High frequency of PTEN mutations in nevi and melanomas from xeroderma pigmentosum patients.
We examined nevi and melanomas in 10 xeroderma pigmentosum (XP) patients with defective DNA repair. The lesions had a lentiginous appearance with markedly increased numbers of melanocytes. Using laser capture microdissection, we performed DNA sequencing of 18 benign and atypical nevi and 75 melanomas (melanoma in situ and invasive melanomas). The nevi had a similar high frequency of PTEN mutations as melanomas [61% (11/18) versus 53% (39/73)]. Both had a very high proportion of UV-type mutations (occurring at adjacent pyrimidines) [91% (10/11) versus 92% (36/39)]. In contrast to melanomas in the general population, the frequency of BRAF mutations (11%, 7/61), NRAS mutations (21%, 13/62), and KIT mutations (21%, 6/28) in XP melanomas was lower than for PTEN. Phospho-S6 immunostaining indicated activation of the mTOR pathway in the atypical nevi and melanomas. Thus, the clinical and histological appearances and the molecular pathology of these UV-related XP nevi and melanomas were different from nevi and melanomas in the general population.
Dermatology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA; Division of Dermatology, Graduate School of Medicine, Kobe University, Kobe, Japan.
Taro
T
Masaki
Yun
Y
Wang
John J
JJ
DiGiovanna
Sikandar G
SG
Khan
Mark
M
Raffeld
Senda
S
Beltaifa
Thomas J
TJ
Hornyak
Thomas N
TN
Darling
Chyi-Chia R
CC
Lee
Kenneth H
KH
Kraemer
D000328:Adult; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D046169:Dermoscopy; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008545:Melanoma / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics; D009381:Neoplasms, Radiation-Induced / Q000235:genetics / Q000473:pathology; D009508:Nevus, Pigmented / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D009857:Oncogenes; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D011230:Precancerous Conditions / Q000209:etiology / Q000235:genetics / Q000473:pathology; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D012878:Skin Neoplasms / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D013472:Sunlight / Q000009:adverse effects; D058570:TOR Serine-Threonine Kinases / Q000502:physiology; D014466:Ultraviolet Rays / Q000009:adverse effects; D014983:Xeroderma Pigmentosum / Q000150:complications* / Q000235:genetics; D055815:Young Adult
D004273:DNA, Neoplasm; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C546842:MTOR protein, human; D019009:Proto-Oncogene Proteins c-kit; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human
DNA repair; PTEN; UV carcinogenesis; mTOR; melanoma; nevi; xeroderma pigmentosum