Researchers from St. Jude Children's Research Hospital have identified subgroups of children and teenagers with medulloblastoma who appear to have specific genetic alterations that fuel their cancer. In a study published in the April 20 Journal of Clinical Oncology (JCO), the research team identified unique gene signatures for each subgroup based on gene expression profiling of tumor samples, and further demonstrated that the signatures were predictive of mutations in genes in intracellular signaling pathways that influence cancer development and growth.
The results, the researchers contend, could have important implications for testing molecularly targeted agents in children with medulloblastoma.
"Patient tumor samples could be rapidly screened for mutation-specific gene expression signatures using relatively simple and widely available techniques such as real-time PCR [polymerase chain reaction] or IHC [immunohistochemistry]," they wrote. "Gene sequencing efforts could then be focused to confirm the presence of the underlying mutation in tumors in these patients before their enrollment onto a clinical trial of an appropriate molecular targeted therapy."
The researchers, led by Dr. Richard J. Gilbertson, performed gene-expression profiles of tumor samples from 46 pediatric medulloblastoma patients. The resulting gene signatures - the unique expression of 400 to 800 genes compared with expression levels in other tumor samples - grouped the samples into 5 subgroups, A through E. Two of these subgroups, B and D, had particularly "robust" gene expression signatures, the authors explained, with high levels of 100 differentially expressed genes.
Further analysis identified associations between the signatures and mutations in important signaling pathways known to be linked to medulloblastoma, particularly the WNT pathway in subgroup B patients and the SHH pathway in subgroup D patients. The researchers also were able to detect previously unidentified genetic alterations linked to medulloblastoma.
Women with mutations in the genes BRCA1 or BRCA2, which greatly increase their risk of breast cancer, have similar rates of in-breast tumor recurrence (IBTR) and higher rates of contralateral breast cancers (CBC) after breast-conserving surgery and radiation therapy than women who do not carry either mutation, reports a study published early online April 24 in JCO.
Researchers compared 160 women with breast cancer who carried either BRCA mutation with 445 women diagnosed with sporadic breast cancer. No significant difference was found in rates of IBTR between the two groups. However, when women with genetic mutations who had undergone prophylactic removal of their ovaries to reduce their estrogen levels were removed from the analysis, IBTR was significantly higher in mutation carriers than controls. Use of tamoxifen, a drug that blocks estrogen, was associated with reduced IBTR in all groups, but the differences were not significant.
Women with BRCA mutations were significantly more likely to develop CBC than women in the control group, and the difference was greater for women who had not had their ovaries removed. Tamoxifen significantly reduced the rate of CBC in all groups. This protective effect was especially strong in women with intact ovaries.
The investigators state that their results "…support consideration of tamoxifen use and bilateral oophorectomy in BRCA1/2 carriers interested in breast conservation for reduction in both ipsilateral and contralateral breast cancers." They also caution that a significantly higher risk of CBC remains in mutation carriers even with these protective measures and that additional risk-reduction interventions need to be developed for long-term control of the disease.
A gene best known for its link to a premature aging syndrome also appears to play a role in the normal aging process, NCI scientists reported last week. Because older age is such a significant risk factor for cancer, said lead investigator Dr. Tom Misteli of NCI's CCR, "understanding the mechanisms involved in aging provides insights into the molecular mechanisms involved in creating the cellular environment required for a cell to become cancerous." The findings were released early online by Science on April 27.
Mutations in the LMNA gene produce a faulty form of the protein lamin A that has been linked to Hutchinson-Gilford Progeria Syndrome (HGPS), which causes children to age very rapidly. Drs. Misteli and Paula Scaffidi examined skin cell lines from HGPS patients, very old individuals, and very young individuals to determine what role, if any, lamin A plays in the normal aging process.
They found that, compared with cells in young individuals, cells from HGPS patients and those of healthy older individuals shared many of the same cellular defects, including more unrepaired DNA damage, lower levels of certain proteins in the nucleus, and altered chemical modification patterns. They also found that when they prevented the production of the faulty lamin A protein in cells from healthy older donors, the defects were reversed, directly implicating the lamin A protein as the cause of the age-related cellular defects.
One of the most intriguing aspects of this work is the observation that unlike other premature aging diseases, HGPS patients do not develop tumors. Exploiting the molecular differences among the various premature aging syndromes will be a valuable tool in understanding the link between aging and cancer, says Dr. Misteli.
The use of surveillance mammography among breast cancer survivors declines significantly over time despite the high risks for recurrence, according to a study published early online April 24 in Cancer.
The retrospective study included 797 women with primary breast cancer in the HMO Administrative Data project, a part of the NCI-sponsored Cancer Research Network. Researchers found that 80 percent of the women "underwent mammograms during the first year after treatment for breast cancer," but the percentage of women having mammograms during each yearly period decreased significantly over time. During the fifth year of follow-up, only 63 percent of the women had mammograms, reported investigators led by Dr. Chyke A. Doubeni of the University of Massachusetts. This decline occurred despite the approximately threefold increased risk of cancer in the previously unaffected breast, the researchers noted.
Older women with other illnesses or late-stage breast cancer were less likely to have follow-up mammograms. On the other hand, patients who underwent breast-conserving surgery were more likely to get subsequent screening.
"The strongest association with surveillance mammography in the current study was found with outpatient visits to gynecologists or primary care physicians," the scientists found. "The primary explanation may be that women who visit gynecologists or primary care physicians have greater awareness of their preventive care needs. This finding suggests that involving primary care physicians and gynecologists in the follow-up of breast cancer survivors…may be beneficial."
They recommend that efforts be made "to increase awareness among health care providers and breast cancer survivors on the value of follow-up mammography."