January 30, 2008 — For almost 50 years, Fanconi
anemia has been associated with leukemia. Not just among those who have
the genetic disorder but among their family members, whose genes, they
were told, made them highly susceptible to a variety of malignancies.
But a new study to examine links between 13 specific Fanconi anemia
genes and cancer risk has determined that in most cases, their risk of
cancer is no greater than that of the rest of the population.
Fanconi anemia is primarily an autosomal recessive genetic
condition, which means that in order for it to develop, a person must
inherit two mutated Fanconi anemia genes, one from each parent. To
date, 13 such genes have been identified and all of them, in Fanconi
anemia patients, are associated with a greater than average risk of
developing solid as well as blood-based cancers, among other conditions.
The question that Rockefeller University Associate Professor Arleen
Auerbach and her team of American and German researchers investigated
is one she says has worried families of Fanconi anemia patients for
decades: whether a single Fanconi anemia gene increases cancer risk. A
pivotal 1971 epidemiological study suggested that cancer risk is,
indeed, elevated in Fanconi carriers, although no molecular genetic
analysis was performed, Auerbach says. When a 2002 study linked Fanconi
anemia to the BRCA2 gene, researchers suggested that inherited
mutations in any of several genes might result in cancer risks for
Fanconi anemia. “This produced a kind of mass hysteria among family
members because they believed carriers were all at increased risk for
cancer in general and breast cancer in particular,” Auerbach says.
But the new data, which Auerbach and her colleagues spent six years
collecting and analyzing, suggests that besides those with BRCA2
mutations, only one subgroup of Fanconi anemia carriers — older women
who carry a single mutated FANCC gene — develop more than the expected
amount of cancer. Investigators further found that the cancer these
women developed was of one type — breast cancer. In this study,
grandmothers of Fanconi anemia patients who carry an FANCC gene were
almost 2.5 times more likely to have developed breast cancer compared
to women without the gene, says Auerbach, director of the Laboratory of
Human Genetics and Hematology and the study’s lead investigator.
“This suggests that the FANCC gene is a breast cancer susceptibility
gene, and that women who carry it should be screened for breast cancer
on a regular basis,” Auerbach says. The FANCC gene is the second most
common Fanconi anemia gene, accounting for about 15 percent of Fanconi
anemia families. Many women may already know they carry a mutated gene
because FANCC is part of the routine pre-pregnancy genetic testing
panel available for persons of Ashkenazi Jewish descent, she says. Half
of all families of this Fanconi subtype (called FA-C) are of Ashkenazi
“Generally speaking, however, these findings are very good news for
many people whose families have been affected by Fanconi anemia,
because for many years, the assumption has been that anyone who
possesses a single mutated gene associated with the disease is at
higher risk of developing cancer,” Auerbach says.
The study examined genes from 784 grandparents and 160 other
relatives; there were six breast cancers observed among the 33
grandmothers who had a FANCC gene mutation, compared to the 2.5 breast
cancers that would be expected. Two other excess breast cancers were
found in other female relatives with a mutant FANCC gene.
In addition to quelling the fears of a number of Fanconi anemia gene
carriers, the study also cast doubts on theories by which Fanconi
anemia genes produce cancer in people who inherit two copies, she says.
All 13 genes had been believed to be related to a cancer-causing
pathway involving BRCA1 and BRCA2, genes known to be involved in
genetic damage repair (but which, when mutated, are breast
susceptibility genes) and which are believed to work with Fanconi
anemia genes. But this study suggests that only one of the 10 known FA
genes found “upstream” of BRCA2, FANCC, may play a role in cancer
Journal reference: Cancer Research 67(19): 9591–9596 (October 1, 2007)
Source : Rockefeller University