ABCC8 p.Arg248Trp
| Predicted by SNAP2: | A: N (87%), C: N (61%), D: N (72%), E: N (72%), F: N (57%), G: N (82%), H: N (72%), I: N (87%), K: N (93%), L: N (78%), M: N (72%), N: N (93%), P: N (82%), Q: N (87%), S: N (93%), T: N (93%), V: N (87%), W: D (59%), Y: N (53%), |
| Predicted by PROVEAN: | A: N, C: D, D: N, E: N, F: D, G: N, H: N, I: D, K: N, L: D, M: N, N: N, P: N, Q: N, S: N, T: N, V: D, W: D, Y: D, |
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[hide] Association between INK4a-ARF and p53 mutations in... J Natl Cancer Inst. 2000 Nov 15;92(22):1841-7. Soufir N, Daya-Grosjean L, de La Salmoniere P, Moles JP, Dubertret L, Sarasin A, Basset-Seguin N
Association between INK4a-ARF and p53 mutations in skin carcinomas of xeroderma pigmentosum patients.
J Natl Cancer Inst. 2000 Nov 15;92(22):1841-7., [PMID:11078762]
Abstract [show]
BACKGROUND: The INK4a-ARF locus encodes two tumor suppressor proteins, p16(INK4a) and p14(ARF), that act through the Rb-CDK4 and p53 pathways, respectively. Data from murine models and sporadic human skin carcinomas implicate p16(INK4a) and p14(ARF) in the development of skin carcinomas. We examined the frequency of INK4a-ARF, p53, and CDK4 mutations in skin carcinomas from patients with xeroderma pigmentosum (XP), a rare autosomal disease that is associated with a defect in DNA repair and that predisposes patients to skin cancer. METHODS: DNA from skin cancers of 28 unrelated XP patients was screened for mutations in p53, INK4a-ARF, and CDK4 coding exons by single-strand conformation polymorphism analysis and automated sequencing. Data were evaluated with the use of the exact unconditional test derived from Fisher's test. All statistical tests were two-sided. RESULTS: Eight of 28 XP-associated tumors had mutations in the INK4a-ARF locus. Three XP-associated tumors had multiple mutations at this locus. In all, 13 mutations in the INK4a-ARF locus were detected in XP-associated tumors, of which seven (54%) were signature UV radiation-induced mutations, i.e., tandem CC : GG-->TT : AA transitions. p53 mutations, mostly of the type induced by UV radiation, were present in 12 tumors (43%). Statistically significant positive associations were found between the frequency of mutations in p53 and in p16(INK4a) (P =.008) and between the frequency of mutations in p53 and in p14(ARF) (P<.001). No mutations were detected within the CDK4 gene. CONCLUSIONS: We have demonstrated for the first time the occurrence of UV radiation-induced mutations in INK4a-ARF in XP-associated skin carcinomas. The simultaneous inactivation of p53 and INK4a-ARF may be linked to the genetic instability caused by XP and could be advantageous for tumor progression.
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No. Sentence Comment
86 p16INK4a , p14ARF , and p53 mutations in 13 xeroderma pigmentosum (XP)-associated skin epithelial tumors* Skin carcinoma Nucleotide p16INK4A complementary DNA position INK4a-ARF sequence change p16INK4Aa aa change p14ARF aa change Previous mutation reference p53 sequence change p53 aa change Tumor site Complementation group Squamous cell carcinoma (SCC) SCC 164 -25 atg agCagg→ agTagg None None - caC Cat→ caT Tat His178His/ His179Tyr Scalp XP-C 24-26 gCATgg→ agTAgg Frameshift None - gaC Cgg→ gaT Tgg Asp281Asp/ Arg282Trp 79 agGagg→ agAagg Glu27Arg None - 341-342 gcCCgt→ gcTTgtg Pro114Leu Ala128 Ala/ Arg129Cys - SCC 586 172 ccCgag→ ccTgag Arg58Ter Pro72Leu Familial melanoma, melanoma tumor and cell lines gtCctg→ gtTctg Pro278Ser Forehead n.d 341 gcCcgtg→ gcTcgtg Pro114Leu Ala128 Ala Melanoma and fibrosarcoma cell lines, astrocytoma gtCCtg→ gtTTtg Pro278Phe SCC 596 171-172 gcGGga→ gcTTga Arg58Ter Pro72Leu Sporadic SCC, melanoma tumor and cell line cgCCat→ cgTTat Ala59Val Neck n.d SCC 188-3 341-342 gcCCgt→ gcTTgt Pro114Leu Ala128 Ala/ Arg129Cys - acCCcc→ acTTcc Pro151Leu Eye XP-C gtCCtg→ gtTTtg Pro278Phe SCC 218-4 237-238 acCCga→ acTTga Arg80Ter Pro94Leu Melanoma cell line aaCCgg→ aaTTgg Asn247Asn/ Arg248Trp Ear XP-C SCC 564 237-238 acCCga→ acTTga Arg80Ter Pro94Leu Melanoma cell line aAcCgg→ aCcTgg Asn247Thr/ Arg248Trp Cheek n.d SCC 594 - wt None None - ccCcgc→ ccTcgc Pro152Ser Cheek n.d SCC 203-10 - wt None None - gaCCgg→ gaTTgg Asp281Asp/ Arg282Trp Ear XP-C Basal cell carcinoma (BCC) BCC 248-6 341-342 gcCCgt→ gcTTgt Pro114Leu Ala128 Ala/ Arg129Cys - wt None unk XP-C BCC 243-10 237-238 acCCga→ acTTga Arg80Ter Pro94Leu Melanoma cell line Sporadic SCC ccCCac→ ccTTac Pro177Pro/ His178Tyr unk XP-C s.a. ggcaGg→ ggcaAg Splicing Splicing Nasopharynx cancer Sporadic SCC acCatg→ acTatg His179Tyr BCC 593 - wt None None - ccCtgt→ ccTtgt Pro142Leu Eyelid XP-C BCC 248-3 - wt None None - ccCCca→ ccATca (d) Pro177His unk n.d acCatg→ acTatg His179Tyr ttCctg→ ttTctg Ser241Phe ccaGGt→ ccaAAt (d) Splicing donor site exon 7 BCC 248-5 - wt None None - caAgat→ caTgat Lys132Met unk n.d gaCCgg→ gaTTgg Asp281Asp/ Arg282Trp *The sequence is written 5Ј→3Ј and shows the nontranscribed strand; the mutated base is shown in uppercase.
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ABCC8 p.Arg248Trp 11078762:86:1332
status: NEWX
ABCC8 p.Arg248Trp 11078762:86:1459
status: NEW[hide] P16 UV mutations in human skin epithelial tumors. Oncogene. 1999 Sep 23;18(39):5477-81. Soufir N, Moles JP, Vilmer C, Moch C, Verola O, Rivet J, Tesniere A, Dubertret L, Basset-Seguin N
P16 UV mutations in human skin epithelial tumors.
Oncogene. 1999 Sep 23;18(39):5477-81., [PMID:10498902]
Abstract [show]
The p16 gene expresses two alternative transcripts (p16alpha and p16beta) involved in tumor suppression via the retinoblastoma (Rb) or p53 pathways. Disruption of these pathways can occur through inactivation of p16 or p53, or activating mutations of cyclin dependant kinase 4 gene (Cdk4). We searched for p16, Cdk4 and p53 gene mutations in 20 squamous cell carcinomas (SSCs), 1 actinic keratosis (AK), and 28 basal cell carcinomas (BCCs), using PCR-SSCP. A deletion and methylation analysis of p16 was also performed. Six different mutations (12%) were detected in exon 2 of p16 (common to p16alpha and p16beta), in five out of 21 squamous lesions (24%) (one AK and four SCCs) and one out of 28 BCCs (3.5%). These included four (66%) ultraviolet (UV)-type mutations (two tandems CC : GG to TT : AA transitions and two C : G to T : A transitions at dipyrimidic site) and two transversions. P53 mutations were present in 18 samples (37%), mostly of UV type. Of these, only two (one BCC and one AK) harboured simultaneously mutations of p16, but with no consequence on p16beta transcript. Our data demonstrate for the first time the presence of p16 UV induced mutations in non melanoma skin cancer, particularly in the most aggressive SCC type, and support that p16 and p53 are involved in two independent pathways in skin carcinogenesis.
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No. Sentence Comment
85 Mutations in samples 79, 121, 132 and 153 are predicted to be UVB induced mutations Table 2 P53 gene mutations characterized in human skin epithelial tumors Tumor size Exon Mutation Codon modi®cation Squamous lesions AK 241 SSC 350 Exon 8 Exon 7 gtcCtgg?gtcTcgg ggcGgc?ggcTgca Pro278Leu gly245Cys Basal cell carcinomas BCC 353 BCC 274 BCC 354 BCC 352 BCC 274 BCC 354 BCC 351 BCC 355 Exon 5 Exon 6 Exon 6 Exon 6 Exon 6 Exon 7 Exon 7 Exon 8 gccCCca?gccTTca tcgAcat?tcgGcat tcgAcat?cgGcat atcCgagt?atcTgagt cctAtga?cctGtga gttCctg?gttTctg aacCgga?aacTgga ctcCgcaa?ctcTcaa Pro177Leu Arg213Arg Arg213Arg Arg196Stop Tyr220Cys Ser241Phe Arg248Trp Arg 290 frameshift* *Indicates mutations which have not previously been described in the IARC p53 database 49 tumors (8/20 SCCs, three of which harbouring a p16 mutation; 7/28 BCC, one having a p16 mutation) (data not shown).
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ABCC8 p.Arg248Trp 10498902:85:635
status: NEW