Predictors of BRAF mutation in melanocytic nevi: analysis across regions with different UV radiation exposure.
BACKGROUND
BRAF mutations have been implicated in initiating promutagenic cellular melanocytic proliferation mostly based on homogeneous Western-based cohorts. Data addressing the possible interaction between exposure to different solar ultraviolet radiation (UVR) magnitudes and BRAF mutation rate (BMR) in melanocytic nevi are limited.


METHODS
Extended BRAF testing for 9 mutations in 225 melanocytic nevus (MN) cases derived from 211 patients from 4 different UVR regions: Lebanon (n = 95; 110 kJ · m(-2) · yr), Syria (n = 23; 93.5 kJ · m(-2) · yr), Kingdom of Saudi Arabia (n = 70; 139 kJ · m(-2) · yr), and Pakistan (n = 37; 118 kJ · m(-2) · yr) was performed. Data collected included age, gender, anatomic location, and lesion size. Histological parameters recorded were MN type (junctional, compound, intradermal, classical blue, cellular blue, compound and intradermal spitz, and congenital) solar elastosis grade, and nevus pigmentation degree. Cumulative 21-year erythemally effective UV averages were derived from The National Center for Atmospheric Research.


RESULTS
BRAF mutation status was obtained in 210 cases (6.7% failed polymerase chain reaction). Overall, BMR was 62.4% (131/210) with V600E mutation accounting for 98.5% of cases. Discordant mutation status was found in 2 of 10 patients with multiple nevi. BMR differed significantly, yet nonsystematically, among UVR regions; the highest was detected in nevi coming from Syria (18/23 cases, 78%), followed by Pakistan (21/30 cases, 70%), Kingdom of Saudi Arabia (47/70 cases, 67%), and Lebanon (45/87 cases, 52%). Mutation rates varied significantly across MN type (P < 0.001); the highest rate was recorded in the intradermal nevus type (33/39 cases, 84.6%), followed by the compound (26/32 cases, 81.2%) and congenital (60/74 cases 81.0%) nevi. Stratified by anatomic location, nevi occurring on the face (61/82, 74%) and trunk (58/78, 74%) had more frequent BMRs compared with those occurring on the upper (7/26, 27%) and lower extremities (5/24, 21%, P < 0.001). Severe pigmentation was less frequent in BRAF mutation-positive nevi [5/131 (4%) vs. 34/79 (43%); P < 0.001]. Multivariate independent predictors of BRAF mutation in MN were age [odds ratio (95% confidence interval ) = 1.43 (1.13-1.74) per 10 years; P = 0.004], anatomic location [P = 0.043 overall], and nevus type [P < 0.001 overall]. UVR region was not an independent predictor of BRAF mutation.


CONCLUSIONS
Increased BRAF mutation with age along with the lack of a UVR magnitude-BRAF mutation association suggests that duration of exposure rather than UVR exposure dose is the more likely link to acquiring the mutation.
Department of Pathology and Laboratory Medicine, American University of Beirut Medical Center, Beirut, Lebanon.
Sarah
S
Karram
Michael
M
Novy
Maya
M
Saroufim
Asif
A
Loya
Suad
S
Taraif
Mohammad A
MA
Houreih
Bettina
B
Rauscher
Robert H
RH
Habib
Christian
C
Oberkanins
Ibrahim
I
Khalifeh
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D001706:Biopsy; D016009:Chi-Square Distribution; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D008877:Middle East; D015999:Multivariate Analysis; D009154:Mutation; D009381:Neoplasms, Radiation-Induced / Q000201:enzymology / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D009508:Nevus, Pigmented / Q000201:enzymology / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D016017:Odds Ratio; D010154:Pakistan; D016133:Polymerase Chain Reaction; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012111:Residence Characteristics; D012307:Risk Factors; D012878:Skin Neoplasms / Q000201:enzymology / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D013472:Sunlight / Q000009:adverse effects*; D013997:Time Factors; D014466:Ultraviolet Rays / Q000009:adverse effects*; D055815:Young Adult
C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf