Identification of a novel truncating PALB2 mutation and analysis of its contribution to early-onset breast cancer in French-Canadian women.
BACKGROUND
PALB2 has recently been identified as a breast cancer susceptibility gene. PALB2 mutations are rare causes of hereditary breast cancer but may be important in countries such as Finland where a founder mutation is present. We sought to estimate the contribution of PALB2 mutations to the burden of breast cancer in French Canadians from Quebec.


METHODS
We screened all coding exons of PALB2 in a sample of 50 French-Canadian women diagnosed with either early-onset breast cancer or familial breast cancer at a single Montreal hospital. The genetic variants identified in this sample were then studied in 356 additional women with breast cancer diagnosed before age 50 and in 6,448 newborn controls.


RESULTS
We identified a single protein-truncating mutation in PALB2 (c.2323 C>T, resulting in Q775X) in 1 of the 50 high-risk women. This variant was present in 2 of 356 breast cancer cases and in none of 6,440 newborn French-Canadian controls (P = 0.003). We also identified two novel new non-synonymous single nucleotide polymorphisms in exon 4 of PALB2 (c.5038 A>G [I76V] and c.5156 G>T [G115V]). G115V was found in 1 of 356 cases and in 15 of 6,442 controls (P = 0.6). The I76V variant was not identified in either the extended case series or the controls.


CONCLUSIONS
We have identified a novel truncating mutation in PALB2. The mutation was found in approximately 0.5% of unselected French-Canadian women with early-onset breast cancer and appears to have a single origin. Although mutations are infrequent, PALB2 can be added to the list of breast cancer susceptibility genes for which founder mutations have been identified in the French-Canadian population.
Foulkes
William D
WD
Program in Cancer Genetics, Departments of Oncology and Human Genetics, McGill University, 546 Pine Ave West, Montréal, QC, Canada H2W 1S6. William.foulkes@mcgill.ca
Ghadirian
Parviz
P
Akbari
Mohammed Reza
MR
Hamel
Nancy
N
Giroux
Sylvie
S
Sabbaghian
Nelly
N
Darnel
Andrew
A
Royer
Robert
R
Poll
Aletta
A
Fafard
Eve
E
Robidoux
André
A
Martin
Ginette
G
Bismar
Tarek A
TA
Tischkowitz
Marc
M
Rousseau
Francois
F
Narod
Steven A
SA
D000328:Adult; D017668:Age of Onset; D001943:Breast Neoplasms / Q000208:ethnology* / Q000235:genetics*; D000076164:Fanconi Anemia Complementation Group N Protein; D005260:Female; D018703:Founder Effect; D005602:France / Q000208:ethnology; D020022:Genetic Predisposition to Disease; D005973:Glutamine; D006801:Humans; D007231:Infant, Newborn; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D011792:Quebec / Q000453:epidemiology; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D000076164:Fanconi Anemia Complementation Group N Protein; D009687:Nuclear Proteins; C512790:PALB2 protein, human; D025521:Tumor Suppressor Proteins; D005973:Glutamine