Evidence of ultraviolet type mutations in xeroderma pigmentosum melanomas

Yun Wang, John J. DiGiovanna, Jere B. Stern, Thomas J. Hornyak, Mark Raffeld, Sikandar G. Khan, Kyu Seon Oh, M. Christine Hollander, Philip A. Dennis, Kenneth H. Kraemer

Research output: Contribution to journalArticlepeer-review

66 Scopus citations


To look for a direct role of ultraviolet radiation (UV) exposure in cutaneous melanoma induction, we studied xeroderma pigmentosum (XP) patients who have defective DNA repair resulting in a 1000-fold increase in melanoma risk. These XP melanomas have the same anatomic distribution as melanomas in the general population. We analyzed laser capture microdissection samples of skin melanomas from XP patients studied at the National Institutes of Health. The tumor suppressor gene PTEN was sequenced and analyzed for UV-induced mutations. Samples from 59 melanomas (47 melanomas in situ and 12 invasive melanomas) from 8 XP patients showed mutations in the PTEN tumor suppressor gene in 56% of the melanomas. Further, 91 % of the melanomas with mutations had 1 to 4 UV type base substitution mutations (occurring at adjacent pyrimidines) (P < 0.0001 compared to random mutations). We found a high frequency of amino-acid-altering mutations in the melanomas and demonstrated that these mutations impaired PTEN function; UV damage plays a direct role in induction of mutations and in inactivation of the PTEN gene in XP melanomas including in situ, the earliest stage of melanoma. This gene is known to be a key regulator of carcinogenesis and therefore these data provide solid mechanistic support for UV protection for prevention of melanoma.

Original languageEnglish (US)
Pages (from-to)6279-6284
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number15
StatePublished - Apr 14 2009
Externally publishedYes


  • DNA repair
  • Laser capture microdissection
  • PTEN
  • Skin cancer
  • Ultraviolet radiation

ASJC Scopus subject areas

  • General


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