A gene whose existence was detected only a couple of years ago may
increase women's risk of breast cancer when inherited in a mutated form,
and may contribute to prostate cancer as well, researchers at
Dana-Farber Cancer Institute and colleagues in Finland report in a new
The gene, known as PALB2, may play a role in only about 1
percent of breast cancer cases in the select population that was studied
(Finnish women), but its discovery sheds light on the complex web of
gene interactions that underlies the disease, say the authors of the
study, which is being published by the journal Nature on its
Web site, www.nature.com/nature, and later in a print edition.
"Breast cancer can arise from a wide variety of genetic
abnormalities, and mutations acquired during the evolution of breast
tumor cells are relatively common in the disease," said the study's
co-lead author, Bing Xia, PhD, of Dana-Farber. "However, only about 10
percent of all cases are the result of inherited mutations, and, of
those, only about 20-30 percent result from mutations in the two main
breast cancer-susceptibility genes, BRCA1 and BRCA2.
So there is room for other such genes to be discovered."
David Livingston, MD
The new study stems from research by Xia and Dana-Farber's David
Livingston, MD, a senior author of the paper, into BRCA2's "binding
partners" — proteins that interact with the BRCA2 protein. They found
that the PALB2 protein is an especially close partner of BRCA2, with
substantial portions of the proteins binding to each other.
"We found that PALB2 helps anchor BRCA2 in key areas of the cell
nucleus, where BRCA2 repairs damaged DNA," Xia said. Mutations in BRCA2
can prevent such repairs from being made, which can lead to runaway
cell growth. If BRCA2 is normal, but PALB2 is defective, BRCA2 may be
out of position for fixing damaged DNA, with similar pathological
effects on cell growth.
To determine whether PALB2 mutations are implicated in both
hereditary and sporadic breast cancer, researchers at Oulu University
Hospital in Finland screened tissue from 113 Finnish families with a
history of the disease. Three of the families were found to have the
same mutation of the gene.
The Finnish team next screened tissue from 1,918 breast cancer
patients, some of whom had inherited cancer-susceptibility genes, some
of whom had not. Eighteen patients — or about 1 percent of the entire
group — were found to carry the same PALB2 mutation; and most of them
turned out to have a family pattern of the disease.
"The mutation causes the middle portion of the PALB2 protein to be
truncated," Xia remarked. "That seems to hinder its ability to bind to
BRCA2, which, in turn, hinders DNA repair. The screening result
suggests that carrying the mutation increases one's risk of breast
cancer approximately four fold."
The Finnish researchers also screened tissue from 141 male breast
cancer patients, 476 colorectal cancer patients, and 639 prostate cancer
patients. In one family where prostate cancer had occurred in several
generations, every family member with prostate cancer whom it was
possible to test was found to carry the PALB2 mutation, suggesting that
the gene plays a role in this form of cancer as well. The mutation did
not turn up in male breast and colorectal cancer patients, however.
"Our research suggests that mutations in PALB2 can be an influential
factor in breast cancer development, like those affecting BRCA2," Xia
observed. "But since we suspect that such mutations occur less
frequently in PALB2 than BRCA2, they are not responsible for as many
breast cancer cases as BRCA2 mutations."
Xia added that the discovery of a PALB2 mutational link to breast
cancer "may well increase one's ability to identify women at elevated
risk for the disease and to devise appropriate prevention and, possibly,
treatment strategies, as well."
Funding for the study was provided by the Foundation for the Finnish
Cancer Institute, the Academy of Finland, the Ida Montin Foundation, the
Cancer Foundation of Northern Finland, the University of Oulu, Oulu
University Hospital, the Reino Lahtikari Foundation, the Sigrid Juselius
Foundation, the National Cancer Institute, and the Shapiro Family
The lead author of the study was Hannele Erkko, of the University of
Oulu and Oulu University Hospital in Finland. In addition to Livingston,
the paper's other senior author is Robert Winqvist, PhD, of the
University of Oulu and Oulu University Hospital. Co-authors include
Alexander Miron, PhD, Qing Sheng, PhD, Guilan Li, and Ronny Drapkin, MD,
PhD, of Dana-Farber; and colleagues at the University of Oulu, the
University of Tampere, the University of Kuopio, and Kuopio University
Hospital, and the University of Helsinki, all in Finland; the Karolinska
Institutet, in Sweden; and Massachusetts General Hospital.
Dana-Farber Cancer Institute (www.dana-farber.org)
is a principal teaching affiliate of the Harvard Medical School and is
among the leading cancer research and care centers in the United States.
It is a founding member of the Dana-Farber/Harvard Cancer Center
(DF/HCC), designated a comprehensive cancer center by the National