Additional Gene Defects Found in BRCA1 and BRCA2 Carriers

SAN DIEGO—Breast cancer patients with an inherited predisposition due to mutations of BRCA1 or BRCA2 are more likely to have an accumulation of other genetic defects than patients with no evidence of a familial clustering, according to a multinational study, said Mika Tirkkonen, of the University of Tampere, Finland.

In this study, the researchers looked at the genetic changes in breast cancer tissue samples from 21 women who had BRCA1 gene mutations, 15 women with BRCA2 mutations, and 55 women with no inherited mutations.

The total number of genetic defects was almost two times higher in tumors from BRCA1 and BRCA2 mutation carriers than in tumors from the control group. What’s more, the specific genetic defects were different from those usually found in breast cancers.

In BRCA1 tumors, losses of 5q (86%), 4q (81%), 4p (64%), 2q (40%), and 12q (40%) were significantly more common than in the control group (7% to 13%). BRCA2 tumors were characterized by the high frequency of losses of 13q (73%) and 6q (60%) and gains of 17q22-q24 (87%) and 20q13 (60%), compared with the control group changes.

The researchers conclude that the multistep tumor progression process and the accumulation of somatic genetic changes appear to follow a unique course in individuals genetically predisposed to cancer, especially by the BRCA1 gene. Genes in the affected chromosomal regions may collaborate with BRCA1 and BRCA2 in the malignant process.

“Although the results suggest that cancers in women with an inherited predisposition may be particularly aggressive, there is yet no solid evidence suggesting that women with inherited cancer types would have a much worse prognosis than other breast cancer patients,” Dr. Tirk-konen said at the American Association for Cancer Research annual meeting. “However, the pattern of genetic changes suggests that the biological properties of these cancers may be different.”

Further research could eventually lead to methods of early diagnosis, such as monitoring the accumulation of additional gene mutations in biopsies of breast tissue from high-risk women, Dr. Tirkkonen added.

Joining the Finnish researchers were scientists from the NIH’s National Human Genome Research Institute, the University of Iceland, and the University of Lund, Sweden.

In a second study presented at the meeting, San Francisco researchers found that Hs-cul-4A, a gene identified two and a half years ago, may play an important role in the development and progression of breast cancer.

The study, from the Geraldine Brush Cancer Research Institute at the California Pacific Medical Center, found overex-pression of Hs-cul-4A in about half of breast cancer tissue samples analyzed, compared with normal breast tissue. The protein product of Hs-cul-4A is thought to be involved in the control of the cell cycle, which regulates cell growth.

In laboratory studies, the researchers noted that Hs-cul-4A was amplified and overexpressed in three of 14 breast cell lines and was overexpressed in an additional nine lines, compared with either proliferating or nonproliferating normal breast tissue.

In tissue samples from untreated primary breast cancers, Hs-cul-4A was amplified in 23 of 107 cases analyzed (23%) and overexpressed in 14 of 30 cases (47%).

“There are multiple levels of control of gene expression, and a cell must escape these controls in order to become malignant,” said Ling-Chun Chen, PhD, who performed the research along with colleague Helene Smith, PhD. “Our studies suggest that one of the mechanisms by which tumor cells may escape this control is by overexpression and/or amplification of Hs-cul-4A.”

Dr. Chen said that study of Hs-cul-4A is continuing “to see if we can eventually develop therapies that knock out this gene, thereby reversing tumor growth.”