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Cancer Epidemiology, Biomarkers & Prevention
Cancer Epidemiology, Biomarkers & Prevention
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Research Articles

Number of Nevi and Early-Life Ambient UV Exposure Are Associated with BRAF-Mutant Melanoma

Nancy E. Thomas, Sharon N. Edmiston, Audrey Alexander, Robert C. Millikan, Pamela A. Groben, Honglin Hao, Dawn Tolbert, Marianne Berwick, Klaus Busam, Colin B. Begg, Dianne Mattingly, David W. Ollila, Chiu Kit Tse, Amanda Hummer, Julia Lee-Taylor and Kathleen Conway
Nancy E. Thomas
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Sharon N. Edmiston
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Audrey Alexander
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Robert C. Millikan
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Pamela A. Groben
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Honglin Hao
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Dawn Tolbert
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Marianne Berwick
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Klaus Busam
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Colin B. Begg
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Dianne Mattingly
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David W. Ollila
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Chiu Kit Tse
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Amanda Hummer
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Julia Lee-Taylor
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Kathleen Conway
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DOI: 10.1158/1055-9965.EPI-06-1038 Published May 2007
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  • Table 1.

    Spectrum of BRAF and NRAS mutations in invasive cutaneous melanomas (N = 214)

    GeneMutationBase changeNo. patients%*
    BRAFV600EGTG to GAG6028.0
    V600KGTG to AAG157.0
    V600EGTG to GAA41.9
    V600RGTG to AGG20.9
    V600DGTG to GAT10.5
    VKS600-602DT†GTG-AAA-TCT to GAT-ACT10.5
    K601EAAA to GAA20.9
    K601NAAA to AAC10.5
    L597RCTA to CGA10.5
    D594NGAT to AAT10.5
    G469AGGA to GCA10.5
    G466EGGA to GAA10.5
    G455RGGG to AGG10.5
    G455EGGG to GAG10.5
    NRASQ61KCAA to AAA146.5
    Q61RCAA to CGA104.7
    Q61LCAA to CTA41.9
    Q61HCAA to CAC10.5
    • ↵* Percentage of melanomas screened that carry this alteration.

    • ↵† A deletion of six bases and an insertion of three bases, with a net loss of three bases. Wild-type residue 603/Arg would then follow the Asp-Thr.

  • Table 2.

    Clinicopathologic characteristics by BRAF and NRAS mutational status among melanoma cases (N = 214)

    CharacteristicBRAF+ (n = 92)NRAS+ (n = 29)Wild-type (n = 93)BRAF+ vs wild-type, OR* (95% CI)NRAS+ vs wild-type, OR* (95% CI)
    Age at diagnosis (y)
        Mean ± SD, y47.3 ± 14.162.1 ± 12.853.9 ± 17.9
        P < 0.001†
        Per 10 y0.8 (0.6-0.9)1.3 (1.0-1.7)
    Gender, n (%)
        Male48 (52)17 (59)52 (56)1.01.0
        Female44 (48)12 (41)41 (44)1.0 (0.5-1.8)1.0 (0.4-2.5)
    Histologic subtype, n (%)
        SSM79 (86)23 (79)67 (72)1.01.0
        NM5 (5)3 (10)2 (2)3.3 (0.6-18.2)2.6 (0.4-17.9)
        LMM5 (5)2 (7)15 (16)0.4 (0.1-1.3)0.2 (0.4-1.1)
        ALM/other‡3 (3)1 (4)9 (10)0.3 (0.1-1.1)0.3 (0.0-2.5)
    Breslow thickness (mm), n (%)
        <0.7542 (46)12 (41)66 (71)1.01.0
        ≥0.7550 (54)17 (59)27 (29)3.2 (1.7-5.9)3.2 (1.3-7.7)
    • Abbreviations: BRAF+, BRAF-mutant; NRAS+, NRAS-mutant melanoma; Wild-type, melanoma negative for BRAF and NRAS mutations; SSM, superficial spreading melanoma; NM, nodular melanoma.

    • ↵* OR values for gender, histologic subtype, and Breslow thickness are adjusted for age as a continuous variable.

    • ↵† Two-sided ANOVA test for comparison of mean ages across BRAF+, NRAS+, and wild-type cases.

    • ↵‡ This category includes two ALMs that were negative for BRAF and NRAS mutations and other melanomas that were nevoid, spitzoid, and unclassifiable.

  • Table 3.

    Phenotypic characteristics by BRAF and NRAS mutational status among melanoma cases (N = 214)

    CharacteristicBRAF+ (N = 92)
    NRAS+ (N = 29)
    Wild-type (N = 93)
    BRAF+ vs wild-type, OR* (95% CI)NRAS+ vs wild-type, OR* (95% CI)
    n† (%)
    No. nevi on the back
        Median (interquartile range)14.5 (7-34)12.0 (4-20)9.0 (3-19)
        0-414 (16)9 (31)32 (36)1.01.0
        5-1431 (34)9 (31)28 (31)2.4 (1.1-5.5)1.2 (0.4-3.7)
        >1445 (50)11 (38)29 (33)3.2 (1.4-7.0)1.7 (0.6-4.8)
        Ptrend0.0060.34
    Nevus density diagrams
        None11 (12)5 (19)27 (30)1.01.0
        Low51 (58)17 (62)49 (55)2.3 (1.0-5.2)2.7 (0.8-8.6)
        Medium to high26 (30)5 (19)13 (15)3.8 (1.4-10.4)3.3 (0.7-14.9)
        Ptrend0.0090.10
    Propensity to tan
        Deep tan20 (23)5 (19)11 (13)1.01.0
        Moderate tan34 (38)13 (48)35 (41)0.5 (0.2-1.3)0.7 (0.2-2.6)
        Mild tan27 (31)6 (22)24 (28)0.7 (0.3-1.8)0.4 (0.1-1.8)
        No tan7 (8)3 (11)15 (18)0.3 (0.1-0.9)0.3 (0.1-1.6)
        Ptrend0.130.09
    Childhood freckles
        None50 (56)13 (45)48 (52)1.01.0
        Few31 (34)14 (48)29 (31)0.9 (0.5-1.8)2.0 (0.8-4.8)
        Many9 (10)2 (7)16 (17)0.5 (0.2-1.2)0.5 (0.1-2.4)
        Ptrend0.180.92
    Hair color
        Black or dark brown28 (30)12 (41)28 (30)1.01.0
        Light brown or blond57 (62)13 (45)50 (54)1.2 (0.6-2.3)0.6 (0.2-1.4)
        Red7 (8)4 (14)14 (15)0.5 (0.2-1.5)0.6 (0.2-2.4)
    Eye color
        Black or brown26 (28)7 (24)26 (28)1.01.0
        Hazel, green, gray or blue66 (72)22 (76)67 (72)1.0 (0.5-2.0)1.3 (0.5-3.4)
    • ↵* OR values are adjusted for age as a continuous variable.

    • ↵† Counts may not sum to the total number of study subjects due to missing data.

  • Table 4.

    Indicators of sun exposure by BRAF and NRAS mutational status among melanoma cases (N = 214)

    CharacteristicBRAF+ (N = 92)
    NRAS+ (N = 29)
    Wild-type (N = 93)
    BRAF+ vs wild-type, OR* (95% CI)NRAS+ vs wild-type, OR* (95% CI)
    n† (%)
    Anatomic site
        Intermittently exposed site (trunk)54 (59)17 (59)37 (40)1.01.0
        Chronically exposed sites (head/neck/extremities)38 (41)12 (41)56 (60)0.5 (0.3-1.0)0.4 (0.2-0.9)
    CSD assessed by histologic solar elastosis
        Non-CSD75 (82)17 (59)59 (63)1.01.0
        CSD17 (18)12 (41)34 (37)0.5 (0.3-1.2)0.7 (0.3-1.9)
    Ambient erythemal UV irradiance, annual total in kJ/m2/y
        Lifetime (average of all decadal ages)
            Low UV (≤804)17 (20)9 (33)30 (33)1.01.0
            High UV (>804)70 (80)18 (67)60 (67)2.0 (1.0-4.0)1.1 (0.4-2.7)
        Early life (average of ages 0 and 10 y)
            Low UV (≤770)14 (16)11 (39)30 (33)1.01.0
            High UV (>770)75 (84)17 (61)60 (67)2.6 (1.2-5.3)0.9 (0.4-2.2)
    By decade‡
        Birth year
            Low UV (≤751)17 (19)11 (39)30 (33)1.01.0
            High UV (>751)72 (81)17 (61)60 (67)2.0 (1.0-4.1)0.9 (0.4-2.2)
        Age 10 y
            Low UV (≤804)17 (19)12 (41)29 (32)1.01.0
            High UV (>804)73 (81)17 (59)61 (68)1.9 (1.0-3.9)0.8 (0.3-1.9)
        Age 20 y
            Low UV (≤783)13 (14)12 (41)29 (33)1.01.0
            High UV (>783)77 (86)17 (59)60 (67)2.7 (1.3-5.7)0.8 (0.3-1.9)
        Age 30 y
            Low UV (≤806)25 (31)14 (48)30 (36)1.01.0
            High UV (>806)57 (69)15 (52)53 (64)1.0 (0.5-1.9)0.7 (0.3-1.8)
        Age 40 y
            Low UV (≤806)14 (22)9 (31)25 (34)1.01.0
            High UV (>806)49 (78)20 (69)48 (66)1.4 (0.6-3.3)1.3 (0.5-3.4)
        Age 50 y
            Low UV (≤806)8 (18)5 (19)20 (38)1.01.0
            High UV (>806)37 (82)21 (81)32 (62)1.2 (0.4-3.8)2.5 (0.7-8.5)
        Age 60 y
            Low UV (≤807)3 (17)4 (25)14 (38)1.01.0
            High UV (>807)15 (83)12 (75)23 (62)1.1 (0.2-7.0)2.0 (0.4-9.8)
    • ↵* OR values are adjusted for age as a continuous variable.

    • ↵† Counts may not sum to the total number of study subjects due to missing data.

    • ↵‡ Logistic regression models above age 60 y were unstable due to sparse data.

  • Table 5.

    Relationship of age at diagnosis, number of back nevi, and estimated early-life ambient erythemal UV irradiance to BRAF and NRAS mutational status among melanoma cases (N = 202)

    CharacteristicBRAF+ vs wild-type, OR* (95% CI)NRAS+ vs wild-type, OR* (95% CI)
    Age at diagnosis (per 10 y)0.8 (0.7-1.0)1.4 (1.1-1.9)
    No. nevi on the back
        0-41.01.0
        5-142.8 (1.2-6.4)1.1 (0.4-3.3)
        >143.4 (1.5-7.8)1.9 (0.6-5.5)
        Ptrend0.0040.27
    Early-life ambient UV irradiance in kJ/m2/y
        Low UV (≤770)1.01.0
        High UV (>770)2.6 (1.2-5.6)0.9 (0.4-2.2)
    • NOTE: Subjects were 202 participants for whom no data were missing for the factors in the model.

    • ↵* OR values are adjusted for all factors in the model.

Additional Files

  • Tables
  • Supplementary Data, Thomas et al

    Files in this Data Supplement:

    • Supplementary Data
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Cancer Epidemiology Biomarkers & Prevention: 16 (5)
May 2007
Volume 16, Issue 5
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Number of Nevi and Early-Life Ambient UV Exposure Are Associated with BRAF-Mutant Melanoma
Nancy E. Thomas, Sharon N. Edmiston, Audrey Alexander, Robert C. Millikan, Pamela A. Groben, Honglin Hao, Dawn Tolbert, Marianne Berwick, Klaus Busam, Colin B. Begg, Dianne Mattingly, David W. Ollila, Chiu Kit Tse, Amanda Hummer, Julia Lee-Taylor and Kathleen Conway
Cancer Epidemiol Biomarkers Prev May 1 2007 (16) (5) 991-997; DOI: 10.1158/1055-9965.EPI-06-1038

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Number of Nevi and Early-Life Ambient UV Exposure Are Associated with BRAF-Mutant Melanoma
Nancy E. Thomas, Sharon N. Edmiston, Audrey Alexander, Robert C. Millikan, Pamela A. Groben, Honglin Hao, Dawn Tolbert, Marianne Berwick, Klaus Busam, Colin B. Begg, Dianne Mattingly, David W. Ollila, Chiu Kit Tse, Amanda Hummer, Julia Lee-Taylor and Kathleen Conway
Cancer Epidemiol Biomarkers Prev May 1 2007 (16) (5) 991-997; DOI: 10.1158/1055-9965.EPI-06-1038
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