Menopausal Hormone Therapy Linked to Ovarian Cancer Risk

Women aged 50-71 who take estrogen plus progestin have a significantly increased risk of developing ovarian cancer compared with women who don't use any menopausal hormone therapy, according to study results in the October 4 Journal of the National Cancer Institute.

Lead author Dr. James Lacey of NCI's Division of Cancer Epidemiology and Genetics notes the importance of the study: "This is a large study of a rare cancer, and our study's comprehensive information on specific hormone therapy regimens offers a detailed picture of ovarian cancer risk associated with use of estrogen plus progestin."

The study evaluated 97,638 women from the NIH-AARP Diet and Health Study Cohort who completed 2 questionnaires from 1995-1997 that collected information on demographic characteristics, dietary intake, health-related behaviors, family history of cancer, anthropometry, physical activity, and use of hormone therapy. Researchers looked at long-term use - 10 or more years - of unopposed estrogen by women with hysterectomy. Dr. Lacey's team also compared women with intact uteri who took only estrogen plus progestin with women with intact uteri who never used hormone therapy.

Women who took unopposed estrogen for 10 or more years had a significantly increased risk of ovarian cancer, whereas women who took unopposed estrogen for less than 10 years had no increased risk. Women with intact uteri who took estrogen plus progestin were approximately twice as likely to develop ovarian cancer as women with intact uteri who didn't use any menopausal hormone therapy.

Previous studies had linked the use of unopposed estrogen to ovarian cancer, but few have evaluated specific estrogen-plus-progestin regimens and ovarian cancer risk. Nonetheless, further research is needed into these associations. "Particular regimens of estrogen and progestin have only been on the market for 15 or 20 years," said Dr. Lacey, "so we will continue to follow this study cohort for years."

Birt-Hogg-Dubé Syndrome Linked to Pathways Involving Energy and Nutrients

Four years after identifying the gene responsible for Birt-Hogg-Dubé (BHD) syndrome, a rare inherited disorder that can lead to kidney cancer, researchers have identified two proteins that interact with the gene's protein product, called folliculin. The interactions suggest that BHD syndrome, which also causes benign hair follicle tumors or hamartomas, may result from changes in molecular pathways that respond to energy levels and nutrient availability in cells.

The NCI research team, of the Center for Cancer Research's (CCR) Laboratory of Immunobiology and Urologic Oncology Branch, which discovered the BHD gene in 2002, now reports that in normal cells folliculin interacts with a novel protein they named folliculin-interacting protein 1 (FNIP1). But mutant forms of folliculin predicted to be present in cells from patients with BHD syndrome do not bind to FNIP1, probably due to loss of its binding site.

Drs. Masaya Baba, Laura Schmidt, and their colleagues found that FNIP1 also interacts with a protein that serves as an "energy sensor" in cells, 5'-AMP-activated protein kinase (AMPK). AMPK negatively regulates the mTOR pathway, which, when dysregulated, has been implicated in several other hamartoma syndromes.

Folliculin and its interacting partner, FNIP1, "may be involved in energy and/or nutrient sensing through the AMPK and mTOR signaling pathways," the researchers conclude in a study published online October 6 in Proceedings of the National Academy of Sciences. They are developing animal models of BHD to investigate further the roles of these proteins in the development of kidney cancer.

"We are excited to have moved from identifying families with BHD syndrome and an increased risk for kidney cancer to isolating the responsible gene and doing functional studies to understand what folliculin does," says Dr. W. Marston Linehan, chief of CCR's Urologic Oncology Branch.

Model Predicts Likelihood of Lynch Syndrome in Individual Patients

A new model developed by investigators at Dana-Farber Cancer Institute and published in the September 27 Journal of the American Medical Association provides clinicians with a tool to estimate the likelihood of individual patients carrying mutations in the MLH1 or MSH2 genes, the primary causes of Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer). This information can be used to better determine which patients would benefit from molecular evaluation and genetic testing. Other commonly used risk models for Lynch-associated mutations are not designed to predict the likelihood of a single individual carrying a genetic mutation.

The investigators used a set of 898 patients with known MLH1 or MSH2 status to develop the model. Variables used in development included personal and family history of Lynch syndrome-associated cancer, and age at diagnosis for patients and any of their first- or second-degree relatives diagnosed with Lynch syndrome-associated cancer. Predicted risk of mutation was broken into five categories: 5 percent or less, 5.1 to 10 percent, 10.1 to 20 percent, 20.1 to 40 percent, and more than 40 percent. The model was then tested and refined in a validation cohort of 1,016 additional patients with colorectal cancer and known mutation status.

"The model demonstrated excellent ability to discriminate between risk groups," stated the authors. The model's sensitivity and specificity depended on the risk category chosen as the cutoff point. Compared with the widely used revised Bethesda Guidelines, the new Dana-Farber model with a cutoff of 10 percent risk would lead to the testing of fewer patients and, at the same time, would miss fewer mutation carriers. The authors have made the model available to health care professionals as a Web-based tool.

Sentinel-Node Biopsy Identifies Metastatic Melanoma Earlier

A large international trial funded by NCI shows that sentinel lymph node biopsy (SNB) can provide important prognostic information about patients who have had surgery for localized primary melanoma. Trial results appear in the September 28 New England Journal of Medicine.

Following surgery to remove melanoma lesions, patients are monitored for recurrence through observation of the lymph nodes. If the cancer does not spread to sentinel nodes - those lymph nodes nearest the tumor site - the risk of recurrence is approximately 15 to 20 percent. However, if the cancer does spread to the sentinel nodes, recurrence is all but certain.

Dr. Donald L. Morton of the John Wayne Cancer Institute in Santa Monica, Calif., and colleagues enrolled more than 2,000 patients in this trial from 18 sites in Europe, Australia, and the United States between 1994 and 2002. Patients were assigned to SNB a few months following the initial surgery or to observation until there was clinical evidence of spread to the sentinel lymph nodes.

Patients at low risk of recurrence can avoid unnecessary surgery and the complications that often follow removal of some or all regional lymph nodes. A negative SNB also can significantly reduce both the costs of follow-up surveillance and the anxiety associated with relapse.

In an editorial, Drs. Charles M. Balch of Johns Hopkins University and Natale Cascinelli of the National Tumor Institute in Milan, Italy, describe the study as the largest and most important trial of SNB ever conducted. "The concept of the sentinel node is now well established," they write, reflecting the fact that studies during the 1990s confirmed SNB to be a reliable prognostic tool to detect micrometastases.

U.S. Scientists Win Nobel Prize for Medicine

On October 2, Dr. Andrew Fire of Stanford University and Dr. Craig Mello of the University of Massachusetts Medical School were announced the winners of the Nobel Prize in physiology or medicine. The scientists were recognized for their discovery of RNA interference (RNAi), a naturally occurring process by which cells regulate the activity of genes. Researchers around the world use RNAi to study genes and their roles in diseases such as cancer. Dr. Mello received NCI support for some of his RNAi research.