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Inherited Genetic Variation Can Contribute to Some Forms of Melanoma
Researchers in NCI's Division of Cancer Epidemiology and Genetics have identified a link between inherited and environmentally induced genetic risk factors for skin melanomas in Caucasians who do not have chronic sun-induced skin damage. Study results appeared online June 29 in Science. Investigators at the University of California, San Francisco (UCSF), the University of Pennsylvania, and Bufalini Hospital in Cesena, Italy, also participated in the study.
The researchers hypothesized that the high frequency of BRAF mutations in these types of melanoma may be due to additional genetic factors that occur at higher frequencies in Caucasians. They selected the melanocortin-1 receptor (MC1R) gene as a candidate for inducing additional genetic risk, and sequenced the genes of melanoma patients in studies conducted in Italy and at UCSF to determine if there was an association between MC1R and BRAF-mutant melanoma.
The researchers found that BRAF mutations were more frequent in nonchronic sun-induced melanoma cases with hereditary MC1R genetic allele-associated variations. They found that BRAF mutations were 6 to 13 times more frequent in those patients with at least 1 MC1R variant allele, and the risk for melanoma with BRAF mutations increased with a rising number of MC1R variant alleles. Comparing data from melanoma patients and healthy controls, the risk for melanomas with BRAF mutations increased from 7 times for individuals with 1 MC1R variant allele to 17 times for those with 2 variant alleles, when compared with individuals with no MC1R variant alleles.
New Algorithm Predicts Presence of Lynch Syndrome
Researchers estimate that 3 to 4 percent of patients diagnosed with colorectal cancer have an inherited syndrome that predisposes them to the disease, of which Lynch syndrome is the most common. Diagnosis of Lynch syndrome helps doctors make prevention and treatment decisions, and alerts family members of a possible increase in cancer risk. A new algorithm published in the June 29 New England Journal of Medicine can help physicians identify the colorectal cancer patients who are most likely to have Lynch syndrome and who would benefit from rigorous genetic testing.
To develop their algorithm, investigators enrolled 870 patients diagnosed with colorectal cancer before the age of 55 into their study. The investigators first divided patients into subgroups using a set of clinical variables - including sex, age, and development of multiple primary cancers - that predict whether a patient with colorectal cancer carries a mutation. Next, subgroups identified as more likely to include carriers underwent immunohistochemical and microsatellite instability testing on tissue samples to find predictors of a genetic mutation. Investigators then compared the combined predictions from both stages of the model with patients' actual mutation status in specific DNA repair genes known to cause Lynch syndrome.
A combination of the clinical variables with one of the laboratory analyses in the second stage had "a positive predictive value of 80 percent and a sensitivity of 62 percent for mutational carriers. This information could be used in preoperative counseling" about surgical procedures and adjuvant therapy, wrote the authors. An electronic version of the algorithm is currently available online.
Lymphatic Mapping May Improve Colorectal Cancer Staging
Use of a process known as lymphatic mapping to identify sentinel lymph nodes may help improve the accuracy of colorectal cancer staging, researchers report in the June Archives of Surgery.
Improved staging, suggests lead investigator Dr. Anton J. Bilchik, of the John Wayne Cancer Institute in Santa Monica, Calif., and colleagues, may aid the selection of patients who are the best candidates for adjuvant chemotherapy.
The lymphatic mapping process, which Dr. Bilchik and colleagues have used extensively in patients with melanoma and breast cancer, entails injecting a blue dye at the primary tumor site just prior to surgical removal. The dye travels through the lymph system and stains the first lymph nodes downstream from the tumor, called the sentinel nodes. The sentinel nodes are then surgically removed, along with other lymph nodes in the same lymph bed and the primary tumor, and further analyzed in the laboratory to search for signs of tumor cells.
"The sentinel lymph node is the first node to receive lymphatic drainage from a primary anatomical site and is therefore the most likely node to harbor a metastasis," Dr. Bilchik said.
Based on the sentinel node analyses, nearly 24 percent of the 132 patients in the prospective trial had their cancer classified as more severe than was initially diagnosed, and the mapping system proved to be highly sensitive (88.2 percent) with a low false-negative rate (7.4 percent).
The results "suggest that lymphatic mapping and sentinel lymph node techniques are feasible and accurate in colon cancer," the authors wrote. "The improved risk stratification afforded by standardization of both surgical and pathological techniques may improve the selection of patients for chemotherapy, thereby avoiding the unnecessary toxic effects and expense for those cured by surgery alone."
Melanoma Diagnosed in Hispanics and Blacks Is Often Advanced
Hispanics and blacks are more likely to be in the advanced stages of melanoma when they are diagnosed with the often fatal skin cancer than are whites, according to a study of patients in Miami-Dade County, Fla. In the study, 26 percent of Hispanics and 52 percent of blacks were diagnosed with late-stage melanoma compared with 16 percent of whites. Dr. Robert Kirsner of the University of Miami's Sylvester Comprehensive Cancer Center led the research.
Melanoma is more common among whites, and public health efforts to improve prevention and early detection have largely targeted this group, particularly individuals with blue eyes and blond or red hair. "Understandably, darker-skinned individuals perceive themselves at either low or no risk for melanoma because much of the public education efforts have targeted the white populations," the researchers write in the June Archives of Dermatology.
They go on to suggest that educating Hispanics and blacks about the risk of melanoma and providing screening are critical to achieve earlier diagnoses, when the disease is more likely to respond to treatment. But until now data on melanoma stage at diagnosis for Hispanics have been sparse. The researchers selected Miami-Dade County for the study because it has the second largest Hispanic population in the United States. They analyzed 1,690 cases diagnosed between 1997 and 2002.
Overall, 16 percent of Hispanics and 31 percent of blacks had melanoma that had metastasized at the time of diagnosis, compared with only 9 percents of whites. The disparity in stage at diagnosis reported in this study is comparable to previous reports, the researchers say, noting that later diagnosis is associated with poorer outcomes in Hispanics and possibly in blacks.
Additional Test Finds Hidden Disease in Locally Advanced Prostate Cancer
Prostate cancer can be lethal, though many newly diagnosed patients will live for decades and die of other causes, especially after surgery to remove the prostate gland and the pelvic lymph nodes. Researchers from the University of Southern California Keck School of Medicine have shown that immunohistochemistry testing can be used to identify patients who - even though their lymph nodes test negative with standard histology - still have occult lymph node metastases and thus should be considered at high risk for recurrence.
Dissected lymph nodes from 285 patients with the same stage of prostate cancer were examined by routine histology: 180 showed no evidence of cancer, while 94 were positive for cancer. However, immunohistochemical tests for cytokeratin revealed that 24 (13.3 percent) of those originally identified as node negative actually had metastasized disease. Patients in the misclassified group were found to have just under half the overall survival of the truly node-negative patients and were 2.27 times more likely to have a recurrence.
Lead author Dr. Vincenzo Pagliarulo and colleagues wrote in the June 20 Journal of Clinical Oncology that these findings echo other studies exploring the value of immunohistochemistry, noting that "a significant correlation between occult lymph node metastases and clinical outcome has been shown in many types of cancers." Such previously unrecognized subpopulations "may benefit from immediate adjuvant systemic treatment" after their prostatectomy, they wrote, such as early androgen deprivation.
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