicated inheritance from the maternal
branch of the family of the index case.
Given the founder effects in French Canadian popula-
tion, the frequency of 13398 G>A mutation was deter-
mined by screening HBC and HBOC families previously
tested negative for BRCA1 and BRCA2 mutations (Ta-
ble 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 Polymor-
phism (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
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-po-
sitive families identified in our study is consistent with
independent reports suggesting that germline TP53 muta-
tions are rare in multiple case breast cancer families, pos-
sibly accounting for <1% of such families [25–32, 34–37].
The higher frequency of mutation-positive families in our
study is likely due to the selection criteria, which excluded
BRCA1 and BRCA2 mutation-positive families. The
Table 2 Primer sequences for
amplification and/or sequencing
a Genomic region amplified
and/or sequenced based on the
Human Genome Browser
Gateway March 2006 (hg18)
assembly described in the
UCSC Genome Bioinformatics
database (genome.ucsc.edu/cgi-
bin/hgGateway)b Primer sequences used for
DNA sequencing only
TP53 exon Genomic regiona Primer sequences Annealing
temperature (�C)
2, 3, and 4 7519877–7520827 F: 5¢-tggaagagagaatgtgaagc-3¢ 60
R: 5¢-caggagtcagagatcacacat-3¢5 and 6 7518762–7519376 F: 5¢-gcttacgcatgtttgtttct-3¢ 55
R: 5¢-acccatttactttgcacatc-3¢7 7518106–7518440 F: 5¢-gacagagcgagattccatc-3¢ 63.5
R: 5¢-tgagaggtggatgggtagta-3¢7b 7518127–7518394 F: 5¢-tgcttgccacaggtctccc-3¢ NA
R: 5¢-tatggaagaaatcggtaagag-3¢8 and 9 7517517–7517967 F: 5¢-gagtagatggagcctggttt-3¢ 55
R: 5¢-cggcattttgagtgttagac-3¢10 7514528–7514895 F: 5¢-taggtacttgaagtgcagtttct-3¢ 55
R: 5¢-ctgggacccaatgagatg-3¢11 7513367–7513852 F: 5¢-ttgatttgaattcccgttg-3¢ 55
R: 5¢-aacccttaactgcaagaaca-3¢
Breast Cancer Res Treat
123
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08
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T–
––
Intr
on
icrs
17
88
08
47
47
10
95
19
9.0
1.0
96
–
Breast Cancer Res Treat
123
identification of two 13398 G>A mutation-positive fami-
lies 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 (Ar-
g290His) 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 re-
ported 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 seg-
regate 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 car-
ried of the same mutation, but was ascertained indepen-
dently 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 germ-
line 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 chil-
dren 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 alleleTa
ble
3co
nti
nu
ed
Cla
ssifi
cati
on
aG
eno
mic
loca
tio
n
and
var
ian
t
Nu
cleo
tid
ebB
ase
chan
ge
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n
chan
ge
Co
do
nA
min
oac
id
chan
ge
Eff
ect
SN
P
des
ign
atio
na
Gen
oty
pes
All
ele
freq
uen
cyC
HR
no
.
Kn
ow
nal
lele
freq
uen
cies
a
AA
AB
BB
AB
A%
B%
Po
lym
orp
his
mE
xl1
+1
19
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17
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No
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]
rs1
04
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26
00
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09
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lass
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esig
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cies
are
bas
edo
nin
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atio
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om
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IAR
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uta
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ase
(ww
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.iar
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),th
eS
ing
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ucl
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de
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lym
orp
his
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atab
ase
(ww
w.n
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nlm
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v/p
roje
cts/
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P/)
and
the
Can
cer
Gen
om
eA
nat
om
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ance
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atab
ase
(sn
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00
can
cer.
nci
.nih
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v).
All
ele
freq
uen
cies
wer
eco
mp
ared
wit
hth
ose
rep
ort
ed
for
Eu
rop
ean
(Cau
cau
sian
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op
ula
tio
ns
wh
enp
oss
ible
bN
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de
po
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bas
edo
nX
54
15
6
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
Breast Cancer Res Treat
123
Family 1444
IV
III
II
I
31Bt 6d. 9
3233ACC 9
2627Br 41
+
29Bt 12
+
30
24
-
25Br 43d. 45
21Bt 1d. 1
9d. 45
10
19ACC ?
20
5
16BiBr 38
17
3Br 53Li 76d. 76
28
13
-
14Sk 66Br 69
Pan 69
+
8Br 74
Pan 75d. 76
11Br 53d. 56
15
1d. 56
2d. 66
4
Family 875
III
II
I
21Bla 33d. 38
9 10
1920Br 44
+
673Br 61Co 81d. 83
-
4d. 28
5Br 62
8Bla 65Psu 73d. 74
11d. 11
12Pan 74d. 74
13Lu 65
Pan 68d. 69
14Kd 66d. 66
15 16
1d. 85
2Br 68d. 75
2
18 2322
6124
Family 1039
III
II
I
8Cx 49
9 10BiBr 38
11 12
3LuLeu
4Br 53
5Br 53
6 7
1 2
6 3
3
+
Breast Cancer Res Treat
123
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 indi-
cated 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 unaf-
fected 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 compari-
son 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 trans-
mitted from the maternal branch of the family, which had
cancer cases, or the paternal branch where the family his-
tory 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
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 war-
ranted. However, during the course of this study indepen-
dent reports appeared showing that germline mutations in
novel candidate breast cancer susceptibility genes ATR
[40] and PALB2 [41] were not identified in French Cana-
dian 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 con-
tributor 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 inde-
pendently ascertained families. Although both indepen-
dently ascertained families with this mutation were
identified in Canada, the familial relationship is unknown.
Given the founder effects in the French Canadian popula-
tion 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 war-
ranted in light of the association of affected carriers with
cancer families featuring different cancer types.
Acknowledgments With thank Marise Roy, Stephanie 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 Quebec (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 donnees of the Reseau 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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