Number of nevi and early-life ambient UV exposure are associated with BRAF-mutant melanoma.

Malignant melanomas often contain BRAF or NRAS mutations, but the relationship of these mutations to ambient UV exposure in combination with phenotypic characteristics is unknown. In a population-based case series from North Carolina, 214 first primary invasive melanoma patients in the year 2000 were interviewed regarding their risk factors. Ambient solar UV exposures were estimated using residential histories and a satellite-based model. Cases were grouped on the basis of BRAF and NRAS somatic mutations, determined using single-strand conformation polymorphism analysis and radiolabeled DNA sequencing, and the risk profiles of these groups were compared. Mutually exclusive BRAF-mutant and NRAS-mutant cases occurred at frequencies of 43.0% and 13.6% with mean ages at diagnosis of 47.3 and 62.1 years, respectively. Tumors from patients with >14 back nevi were more likely to harbor either a BRAF mutation [age-adjusted odds ratio (OR), 3.2; 95% confidence interval (95% CI), 1.4-7.0] or an NRAS mutation (age-adjusted OR, 1.7; 95% CI, 0.6-4.8) compared with patients with 0 to 4 back nevi. However, BRAF-mutant and NRAS-mutant tumors were distinctive in that BRAF-mutant tumors were characteristic of patients with high early-life ambient UV exposure (adjusted OR, 2.6; 95% CI, 1.2-5.3). When ambient UV irradiance was analyzed by decadal age, high exposure at ages 0 to 20 years was associated with BRAF-mutant cases, whereas high exposure at ages 50 and 60 years was characteristic of NRAS-mutant cases. Our results suggest that although nevus propensity is important for the occurrence of both BRAF and NRAS-mutant melanomas, ambient UV irradiance influences risk differently based on the age of exposure. The association of BRAF mutations with early-life UV exposure provides evidence in support of childhood sun protection for melanoma prevention.

Distance to diagnosing provider as a measure of access for patients with melanoma.

OBJECTIVE: To examine the effect of travel distance and other sociodemographic factors on access to a diagnosing provider for patients with melanoma. DESIGN: Analysis was performed of all incident cases of melanoma in 2000 from 42 North Carolina counties. SETTING: Academic research. PARTICIPANTS: Patients and providers from 42 North Carolina counties were geocoded to street address. MAIN OUTCOME MEASURES: Associations between Breslow thickness and clinical and sociodemographic factors (age, sex, poverty rate, rurality, provider supply, and distance to diagnosing provider) were examined. RESULTS: Of 643 eligible cases, 4.4% were excluded because of missing data. The median Breslow thickness was 0.6 mm (range, 0.1-20.0 mm). The median distance to diagnosing provider was 8 miles (range, 0-386 miles). For each 1-mile increase in distance, Breslow thickness increased by 0.6% (P =.003). For each 1% increase in poverty rate, Breslow thickness increased by 1% (P =.04). Breslow thickness was 19% greater for patients aged 51 to 80 years than for those aged 0 to 50 years (P =.02) and was 109% greater for patients older than 80 years than for those aged 0 to 50 years (P < .001). Sex, rurality, and supply of dermatologists were not associated with Breslow thickness. CONCLUSIONS: For patients with melanoma, distance to the diagnosing provider is a meaningful measure of access that captures different information than community-level measures of rurality, provider supply, and socioeconomic status. Future work should be targeted at identifying factors that may affect distance to diagnosing provider and serve as barriers to melanoma care.

The positive predictive value for diagnosis of breast cancer full-field digital mammography versus film-screen mammography in the diagnostic mammographic population.

RATIONALE AND OBJECTIVES: Diagnostic mammography is performed on women with clinical symptoms that suggest breast cancer or women for whom further mammographic evaluation has been requested because of an abnormal screening mammography. We assessed whether the use of full-field digital mammography would improve the positive predictive value (PPV) for the diagnosis of breast cancer in a diagnostic population compared with film-screen mammography. MATERIALS AND METHODS: From January 2002 to December 2003, 11,621 patients underwent diagnostic mammography at the University of North Carolina Hospital, Chapel Hill. Among these 11,621 patients, 1400 lesions in 1121 patients underwent biopsy. We included the biopsy-performed lesions, so PPV3 was used for comparison of PPVs between film-screen mammography and full-field digital mammography. Six breast radiologists interpreted the images using the Breast Imaging Reporting and Data System of the American College of Radiology. PPV3s were compared between film-screen and full-field digital mammography in the entire study cohort and in specified subgroups according to different radiologists, breast density, and lesion type on mammography. The chi(2) and Fisher's exact tests were used for comparison of PPV3s between two modalities of mammography with the Bonferroni procedure for subgroup analysis. RESULTS: In the entire study cohort, PPV3s of full-field digital mammography and film-screen mammography were similar (difference in PPV3,-0.007; 95% confidence interval, -0.081 to 0.068; P = .8602). In predefined subgroups, there was no difference in PPV3 by the radiologist, breast density, or lesion type between two modalities of mammography (P > .005). CONCLUSION: There is no improvement in PPV for the diagnosis of breast cancer with full-field digital mammography compared with film-screen mammography in a large diagnostic population.

Tandem BRAF mutations in primary invasive melanomas.

The RAS/RAF/MAPK pathway likely mediates critical cell proliferation and survival signals in melanoma. BRAF mutations have been found in a high percentage of melanoma cell lines and metastases; however, only a few studies with a limited number of specimens have focused on primary melanomas. We examined BRAF exon 15 mutational status in 37 primary invasive melanomas of varying thicknesses, which had undergone a standardized pathology review. BRAF mutational status was determined using direct manual sequencing of PCR products, followed by resequencing separately amplified DNA aliquots to confirm each mutation. BRAF exon 15 mutations were found in 17 of 37 (46%) primary melanomas. Tumor-specific tandem mutations, encoding either V599K, V599R, or V599E, were found in 5 of 17 (29%) melanomas with BRAF exon 15 mutations. Cloning of BRAF double base-pair substitutions confirmed that both base changes were on the same allele and can result in a positive charge at codon 599. BRAF mutations, including tandem mutations, were frequently found in both thin and thick primary melanomas, implying that these mutations can occur early in the progression of melanoma. The finding of tandem mutations in thin melanomas makes it more likely that they arise as a simultaneous rather than sequential event.

Making epidemiologic studies responsive to the needs of participants and communities: the Carolina Breast Cancer Study experience.

In this report, we present the results of surveys administered to participants and nonparticipants in the Carolina Breast Cancer Study (CBCS). Surveys and structured interviews were administered to determine women's concerns regarding participation in research studies, access to health care, and beliefs regarding causes of breast cancer. Survey results showed the highest concern for the growing number of women diagnosed with breast cancer in North Carolina and potential environmental agents that may cause breast cancer. Negative responses were noted for time constraints related to participation and lack of familiarity with epidemiologic research; another concern noted was the lack of centralized information regarding breast cancer treatment. These issues were addressed by (1) developing a web site that provided background information about the CBCS, summaries of published study results, and information about the etiology of breast cancer; and (2) creating a statewide, comprehensive breast cancer resource directory for women who need information about breast cancer diagnosis, treatment, and support. These two projects were carried out in collaboration with breast cancer advocates, and demonstrate the important role that advocates can play in making epidemiologic research more responsive to the needs of communities.