Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043346 (xeroderma pigmentosum)
 2,924 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Evidence of ultraviolet type mutations in xeroderma pigmentosum melanomas. 1932 85

Nonmelanoma skin cancer is the most common cancer in the United States, where DNA-damaging ultraviolet B (UVB) radiation from the sun remains the major environmental risk factor. However, the critical genetic targets of UVB radiation are undefined. Here we show that attenuating PTEN in epidermal keratinocytes is a predisposing factor for UVB-induced skin carcinogenesis in mice. In skin papilloma and squamous cell carcinoma (SCC), levels of PTEN were reduced compared with skin lacking these lesions. Likewise, there was a reduction in PTEN levels in human premalignant actinic keratosis and malignant SCCs, supporting a key role for PTEN in human skin cancer formation and progression. PTEN downregulation impaired the capacity of global genomic nucleotide excision repair (GG-NER), a critical mechanism for removing UVB-induced mutagenic DNA lesions. In contrast to the response to ionizing radiation, PTEN downregulation prolonged UVB-induced growth arrest and increased the activation of the Chk1 DNA damage pathway in an AKT-independent manner, likely due to reduced DNA repair. PTEN loss also suppressed expression of the key GG-NER protein xeroderma pigmentosum C (XPC) through the AKT/p38 signaling axis. Reconstitution of XPC levels in PTEN-inhibited cells restored GG-NER capacity. Taken together, our findings define PTEN as an essential genomic gatekeeper in the skin through its ability to positively regulate XPC-dependent GG-NER following DNA damage.
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PMID:PTEN positively regulates UVB-induced DNA damage repair. 2177 8

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.
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PMID:High frequency of PTEN mutations in nevi and melanomas from xeroderma pigmentosum patients. 2448 90

Conjunctival tumors encompass a broad range of diagnoses. The 3 most important malignant tumors include ocular surface squamous neoplasia (OSSN) (14%), melanoma (12%), and lymphoma (7%). Conjunctival malignancies are rarely found in children. Regarding OSSN, pre-disposing conditions include chronic solar radiation, immune deficiency (HIV), organ transplant, autoimmune conditions, xeroderma pigmentosum, and chronic exposure to cigarette smoke. OSSN is managed surgically or with topical/injection immunotherapy or chemotherapy. Metastasis occurs in <1%. Regarding melanoma, predisposing conditions include primary acquired melanosis (PAM), chronic nevus, and chronic solar radiation. Treatment of PAM or nevus can prevent melanoma. Melanoma management involves surgical resection with clean margins and avoidance of direct tumor manipulation ("no touch" technique). The first surgery is most important, to minimize tumor seeding. Biomarkers including BRAF, TERT, and PTEN provide information regarding risk for metastasis and allow for targeted antibiomarker therapies. Ten-year risk for melanoma metastasis is 25%. Tumors >2 mm thickness or those located in fornix, caruncle, or orbit are at highest risk for metastasis. Regarding lymphoma, predisposing conditions include benign reactive lymphoid hyperplasia, immune deficiency (HIV), immune dysfunction, and chronic inflammation/infection (Helicobacter pylori, Chlamydia psittaci). The 4 most important subtypes include extranodal marginal zone lymphoma (ENMZL), follicular lymphoma, mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma. Treatment includes surgical resection, cryotherapy, radiotherapy, systemic chemotherapy, or targeted anti-B-cell therapy (rituximab). Lymphoma-related survival (5-year) depends on subtype and ranges from 97% (ENMZL) to 9% (MCL). Recognizing conjunctival tumors and understanding predisposing factors, biomarkers, and treatment strategies are vital to patient outcomes.
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PMID:Conjunctival Tumors: Review of Clinical Features, Risks, Biomarkers, and Outcomes--The 2017 J. Donald M. Gass Lecture. 2839 47