BRCA2 Gene Mutations Linked to Ovarian Cancer Cases

WASHINGTON--University of Pennsylvania researchers have obtainedthe first "conclusive" evidence linking mutations inthe recently cloned BRCA2 breast cancer gene to ovarian cancer,a discovery they say indicates that inheritance plays a significantlygreater role in the disease than previously thought.

An anomaly of the study was that some women with inherited BRCA2mutations in their ovarian tumors did not have a family historyof either breast or ovarian cancer, and, unlike women with theBRCA1 mutation, who tend to have early onset disease, they generallydeveloped their cancers after age 60.

Linkage studies and pedigree analyses have suggested that inheritedmutations of BRCA2 account for up to 50% of all hereditary breastcancer cases "and a much smaller, but as yet undeterminedfraction of hereditary ovarian cancer cases," Jeffrey A.Boyd, PhD, said at a press briefing at the American Associationfor Cancer Research meeting.

Dr. Boyd and his colleagues set out to determine the extent ofthe gene's involvement in ovarian cancer. They examined the BRCA2region on chromosome 13 in tumors obtained from 130 consecutive,unselected ovarian cancer patients treated at the University ofPennsylvania Medical Center, Philadelphia, where Dr. Boyd is directorof the Gynecologic Oncology Research Laboratory.

Approximately 45% of those cancers displayed loss of heterozygosityat polymorphic markers that overlapped the BRCA2 locus, Dr. Boydreported, including five frameshift mutations and one missensemutation. "This suggests that approximately 5% of all ovariancarcinomas contain BRCA2 mutations," he said.

Original Estimates Too Low?

Prior to this study, research based on estimates derived fromfamilial clustering and unusual medical histories had suggestedthat an inherited predisposition played a role in 5% to 10% ofall ovarian cancers.

But Dr. Boyd's data suggest that hereditary ovarian cancer ismore common. Moreover, the study probably understates the actualnumber of BRCA2 mutations because the technique the team usedin its study, SSCP screening, has a mutation detection efficiencyof about 60% to 90%.

Evidence from a Scottish study, also presented at AACR, indicatesthat mutations in the BRCA1 gene alone account for 6% of inheritedovarian cancers, Donald M. Black, PhD, of the Beatson Institutefor Cancer Research, Glasgow, Scotland, said at the press briefing.

Therefore, the actual percentage of hereditary cases, includingthose due to mutations of BRCA1, BRCA2, and other as yet undiscoveredtumor suppressor genes, may be as high as 20%, Dr. Boyd said.

The discovery of inherited BRCA2 mutations in women with no familyhistory of breast or ovarian cancers runs counter to the patternseen in other tumor suppressor genes and stands in sharp contrastto what researchers have learned about BRCA1, Dr. Boyd said.

The Penn team found that BRCA2-related cancers tend to occur ata later age than usual for inherited ovarian carcinomas. The womenin Dr. Boyd's study were in their mid- to late 60s. Women withinherited BRCA1 mutations usually develop ovarian cancer in theirmid-40s to mid-50s.

Finally, Dr. Boyd reported, the study indicates that sporadiccases of ovarian carcinoma do not arise from somatic mutationsof BRCA2. This suggests the presence of another tumor suppressorgene on the same chromosome as BRCA2 and near to it.

Dr. Boyd said he expected that the linking of BRCA2 to ovariancancer would have "profound implications, in the scientificsense," on genetic screening. However, he added that thework was simply too new to make any recommendations for BRCA2screening of high-risk women at this time.