TY - JOUR
T1 - Analysis of PALB2/FANCN-associated breast cancer families
AU - Tischkowitz, Marc
AU - Xia, Bing
AU - Sabbaghian, Nelly
AU - Reis-Filho, Jorge S.
AU - Hamel, Nancy
AU - Li, Guilan
AU - Van Beers, Erik H.
AU - Li, Lili
AU - Khalil, Tayma
AU - Quenneville, Louise A.
AU - Omeroglu, Atilla
AU - Poll, Aletta
AU - Lepage, Pierre
AU - Wong, Nora
AU - Nederlof, Petra M.
AU - Ashworth, Alan
AU - Tonin, Patricia N.
AU - Narod, Steven A.
AU - Livingston, David M.
AU - Foulkes, William D.
PY - 2007/4/17
Y1 - 2007/4/17
N2 - No more than ≈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 (229deIT) 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 (2521deIA) 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.
AB - No more than ≈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 (229deIT) 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 (2521deIA) 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.
KW - DNA repair
KW - FANCN
KW - Fanconi anemia
KW - Hereditary predisposition
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U2 - 10.1073/pnas.0701724104
DO - 10.1073/pnas.0701724104
M3 - Article
C2 - 17420451
AN - SCOPUS:34249857115
SN - 0027-8424
VL - 104
SP - 6788
EP - 6793
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 16
ER -