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Melanoma: HELP
Articles by Pamela A. Groben
Based on 13 articles published since 2009
(Why 13 articles?)
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Between 2009 and 2019, Pamela A. Groben wrote the following 13 articles about Melanoma.
 
+ Citations + Abstracts
1 Article Association Between NRAS and BRAF Mutational Status and Melanoma-Specific Survival Among Patients With Higher-Risk Primary Melanoma. 2015

Thomas, Nancy E / Edmiston, Sharon N / Alexander, Audrey / Groben, Pamela A / Parrish, Eloise / Kricker, Anne / Armstrong, Bruce K / Anton-Culver, Hoda / Gruber, Stephen B / From, Lynn / Busam, Klaus J / Hao, Honglin / Orlow, Irene / Kanetsky, Peter A / Luo, Li / Reiner, Anne S / Paine, Susan / Frank, Jill S / Bramson, Jennifer I / Marrett, Lorraine D / Gallagher, Richard P / Zanetti, Roberto / Rosso, Stefano / Dwyer, Terence / Cust, Anne E / Ollila, David W / Begg, Colin B / Berwick, Marianne / Conway, Kathleen / Anonymous2880835. · ·JAMA Oncol · Pubmed #26146664.

ABSTRACT: IMPORTANCE: NRAS and BRAF mutations in melanoma inform current treatment paradigms, but their role in survival from primary melanoma has not been established. Identification of patients at high risk of melanoma-related death based on their primary melanoma characteristics before evidence of recurrence could inform recommendations for patient follow-up and eligibility for adjuvant trials. OBJECTIVE: To determine tumor characteristics and survival from primary melanoma by somatic NRAS and BRAF status. DESIGN, SETTING, AND PARTICIPANTS: A population-based study with a median follow-up of 7.6 years (through 2007), including 912 patients from the United States and Australia in the Genes, Environment, and Melanoma (GEM) Study, with first primary cutaneous melanoma diagnosed in the year 2000 and analyzed for NRAS and BRAF mutations. MAIN OUTCOMES AND MEASURES: Tumor characteristics and melanoma-specific survival of primary melanoma by NRAS and BRAF mutational status. RESULTS: The melanomas were 13% NRAS+, 30% BRAF+, and 57% with neither NRAS nor BRAF mutation (wildtype [WT]). In a multivariable model including clinicopathologic characteristics, relative to WT melanoma (with results reported as odds ratios [95% CIs]), NRAS+ melanoma was associated with presence of mitoses (1.8 [1.0-3.3]), lower tumor-infiltrating lymphocyte (TIL) grade (nonbrisk, 0.5 [0.3-0.8]; and brisk, 0.3 [0.5-0.7] [vs absent TILs]), and anatomic site other than scalp/neck (0.1 [0.01-0.6] for scalp/neck vs trunk/pelvis), and BRAF+ melanoma was associated with younger age (ages 50-69 years, 0.7 [0.5-1.0]; and ages >70 years, 0.5 [0.3-0.8] [vs <50 years]), superficial spreading subtype (nodular, 0.5 [0.2-1.0]; lentigo maligna, 0.4 [0.2-0.7]; and unclassified/other, 0.2 [0.1-0.5] [vs superficial spreading]), and presence of mitoses (1.7 [1.1-2.6]) (P < .05 for all). There was no significant difference in melanoma-specific survival (reported as hazard ratios [95% CIs]) for melanoma harboring mutations in NRAS (1.7 [0.8-3.4]) or BRAF (1.5 [0.8-2.9]) compared with WT melanoma, as adjusted for age, sex, site, American Joint Committee on Cancer (AJCC) tumor stage, TIL grade, and study center. However, melanoma-specific survival was significantly poorer for higher-risk (T2b or higher stage) tumors with NRAS (2.9 [1.1-7.7]) or BRAF (3.1 [1.2-8.5]) mutations (P = .04) but not for lower-risk (T2a or lower) tumors with NRAS (0.9 [0.3-3.0]) or BRAF (0.6 [0.2-1.7]) (P = .65), as adjusted for age, sex, site, AJCC tumor stage, TIL grade, and study center. CONCLUSIONS AND RELEVANCE: Lower TIL grade for NRAS+ melanoma suggests it has a more immunosuppressed microenvironment, which may affect its response to immunotherapies. The approximate 3-fold increased risk of death for higher-risk tumors harboring NRAS or BRAF mutations after adjusting for other prognostic factors compared with WT melanomas indicates that the prognostic implication of these mutations deserves further investigation, particularly in higher–AJCC stage primary melanomas.

2 Article IL2 Inducible T-cell Kinase, a Novel Therapeutic Target in Melanoma. 2015

Carson, Craig C / Moschos, Stergios J / Edmiston, Sharon N / Darr, David B / Nikolaishvili-Feinberg, Nana / Groben, Pamela A / Zhou, Xin / Kuan, Pei Fen / Pandey, Shaily / Chan, Keefe T / Jordan, Jamie L / Hao, Honglin / Frank, Jill S / Hopkinson, Dennis A / Gibbs, David C / Alldredge, Virginia D / Parrish, Eloise / Hanna, Sara C / Berkowitz, Paula / Rubenstein, David S / Miller, C Ryan / Bear, James E / Ollila, David W / Sharpless, Norman E / Conway, Kathleen / Thomas, Nancy E. ·Department of Dermatology, The University of North Carolina, Chapel Hill, North Carolina. · Department of Medicine, The University of North Carolina, Chapel Hill, North Carolina. Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina. · Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina. · Department of Pathology and Laboratory Medicine, The University of North Carolina, Chapel Hill, North Carolina. · Department of Biostatistics, The University of North Carolina, Chapel Hill, North Carolina. · Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina. Department of Biostatistics, The University of North Carolina, Chapel Hill, North Carolina. · Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina. Department of Cell Biology and Physiology, The University of North Carolina, Chapel Hill, North Carolina. · Department of Surgery, The University of North Carolina, Chapel Hill, North Carolina. · Department of Dermatology, The University of North Carolina, Chapel Hill, North Carolina. Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina. · Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina. Department of Pathology and Laboratory Medicine, The University of North Carolina, Chapel Hill, North Carolina. Department of Neurology, The University of North Carolina, Chapel Hill, North Carolina. Neuroscience Center, The University of North Carolina, Chapel Hill, North Carolina. · Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina. Department of Surgery, The University of North Carolina, Chapel Hill, North Carolina. · Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina. Department of Epidemiology, The University of North Carolina, Chapel Hill, North Carolina. · Department of Dermatology, The University of North Carolina, Chapel Hill, North Carolina. Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina. nthomas@med.unc.edu. ·Clin Cancer Res · Pubmed #25934889.

ABSTRACT: PURPOSE: IL2 inducible T-cell kinase (ITK) promoter CpG sites are hypomethylated in melanomas compared with nevi. The expression of ITK in melanomas, however, has not been established and requires elucidation. EXPERIMENTAL DESIGN: An ITK-specific monoclonal antibody was used to probe sections from deidentified, formalin-fixed paraffin-embedded tumor blocks or cell line arrays and ITK was visualized by IHC. Levels of ITK protein differed among melanoma cell lines and representative lines were transduced with four different lentiviral constructs that each contained an shRNA designed to knockdown ITK mRNA levels. The effects of the selective ITK inhibitor BI 10N on cell lines and mouse models were also determined. RESULTS: ITK protein expression increased with nevus to metastatic melanoma progression. In melanoma cell lines, genetic or pharmacologic inhibition of ITK decreased proliferation and migration and increased the percentage of cells in the G0-G1 phase. Treatment of melanoma-bearing mice with BI 10N reduced growth of ITK-expressing xenografts or established autochthonous (Tyr-Cre/Pten(null)/Braf(V600E)) melanomas. CONCLUSIONS: We conclude that ITK, formerly considered an immune cell-specific protein, is aberrantly expressed in melanoma and promotes tumor development and progression. Our finding that ITK is aberrantly expressed in most metastatic melanomas suggests that inhibitors of ITK may be efficacious for melanoma treatment. The efficacy of a small-molecule ITK inhibitor in the Tyr-Cre/Pten(null)/Braf(V600E) mouse melanoma model supports this possibility.

3 Article Inherited variation at MC1R and histological characteristics of primary melanoma. 2015

Taylor, Nicholas J / Busam, Klaus J / From, Lynn / Groben, Pamela A / Anton-Culver, Hoda / Cust, Anne E / Begg, Colin B / Dwyer, Terence / Gallagher, Richard P / Gruber, Stephen B / Orlow, Irene / Rosso, Stefano / Thomas, Nancy E / Zanetti, Roberto / Rebbeck, Timothy R / Berwick, Marianne / Kanetsky, Peter A. ·Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida, United States of America. · Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America. · Women's College Hospital, Toronto, Ontario, Canada. · Departments of Dermatology, Pathology and Laboratory Medicine, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, United States of America. · Department of Epidemiology, University of California, Irvine, California, United States of America. · Sydney School of Public Health, University of Sydney, Sydney, NSW, Australia. · Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America. · International Agency for Cancer Research, Lyon, France. · British Columbia Cancer Agency, Vancouver, British Columbia, Canada. · Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California, United States of America. · Piedmont Tumor Registry, Turin, Italy. · Department of Dermatology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, United States of America. · Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America; Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America. · Departments of Internal Medicine and Dermatology, University of New Mexico, Albuquerque, New Mexico, United States of America. ·PLoS One · Pubmed #25790105.

ABSTRACT: Variation in the melanocortin-1receptor (MC1R) gene is associated with pigmentary phenotypes and risk of malignant melanoma. Few studies have reported on MC1R variation with respect to tumor characteristics, especially clinically important prognostic features. We examined associations between MC1R variants and histopathological melanoma characteristics. Study participants were enrolled from nine geographic regions in Australia, Canada, Italy and the United States and were genotyped for MC1R variants classified as high-risk [R] (D84E, R142H, R151C, R160W, and D294H, all nonsense and insertion/deletion) or low-risk [r] (all other nonsynonymous) variants. Tissue was available for 2,160 white participants of the Genes, Environment and Melanoma (GEM) Study with a first incident primary melanoma diagnosis, and underwent centralized pathologic review. No statistically significant associations were observed between MC1R variants and AJCC established prognostic tumor characteristics: Breslow thickness, presence of mitoses or presence of ulceration. However, MC1R was significantly associated with anatomic site of melanoma (p = 0.002) and a positive association was observed between carriage of more than one [R] variant and melanomas arising on the arms (OR = 2.39; 95% CI: 1.40, 4.09). We also observed statistically significant differences between sun-sensitive and sun-resistant individuals with respect to associations between MC1R genotype and AJCC prognostic tumor characteristics. Our results suggest inherited variation in MC1R may play an influential role in anatomic site presentation of melanomas and may differ with respect to skin pigmentation phenotype.

4 Article Comparison of clinicopathologic features and survival of histopathologically amelanotic and pigmented melanomas: a population-based study. 2014

Thomas, Nancy E / Kricker, Anne / Waxweiler, Weston T / Dillon, Patrick M / Busman, Klaus J / From, Lynn / Groben, Pamela A / Armstrong, Bruce K / Anton-Culver, Hoda / Gruber, Stephen B / Marrett, Loraine D / Gallagher, Richard P / Zanetti, Roberto / Rosso, Stefano / Dwyer, Terence / Venn, Alison / Kanetsky, Peter A / Orlow, Irene / Paine, Susan / Ollila, David W / Reiner, Anne S / Luo, Li / Hao, Honglin / Frank, Jill S / Begg, Colin B / Berwick, Marianne / Anonymous4450804. · ·JAMA Dermatol · Pubmed #25162299.

ABSTRACT: IMPORTANCE Previous studies have reported that histopathologically amelanotic melanoma is associated with poorer survival than pigmented melanoma; however, small numbers of amelanotic melanomas, selected populations, lack of centralized pathologic review, or no adjustment for stage limit the interpretation or generalization of results from prior studies.OBJECTIVE To compare melanoma-specific survival between patients with histopathologically amelanotic and those with pigmented melanoma in a large international population-based study.DESIGN, SETTING, AND PARTICIPANTS Survival analysis with a median follow-up of 7.6 years.The study population comprised 2995 patients with 3486 invasive primary melanomas centrally scored for histologic pigmentation from the Genes, Environment, and Melanoma(GEM) Study, which enrolled incident cases of melanoma diagnosed in 1998 through 2003 from international population-based cancer registries.MAIN OUTCOMES AND MEASURES Clinicopathologic predictors and melanoma-specific survival of histologically amelanotic and pigmented melanoma were compared using generalized estimating equations and Cox regression models, respectively.RESULTS Of 3467 melanomas, 275 (8%) were histopathologically amelanotic. Female sex,nodular and unclassified or other histologic subtypes, increased Breslow thickness, presence of mitoses, severe solar elastosis, and lack of a coexisting nevus were independently associated with amelanotic melanoma (each P < .05). Amelanotic melanoma was generally ofa higher American Joint Committee on Cancer (AJCC) tumor stage at diagnosis (odds ratios[ORs] [95%CIs] between 2.9 [1.8-4.6] and 11.1 [5.8-21.2] for tumor stages between T1b and T3b and ORs [95%CIs] of 24.6 [13.6-44.4] for T4a and 29.1 [15.5-54.9] for T4b relative to T1a;P value for trend, <.001) than pigmented melanoma. Hazard of death from melanoma was higher for amelanotic than for pigmented melanoma (hazard ratio [HR], 2.0; 95%CI, 1.4-3.0)(P < .001), adjusted for age, sex, anatomic site, and study design variables, but survival did not differ once AJCC tumor stage was also taken into account (HR, 0.8; 95%CI, 0.5-1.2)(P = .36).CONCLUSIONS AND RELEVANCE At the population level, survival after diagnosis of amelanotic melanoma is poorer than after pigmented melanoma because of its more advanced stage at diagnosis. It is probable that amelanotic melanomas present at more advanced tumor stages because they are difficult to diagnose. The association of amelanotic melanoma with presence of mitoses independently of Breslow thickness and other clinicopathologic characteristics suggests that amelanotic melanomas might also grow faster than pigmented melanomas. New strategies for early diagnosis and investigation of the biological properties of amelanotic melanoma are warranted.

5 Article Sun exposure and melanoma survival: a GEM study. 2014

Berwick, Marianne / Reiner, Anne S / Paine, Susan / Armstrong, Bruce K / Kricker, Anne / Goumas, Chris / Cust, Anne E / Thomas, Nancy E / Groben, Pamela A / From, Lynn / Busam, Klaus / Orlow, Irene / Marrett, Loraine D / Gallagher, Richard P / Gruber, Stephen B / Anton-Culver, Hoda / Rosso, Stefano / Zanetti, Roberto / Kanetsky, Peter A / Dwyer, Terry / Venn, Alison / Lee-Taylor, Julia / Begg, Colin B / Anonymous4670801. ·Department of Internal Medicine, Division of Epidemiology, Biostatistics and Preventive Medicine, University of New Mexico, Albuquerque, New Mexico. mberwick@salud.unm.edu. · Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York. · Department of Internal Medicine, Division of Epidemiology, Biostatistics and Preventive Medicine, University of New Mexico, Albuquerque, New Mexico. · University of Sydney, Sydney, New South Wales, Australia. · Departments of Dermatology and Pathology and Laboratory Medicine, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina. · Women's College Hospital, Toronto, Ontario, Canada. · Cancer Care Ontario, Toronto, Ontario, Canada. · British Columbia Cancer Agency, Vancouver, British Columbia, Canada. · Keck School of Medicine, University of Southern California, Los Angeles, California. · Department of Epidemiology, University of California, Irvine, California. · AOU San Giovanni Battista, Turin, Italy. · Piedmont Cancer Registry, Centre for Epidemiology and Prevention in Oncology in Piedmont, Turin, Italy. · Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida. · Murdoch Childrens Research Institute, Melbourne, Victoria, Australia. · Menzies Research Institute, University of Tasmania, Hobart, Tasmania, Australia. · Atmospheric Chemistry Division, National Center for Atmospheric Research, Boulder, Colorado. ·Cancer Epidemiol Biomarkers Prev · Pubmed #25069694.

ABSTRACT: BACKGROUND: We previously reported a significant association between higher UV radiation exposure before diagnosis and greater survival with melanoma in a population-based study in Connecticut. We sought to evaluate the hypothesis that sun exposure before diagnosis was associated with greater survival in a larger, international population-based study with more detailed exposure information. METHODS: We conducted a multicenter, international population-based study in four countries-Australia, Italy, Canada, and the United States-with 3,578 cases of melanoma with an average of 7.4 years of follow-up. Measures of sun exposure included sunburn, intermittent exposure, hours of holiday sun exposure, hours of water-related outdoor activities, ambient ultraviolet B (280-320 nm) dose, histologic solar elastosis, and season of diagnosis. RESULTS: Results were not strongly supportive of the earlier hypothesis. Having had any sunburn in 1 year within 10 years of diagnosis was inversely associated with survival; solar elastosis-a measure of lifetime cumulative exposure-was not. In addition, none of the intermittent exposure measures-water-related activities and sunny holidays-were associated with melanoma-specific survival. Estimated ambient UVB dose was not associated with survival. CONCLUSION: Although there was an apparent protective effect of sunburns within 10 years of diagnosis, there was only weak evidence in this large, international, population-based study of melanoma that sun exposure before diagnosis is associated with greater melanoma-specific survival. IMPACT: This study adds to the evidence that sun exposure before melanoma diagnosis has little effect on survival with melanoma.

6 Article DNA methylation profiles in primary cutaneous melanomas are associated with clinically significant pathologic features. 2014

Thomas, Nancy E / Slater, Nathaniel A / Edmiston, Sharon N / Zhou, Xin / Kuan, Pei-Fen / Groben, Pamela A / Carson, Craig C / Hao, Honglin / Parrish, Eloise / Moschos, Stergios J / Berwick, Marianne / Ollila, David W / Conway, Kathleen. ·Department of Dermatology, University of North Carolina, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA. ·Pigment Cell Melanoma Res · Pubmed #24986547.

ABSTRACT: DNA methylation studies have elucidated a methylation signature distinguishing primary melanomas from benign nevi and provided new insights about genes that may be important in melanoma development. However, it is unclear whether methylation differences among primary melanomas are related to tumor pathologic features with known clinical significance. We utilized the Illumina GoldenGate Cancer Panel array to investigate the methylation profiles of 47 primary cutaneous melanomas. Arraywide methylation patterns revealed a positive association of methylation with Breslow thickness and mutated BRAF, a negative association with mitotic rate, and a weak association with ulceration. Hierarchical clustering on CpG sites exhibiting the most variable methylation (n = 235) divided the melanoma samples into three clusters, including a highly methylated cluster that was positively associated with Breslow thickness and an intermediately methylated cluster associated with Breslow thickness and mitotic rate. Our findings provide support for the existence of methylation-defined subsets in melanomas with increased methylation associated with Breslow thickness.

7 Article Validation of the VE1 immunostain for the BRAF V600E mutation in melanoma. 2014

Pearlstein, Michelle V / Zedek, Daniel C / Ollila, David W / Treece, Amanda / Gulley, Margaret L / Groben, Pamela A / Thomas, Nancy E. ·Department of Dermatology, UNC School of Medicine, Chapel Hill, NC, USA. ·J Cutan Pathol · Pubmed #24917033.

ABSTRACT: BACKGROUND: BRAF mutation status, and therefore eligibility for BRAF inhibitors, is currently determined by sequencing methods. We assessed the validity of VE1, a monoclonal antibody against the BRAF V600E mutant protein, in the detection of mutant BRAF V600E melanomas as classified by DNA pyrosequencing. METHODS: The cases were 76 metastatic melanoma patients with only one known primary melanoma who had had BRAF codon 600 pyrosequencing of either their primary (n = 19), metastatic (n = 57) melanoma, or both (n = 17). All melanomas (n = 93) were immunostained with the BRAF VE1 antibody using a red detection system. The staining intensity of these specimens was scored from 0 to 3+ by a dermatopathologist. Scores of 0 and 1+ were considered as negative staining while scores of 2+ and 3+ were considered positive. RESULTS: The VE1 antibody showed a sensitivity of 85% and a specificity of 100% as compared to DNA pyrosequencing results. There was 100% concordance between VE1 immunostaining of primary and metastatic melanomas from the same patient. V600K, V600Q, and V600R BRAF melanomas did not positively stain with VE1. CONCLUSIONS: This hospital-based study finds high sensitivity and specificity for the BRAF VE1 immunostain in comparison to pyrosequencing in detection of BRAF V600E in melanomas.

8 Article Development of DNA damage response signaling biomarkers using automated, quantitative image analysis. 2014

Nikolaishvilli-Feinberg, Nana / Cohen, Stephanie M / Midkiff, Bentley / Zhou, Yingchun / Olorvida, Mark / Ibrahim, Joseph G / Omolo, Bernard / Shields, Janiel M / Thomas, Nancy E / Groben, Pamela A / Kaufmann, William K / Miller, C Ryan. ·Translational Pathology Laboratory (NNF, SMC, BM, MO, CRM), University of North Carolina School of Medicine, NC, USA. ·J Histochem Cytochem · Pubmed #24309508.

ABSTRACT: The DNA damage response (DDR) coordinates DNA repair with cell cycle checkpoints to ameliorate or mitigate the pathological effects of DNA damage. Automated quantitative analysis (AQUA) and Tissue Studio are commercial technologies that use digitized immunofluorescence microscopy images to quantify antigen expression in defined tissue compartments. Because DDR is commonly activated in cancer and may reflect genetic instability within the lesion, a method to quantify DDR in cancer offers potential diagnostic and/or prognostic value. In this study, both AQUA and Tissue Studio algorithms were used to quantify the DDR in radiation-damaged skin fibroblasts, melanoma cell lines, moles, and primary and metastatic melanomas. Digital image analysis results for three markers of DDR (γH2AX, P-ATM, P-Chk2) correlated with immunoblot data for irradiated fibroblasts, whereas only γH2AX and P-Chk2 correlated with immunoblot data in melanoma cell lines. Melanoma cell lines displayed substantial variation in γH2AX and P-Chk2 expression, and P-Chk2 expression was significantly correlated with radioresistance. Moles, primary melanomas, and melanoma metastases in brain, lung and liver displayed substantial variation in γH2AX expression, similar to that observed in melanoma cell lines. Automated digital analysis of immunofluorescent images stained for DDR biomarkers may be useful for predicting tumor response to radiation and chemotherapy.

9 Article Tumor-infiltrating lymphocyte grade in primary melanomas is independently associated with melanoma-specific survival in the population-based genes, environment and melanoma study. 2013

Thomas, Nancy E / Busam, Klaus J / From, Lynn / Kricker, Anne / Armstrong, Bruce K / Anton-Culver, Hoda / Gruber, Stephen B / Gallagher, Richard P / Zanetti, Roberto / Rosso, Stefano / Dwyer, Terence / Venn, Alison / Kanetsky, Peter A / Groben, Pamela A / Hao, Honglin / Orlow, Irene / Reiner, Anne S / Luo, Li / Paine, Susan / Ollila, David W / Wilcox, Homer / Begg, Colin B / Berwick, Marianne. ·Nancy E. Thomas, Pamela A. Groben, Honglin Hao, and David W. Ollila, University of North Carolina, Chapel Hill, NC · Klaus J. Busam, Irene Orlow, Anne S. Reiner, and Colin B. Begg, Memorial Sloan-Kettering Cancer Center, New York, NY · Lynn From, Women's College Hospital, Toronto, Ontario · Richard P. Gallagher, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada · Anne Kricker and Bruce K. Armstrong, The University of Sydney, Sydney, New South Wales · Alison Venn, Menzies Research Institute, Tasmania, Australia · Hoda Anton-Culver, University of California, Irvine · Stephen B. Gruber, University of Southern California, Los Angeles, CA · Roberto Zanetti and Stefano Rosso, Center for Cancer Prevention, Torino, Italy · Terence Dwyer, International Agency for Research on Cancer, Lyon, France · Peter A. Kanetsky, University of Pennsylvania, Philadelphia, PA · Li Luo, Susan Paine, and Marianne Berwick, University of New Mexico, Albuquerque, NM · and Homer Wilcox, New Jersey Department of Health, Trenton, NJ. ·J Clin Oncol · Pubmed #24127443.

ABSTRACT: PURPOSE: Although most hospital-based studies suggest more favorable survival with tumor-infiltrating lymphocytes (TILs) present in primary melanomas, it is uncertain whether TILs provide prognostic information beyond existing melanoma staging definitions. We addressed the issue in an international population-based study of patients with single and multiple primary melanomas. PATIENTS AND METHODS: On the basis of the Genes, Environment and Melanoma (GEM) study, we conducted follow-up of 2,845 patients diagnosed from 1998 to 2003 with 3,330 invasive primary melanomas centrally reviewed for TIL grade (absent, nonbrisk, or brisk). The odds of TIL grades associated with clinicopathologic features and survival by TIL grade were examined. RESULTS: Independent predictors (P < .05) for nonbrisk TIL grade were site, histologic subtype, and Breslow thickness, and for brisk TIL grade, they were age, site, Breslow thickness, and radial growth phase. Nonbrisk and brisk TIL grades were each associated with lower American Joint Committee on Cancer (AJCC) tumor stage compared with TIL absence (P(trend) < .001). Death as a result of melanoma was 30% less with nonbrisk TIL grade (hazard ratio [HR], 0.7; 95% CI, 0.5 to 1.0) and 50% less with brisk TIL grade (HR, 0.5; 95% CI, 0.3 to 0.9) relative to TIL absence, adjusted for age, sex, site, and AJCC tumor stage. CONCLUSION: At the population level, higher TIL grade of primary melanoma is associated with a lower risk of death as a result of melanoma independently of tumor characteristics currently used for AJCC tumor stage. We conclude that TIL grade deserves further prospective investigation to determine whether it should be included in future AJCC staging revisions.

10 Article Survival for patients with single and multiple primary melanomas: the genes, environment, and melanoma study. 2013

Kricker, Anne / Armstrong, Bruce K / Goumas, Chris / Thomas, Nancy E / From, Lynn / Busam, Klaus / Kanetsky, Peter A / Gallagher, Richard P / Marrett, Loraine D / Groben, Pamela A / Gruber, Stephen B / Anton-Culver, Hoda / Rosso, Stefano / Dwyer, Terence / Berwick, Marianne / Anonymous5480761. ·Cancer Epidemiology and Services Research, Sydney School of Public Health, University of Sydney, Sydney, Australia. ·JAMA Dermatol · Pubmed #23784017.

ABSTRACT: IMPORTANCE: Little is known about survival after a diagnosis of a second or higher-order (multiple) primary melanoma, and no study has explored survival in a population-based sample that included patients with single primary melanomas (SPMs) and multiple primary melanomas (MPMs) of any stage. Because people with a first primary melanoma are known to have an increased risk of being diagnosed with another, evidence for prognosis is needed. OBJECTIVE: To determine whether survival after diagnosis was better in patients with MPMs than with SPMs, as suggested in a recent study. DESIGN Survival analysis with median follow-up of 7.6 (range, 0.4-10.6) years. SETTING: The Genes, Environment, and Melanoma Study enrolled incident cases of melanoma from population-based cancer registries in Australia, Canada, Italy, and the United States. Multiple primary melanomas were ascertained during a longer period than SPM. PARTICIPANTS: Two thousand three hundred seventy-two patients with SPM and 1206 with MPM. EXPOSURE: Diagnosis with melanoma. MAIN OUTCOMES AND MEASURES: Melanoma-specific fatality hazard ratios (HR) and 95% confidence intervals associated with clinical and pathological characteristics of SPM, MPM, and both in Cox proportional hazards regression models. RESULTS: Melanoma thickness was the main determinant of fatality (HR for >4 mm, 7.68 [95% CI, 4.46-13.23]); other independent predictors were ulceration, mitoses, and scalp location. After adjustment for these other predictors, we found little difference in fatality between MPM and SPM (HR for MPM relative to SPM, 1.24 [95% CI, 0.91-1.69; P = .18]). Thicker SPM, however, had higher fatality (HR for >4 mm, 13.56 [95% CI, 6.47-28.40]) than thicker MPM (2.93 [1.17-7.30]). CONCLUSIONS AND RELEVANCE: Although overall fatalities due to SPM and MPM were similar, relative fatality for thicker SPM was greater than that for thicker MPM. This finding may offer support for a difference in outcome between patients with SPM and MPM related to factors other than closer surveillance and earlier diagnosis. The better outcomes are worth further exploration.

11 Article P-Rex1 is required for efficient melanoblast migration and melanoma metastasis. 2011

Lindsay, Colin R / Lawn, Samuel / Campbell, Andrew D / Faller, William J / Rambow, Florian / Mort, Richard L / Timpson, Paul / Li, Ang / Cammareri, Patrizia / Ridgway, Rachel A / Morton, Jennifer P / Doyle, Brendan / Hegarty, Shauna / Rafferty, Mairin / Murphy, Ian G / McDermott, Enda W / Sheahan, Kieran / Pedone, Katherine / Finn, Alexander J / Groben, Pamela A / Thomas, Nancy E / Hao, Honglin / Carson, Craig / Norman, Jim C / Machesky, Laura M / Gallagher, William M / Jackson, Ian J / Van Kempen, Leon / Beermann, Friedrich / Der, Channing / Larue, Lionel / Welch, Heidi C / Ozanne, Brad W / Sansom, Owen J. ·The Beatson Institute for Cancer Research, Glasgow G61 1BD, UK. ·Nat Commun · Pubmed #22109529.

ABSTRACT: Metastases are the major cause of death from melanoma, a skin cancer that has the fastest rising incidence of any malignancy in the Western world. Molecular pathways that drive melanoblast migration in development are believed to underpin the movement and ultimately the metastasis of melanoma. Here we show that mice lacking P-Rex1, a Rac-specific Rho GTPase guanine nucleotide exchange factor, have a melanoblast migration defect during development evidenced by a white belly. Moreover, these P-Rex1(-/-) mice are resistant to metastasis when crossed to a murine model of melanoma. Mechanistically, this is associated with P-Rex1 driving invasion in a Rac-dependent manner. P-Rex1 is elevated in the majority of human melanoma cell lines and tumour tissue. We conclude that P-Rex1 has an important role in melanoblast migration and cancer progression to metastasis in mice and humans.

12 Article DNA-methylation profiling distinguishes malignant melanomas from benign nevi. 2011

Conway, Kathleen / Edmiston, Sharon N / Khondker, Zakaria S / Groben, Pamela A / Zhou, Xin / Chu, Haitao / Kuan, Pei Fen / Hao, Honglin / Carson, Craig / Berwick, Marianne / Olilla, David W / Thomas, Nancy E. ·Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, NC, USA. kconway@med.unc.edu ·Pigment Cell Melanoma Res · Pubmed #21375697.

ABSTRACT: DNA methylation, an epigenetic alteration typically occurring early in cancer development, could aid in the molecular diagnosis of melanoma. We determined technical feasibility for high-throughput DNA-methylation array-based profiling using formalin-fixed paraffin-embedded tissues for selection of candidate DNA-methylation differences between melanomas and nevi. Promoter methylation was evaluated in 27 common benign nevi and 22 primary invasive melanomas using a 1505 CpG site microarray. Unsupervised hierarchical clustering distinguished melanomas from nevi; 26 CpG sites in 22 genes were identified with significantly different methylation levels between melanomas and nevi after adjustment for age, sex, and multiple comparisons and with β-value differences of ≥ 0.2. Prediction analysis for microarrays identified 12 CpG loci that were highly predictive of melanoma, with area under the receiver operating characteristic curves of > 0.95. Of our panel of 22 genes, 14 were statistically significant in an independent sample set of 29 nevi (including dysplastic nevi) and 25 primary invasive melanomas after adjustment for age, sex, and multiple comparisons. This first report of a DNA-methylation signature discriminating melanomas from nevi indicates that DNA methylation appears promising as an additional tool for enhancing melanoma diagnosis.

13 Minor Relationship between germline MC1R variants and BRAF-mutant melanoma in a North Carolina population-based study. 2010

Thomas, Nancy E / Kanetsky, Peter A / Edmiston, Sharon N / Alexander, Audrey / Begg, Colin B / Groben, Pamela A / Hao, Honglin / Busam, Klaus / Ollila, David W / Berwick, Marianne / Conway, Kathleen. · ·J Invest Dermatol · Pubmed #20043015.

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