Analysis of PALB2/FANCN-associated breast cancer families.
No more than approximately 30% of hereditary breast cancer has been accounted for by mutations in known genes. Most of these genes, such as BRCA1, BRCA2, TP53, CHEK2, ATM, and FANCJ/BRIP1, function in DNA repair, raising the possibility that germ line mutations in other genes that contribute to this process also predispose to breast cancer. Given its close relationship with BRCA2, PALB2 was sequenced in affected probands from 68 BRCA1/BRCA2-negative breast cancer families of Ashkenazi Jewish, French Canadian, or mixed ethnic descent. The average BRCAPRO score was 0.58. A truncating mutation (229delT) was identified in one family with a strong history of breast cancer (seven breast cancers in three female mutation carriers). This mutation and its associated breast cancers were characterized with another recently reported but unstudied mutation (2521delA) that is also associated with a strong family history of breast cancer. There was no loss of heterozygosity in tumors with either mutation. Moreover, comparative genomic hybridization analysis showed major similarities to that of BRCA2 tumors but with some notable differences, especially loss of 18q, a change that was previously unknown in BRCA2 tumors and less common in sporadic breast cancer. This study supports recent observations that PALB2 mutations are present, albeit not frequently, in breast cancer families. The apparently high penetrance noted in this study suggests that at least some PALB2 mutations are associated with a substantially increased risk for the disease.
Tischkowitz
Marc
M
Program in Cancer Genetics, Departments of Oncology and Human Genetics and Departments of Medicine and Human Genetics, McGill University, Montréal, QC, Canada.
Xia
Bing
B
Sabbaghian
Nelly
N
Reis-Filho
Jorge S
JS
Hamel
Nancy
N
Li
Guilan
G
van Beers
Erik H
EH
Li
Lili
L
Khalil
Tayma
T
Quenneville
Louise A
LA
Omeroglu
Atilla
A
Poll
Aletta
A
Lepage
Pierre
P
Wong
Nora
N
Nederlof
Petra M
PM
Ashworth
Alan
A
Tonin
Patricia N
PN
Narod
Steven A
SA
Livingston
David M
DM
Foulkes
William D
WD
D000328:Adult; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000097:blood / Q000235:genetics*; D018567:Breast Neoplasms, Male / Q000097:blood / Q000235:genetics; D004252:DNA Mutational Analysis; D005199:Fanconi Anemia / Q000097:blood / Q000235:genetics; D000076164:Fanconi Anemia Complementation Group N Protein; D005260:Female; D016368:Frameshift Mutation; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008545:Melanoma / Q000097:blood / Q000235:genetics; D008875:Middle Aged; D009687:Nuclear Proteins / Q000097:blood / Q000235:genetics*; D010375:Pedigree; D017354:Point Mutation; D025521:Tumor Suppressor Proteins / Q000097:blood / Q000235:genetics*
D000076164:Fanconi Anemia Complementation Group N Protein; D009687:Nuclear Proteins; C512790:PALB2 protein, human; D025521:Tumor Suppressor Proteins