Common Genetic Variants Linked to Breast Cancer

Researchers have identified common genetic variations associated with breast cancer in several populations of women. The variants occur in a tumor suppressor gene called FGFR2 (Fibroblast Growth Factor Receptor 2), which was previously reported to be amplified or overexpressed in some breast cancers.

Two independent research teams - one in the U.S. and one in the U.K. - made the discovery by conducting genome-wide association studies to look for breast cancer susceptibility genes. They scanned DNA from thousands of women with breast cancer and from healthy women. In both studies, variants in FGFR2 were linked to disease risk.

"This gene is a substantial new risk factor for breast cancer," says Dr. David Hunter of the Harvard School of Public Health and NCI, and lead author of the U.S. study. "The discovery opens up new avenues for research on the gene and its signaling pathway, which may have relevance to treatment and prevention."

For women of European descent, a single copy of the variant gene increases breast cancer risk by 20 percent while two copies increase risk by 60 percent, or about the same amount as having a single family member with the disease. Approximately 15 percent of white women are estimated to carry two copies of the variant gene.

Dr. Hunter says that it would be premature to test women for the FGFR2 risk variants. Additional variants are likely to be found as the researchers analyze the genome data generated as part of the study, conducted under NCI's Cancer Genetic Markers of Susceptibility (CGEMS) program.

In the study's next phase, CGEMS researchers are evaluating 29,000 variants linked to breast cancer risk during a series of collaborative studies, mostly drawn from the NCI Breast & Prostate Cancer Cohort Consortium. The aim is to build a catalogue of genetic risk factors that can be evaluated along with environmental factors, such as hormone use.

"As we sift through the genome-wide association studies, we are almost certain to find more hits that will have important implications for our understanding of breast cancer genetics," says Dr. Hunter, who is an NCI Eminent Scholar.

The findings appeared online in Nature Genetics on May 27. The same day, the U.K. group, which included researchers from NCI's Division of Cancer Epidemiology and Genetics (DCEG), published findings online in Nature. Dr. Douglas Easton of Cancer Research UK at the University of Cambridge and his colleagues identified FGFR2 and three other novel breast cancer susceptibility genes (TNRC9, MAP3K1, and LSP1).

The function of these genes in breast cancer susceptibility is not known. Taken together, the new findings provide leads for identifying new biological processes in breast cancer and may contribute to the familial risk not explained by BRCA mutations.

"It's exciting and also very reassuring to see that we quickly identified a gene that was also found by another group," says Dr. Stephen Chanock, director of the NCI Core Genotyping Facility in DCEG and senior author of the CGEMS study.

Dasatinib Effective Against Difficult-to-Treat ALL

The results of a 36-patient phase II clinical trial indicate that the multitargeted drug dasatinib (Sprycel) may be extremely beneficial in adult patients with a form of acute lymphoblastic leukemia (ALL) who have developed resistance or do not respond to another targeted agent, imatinib (Gleevec). The drug's effectiveness did not appear to be hampered by most of the mutations in a key protein that have been associated with imatinib resistance.

Patients in the trial had a specific chromosomal translocation, often referred to as the Philadelphia chromosome, that is associated with a rapid course of disease after ALL diagnosis and poor survival. The translocation creates a fused protein known as BCR-ABL, the same protein typically seen in chronic myelogenous leukemia, for which imatinib has proven to be an effective treatment.

"These data are highly significant given the refractory nature of patients enrolled in this trial to current treatment modalities, including imatinib," wrote study leader Dr. Olivier Ottmann from Johann Wolfgang Goethe University in Germany and colleagues in a May 11 early online release in Blood.

In the study, patients given dasatinib at 70 mg twice daily had strong hematologic and cytogenetic response rates - meaning a return of normal white blood cell counts and a significantly reduced number of cells positive for the Philadelphia chromosome, respectively. At 8 months, 42 percent of patients had a major hematologic response, of whom two-thirds exhibited no disease progression; 58 percent of patients had complete cytogenetic responses.

Cisplatin Improves Survival for Women with Cervical Cancer

Long-term follow-up results from a Gynecologic Oncology Group clinical trial that compared cisplatin-based chemotherapy with hydroxyurea in addition to radiation therapy for locally or regionally advanced cervical cancer, published online in the Journal of Clinical Oncology, showed that cisplatin-based chemotherapy significantly improved both progression-free and overall survival compared with hydroxyurea alone. The percentage of women experiencing late side effects did not significantly differ between the treatment groups.

The investigators randomly assigned participating women to one of three groups. One group received cisplatin alone, the second received the chemotherapy drug hydroxyurea alone, and the third received a combination of cisplatin, hydroxyurea, and the drug 5-fluorouracil (5-FU). All drugs were given during radiation therapy, and all women received the same type and amount of radiation therapy.

Patients were followed for an average of almost 9 years. Women who received either cisplatin or the combination of cisplatin, 5-FU, and hydroxyurea had significantly longer progression-free survival and overall survival than women who received hydroxyurea alone, regardless of whether the cancer had spread locally or regionally. After adjusting for the fact that more patients who received cisplatin or the combination regimen were alive for the analysis of side effects, the investigators did not observe a significant difference in late-occurring side effects between the groups.

"Collectively, this follow-up analysis continues to support the use of cisplatin-based concurrent chemotherapy with pelvic radiation therapy for locally advanced stage cervical cancer," summarized the authors.

Caspase-8 Drives TRAIL Resistance in Ewing's Sarcoma

Scientists at the Albert Ludwigs University of Freiburg in Germany and their collaborators at NCI's Center for Cancer Research (CCR) have identified both a potential mechanism for resistance of Ewing's sarcoma (ES) to an experimental therapeutic protein called tumor necrosis factor apoptosis-inducing ligand (TRAIL), and a possible method for overcoming this resistance. Their results were published in the June issue of the American Journal of Pathology.

The investigators focused on caspase-8 expression because lack of the protein has been linked in laboratory studies to TRAIL resistance in ES cells and other tumors. They first looked at tissue samples taken from 47 patients with ES. In three-quarters of the samples, caspase-8 expression was detected in 60 to 100 percent of the cells. In the rest of the samples, caspase-8 expression was detected in only 0 to 50 percent of the cells. Therefore, within any individual ES tumor, cells that lack caspase-8 could cause resistance to TRAIL.

The investigators next tested whether interferon-gamma (IFN-γ), which has been shown in the laboratory to increase caspase-8 expression in cells, could sensitize ES cells with low expression of caspase-8 to treatment with TRAIL. They found that doses of IFN-γ within the range easily tolerated by patients increased caspase-8 expression in caspase-8-deficient cell lines. When the IFN-γ-treated cells were treated with TRAIL, they underwent apoptosis, indicating restored sensitivity to TRAIL.

Additional in vitro experiments showed that chemotherapy does not select for tumor cells that lack caspase-8, which would make subsequent treatment with TRAIL less effective. Changing the levels of caspase-8 expressed by the cells, either genetically or by adding IFN-γ, did not alter their sensitivity to chemotherapy, indicating "that the combination of TRAIL and IFN-γ with standard chemotherapeutics in ES could be feasible," stated the authors.

WTX Found to be a Tumor Suppressor in Wilms' Tumor

A new study has found that a protein called WTX is an important factor in the protein-destruction complex targeting β-catenin when Wnt signaling is misguided, according to results published online May 18 in Science. β-catenin activation causes Wilms' tumor.

Dr. Michael B. Major of the Howard Hughes Medical Institute and colleagues initially used proteomic methods to determine which proteins bind to β-catenin in cell lysates. They found that WTX interacts with β-catenin in the protein-destruction complex. To further investigate WTX activity, researchers generated cultured cells that express WTX. They also manipulated xenopus and zebrafish embryos to examine the effects of the Wnt gene with and without WTX.

Looking at the generated cultured cells, researchers found that WTX partners with other destruction-complex proteins to promote degradation of β-catenin. They also found that the xenopus embryos injected with the Wnt gene developed two heads, while those injected with Wnt and WTX developed milder head anomalies. They saw similar results in the zebrafish embryos. The researchers concluded that WTX negatively regulates Wnt/β-catenin signaling. Additionally, based on the ability of WTX to regulate β-catenin, it is a tumor suppressor gene in Wilms' tumor.

In an editorial, Dr. Roel Nusse of Stanford University School of Medicine noted that "β-catenin activity has been detected in other human cancers, mostly by virtue of the nuclear presence of the β-catenin protein. In many of those cases, there has been no evidence that the known components of the WNT signaling pathway are mutated, suggesting that β-catenin becomes activated without any genetic alterations. But the new knowledge by Major et al. invites speculation that WTX is in fact mutated in these cancers."