PURPOSE Loss of function of PTEN is a frequent event in melanoma, particularly in tumors with BRAFV600 mutations. The prevalence, pathological features, and clinical outcomes associated with PTEN loss in patients with stage IIIB/C melanoma were interrogated to improve our understanding of the clinical significance of this molecular event. EXPERIMENTAL DESIGN Archival tissue from lymphadenectomy specimens among patients (n=136) with stage IIIB or IIIC melanoma were assessed by DNA sequencing for activating BRAF and NRAS mutations, and by immunohistochemistry (IHC) for the expression of PTEN protein. Associations of these molecular aberrations with demographics, tumor characteristics, and clinical outcomes were determined. RESULTS The prevalence of BRAFV600 mutations (40% overall), NRAS mutations (10%), and PTEN loss (25%) did not vary by pathological substage. BRAF/NRAS mutation status did not correlate with distant disease-free survival (DDFS) or overall survival (OS). Complete loss of PTEN expression correlated with shorter OS but not DDFS. When stratified by specific sites of distant metastasis, PTEN loss was associated with significantly shorter time to melanoma brain metastasis (MBM), but not to liver, lung, or bone. Analysis of PTEN in mutationally-defined subsets showed that PTEN loss was significantly associated with OS and time to MBM in patients with BRAFV600 mutations. CONCLUSIONS Loss of PTEN protein expression correlates significantly with decreased OS and time to MBM in stage IIIB/C melanoma patients with BRAFV600 mutations. The findings add to evidence supporting a significant role for PTEN loss and the PI3K-AKT pathway in melanoma.

The management of melanoma has evolved due to improved understanding of its molecular drivers. To augment the current understanding of the prevalence, patterns, and associations of mutations in this disease, the results of clinical testing of 699 advanced melanoma patients using a pan-cancer next generation sequencing (NGS) panel of hotspot regions in 46 genes were reviewed. Mutations were identified in 43 of the 46 genes on the panel. The most common mutations were BRAFV600 (36%), NRAS (21%), TP53 (16%), BRAFNon-V600 (6%), and KIT (4%). Approximately one-third of melanomas had >1 mutation detected, and the number of mutations per tumor was associated with melanoma subtype. Concurrent TP53 mutations were the most frequent event in tumors with BRAFV600 and NRAS mutations. Melanomas with BRAFNon-V600 mutations frequently harbored concurrent NRAS mutations (18%), which were rare in tumors with BRAFV600 mutations (1.6%). The prevalence of BRAFV600 and KIT mutations were significantly associated with melanoma subtypes, and BRAFV600 and TP53 mutations were significantly associated with cutaneous primary tumor location. Multiple potential therapeutic targets were identified in metastatic unknown primary and cutaneous melanomas that lacked BRAFV600 and NRAS mutations. These results enrich our understanding of the patterns and clinical associations of oncogenic mutations in melanoma.

BackgroundWhile clinical outcomes following immunotherapy have shown an association with tumor mutation load using whole exome sequencing (WES), its clinical applicability is currently limited by cost and bioinformatics requirements.MethodsWe developed a method to accurately derive the predicted total mutation load (PTML) within individual tumors from a small set of genes that can be used in clinical next generation sequencing (NGS) panels. PTML was derived from the actual total mutation load (ATML) of 575 distinct melanoma and lung cancer samples and validated using independent melanoma (n = 312) and lung cancer (n = 217) cohorts. The correlation of PTML status with clinical outcome, following distinct immunotherapies, was assessed using the Kaplan–Meier method.ResultsPTML (derived from 170 genes) was highly correlated with ATML in cutaneous melanoma and lung adenocarcinoma validation cohorts (R2 = 0.73 and R2 = 0.82, respectively). PTML was strongly associated with clinical outcome to ipilimumab (anti-CTLA-4, three cohorts) and adoptive T-cell therapy (1 cohort) clinical outcome in melanoma. Clinical benefit from pembrolizumab (anti-PD-1) in lung cancer was also shown to significantly correlate with PTML status (log rank P value < 0.05 in all cohorts).ConclusionsThe approach of using small NGS gene panels, already applied to guide employment of targeted therapies, may have utility in the personalized use of immunotherapy in cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-016-0705-4) contains supplementary material, which is available to authorized users.

Metastatic Crohn disease is a rare cutaneous disorder characterized by noncaseating, granulomatous skin lesions present at sites anatomically separate from the gastrointestinal tract. It is the least common dermatologic manifestation of Crohn disease, and the differential diagnosis includes numerous similarly appearing, granulomatous skin entities. Males and females appear to be equally affected, and children tend to present with clinical lesions different from those of adults. An integration of clinical information, microscopic findings, and ancillary studies is necessary to accurately diagnose this rare cutaneous disease. Our objective is to review the clinical features, histopathologic characteristics, suggested pathogenesis, differential diagnosis, and current therapeutic options of metastatic Crohn disease.

Summary Triple-negative breast cancer (TNBC) comprises 10-15% of newly-diagnosed breast cancer and lacks expression of the estrogen, progesterone and HER-2/neu receptors. Many such tumors are basal-like, a molecular intrinsic subtype of breast cancer associated with poor clinical outcomes. Patients with early-stage basal-like TNBC are at a high risk of relapse and may therefore benefit from novel therapies, including immunotherapy. MUC1 is a tumor antigen expressed on adenocarcinomas and represents an ideal target for MUC1-based vaccination. We evaluated 52 cases of early-stage basal-like TNBC for MUC1 expression by immunohistochemistry. The intensity of staining was graded according to the intensity (negative (0), positive (1) or strongly-positive (2) and percent (0 to 100%) of tumor cells staining for MUC1. An overall score of 0 to 2.0 was calculated for each case by multiplying the intensity of staining by the percent of tumor cells staining positively. Four staining patterns for MUC1 were identified: apical, cytoplasmic, membranous, and combination. Forty nine of the 52 cases of basal-like TNBC (94%) were positive for MUC1 expression. The mean score was 0.90 (range 0 - 1.9). Cases were evenly distributed over this range, where most (67%) exhibited moderate to strong MUC1 expression (score 0.5 to 1.90), 27% demonstrated weak MUC1 expression, and 6% lacked MUC1 expression. There was a significant difference in MUC1 score and percent MUC1+ cells in favor of the combination pattern. This study indicates that a large proportion of early-stage basal-like TNBC expresses MUC1 and provides a rationale for MUC1-based immunotherapy in this high-risk patient cohort.