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Expression of mismatch repair enzymes, hMLH1 and hMSH2 is not associated with microsatellite instability and P53 protein accumulation in basal cell carcinoma

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Abstract

Microsatellite instability (MSI) constitutes an alternative—to the chromosomal instability—pathway of carcinogenesis for certain tumour types with prognostic and therapeutic significance for the respective patients. MSI is caused by mutations in mismatch repair (MMR) genes, mainly hMLH1, hMSH2, leading to a defective MMR system. The role of MSI in basal cell carcinoma (BCC) has not been clearly delineated yet. p53 gene as a target for ultraviolet radiation-induced mutations may enhance genomic instability in BCC, with loss of its function. Our aim was to investigate the involvement of MSI and expression of hMLH1 and hMSH2 in parallel with P53 protein accumulation in the pathogenesis of BCC and its possible correlation to the clinicopathological features of the patients. The presence of MSI was investigated in 76 BCCs using mononucleotide microsatellite markers, BAT-25, BAT-26 and TGF-beta receptor type II (TGF-β-RII). Additionally, 3 dinucleotide markers were analysed in 20 cases in which matched normal tissue was available. The expression of hMLH1, hMSH2 and P53 proteins was evaluated by immunohistochemical analysis. Alterations of the BAT-26 marker were observed in one fibroepithelioma of Pincus, one nodular and one multifocal superficial BCC. A keratotic BCC showed an altered BAT-25 locus. Two samples, a multifocal superficial and a nodular BCC, displayed MSI at two markers (BAT-25 and BAT-26; and BAT-25 and TGF-β-RII, respectively). Three more cases, a metatypical, a multifocal superficial and a signet ring BCC exhibited frameshift mutations in the TGF-β-RII. No sample showed length alterations at the dinucleotide markers examined. hMLH1 and hMSH2 protein immunohistochemical expression was scored positive in 46 and 49 out of 52 cases respectively. P53 accumulation was observed in 27 out of 56 samples. Correlation of the molecular and immunohistochemical findings with the clinicopathological parameters produced no statistically significant results. No correlation between MSI and hMLH1, hMSH2 or P53 protein expression was determined. MSI appears to play a minor role in the pathogenesis of BCCs being present only in a small subset of such tumours.

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Abbreviations

BCC:

Basal cell carcinoma

MSI:

Microsatellite instability

MMR:

Mismatch repair

PCR:

Polymerase chain reaction

References

  1. Boland CR, Thibodeau S, Hamilton S, Sidransky D, Eshlemam J, Burt R, Meltzer S, Rodriguez-Bigas M, Fodde R, Ranzani N, Srivastava SA (1998) National Cancer Institute workshop on microsatellite instability for cancer detection and familial predisposition: development on international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 58:5248–5257

    PubMed  CAS  Google Scholar 

  2. Bolshakov S, Walker CM, Strom SS, Selvan MS, Clayman GL, El-Naggar A, Lippman SM, Kripke ML, Ananthaswamy HN (2003) p53 mutations in human aggressive and nonaggressive basal and squamous cell carcinomas. Clin Cancer Res 9:228–234

    PubMed  CAS  Google Scholar 

  3. Dietmaier W, Wallinger S, Bocker T, Kullmann F, Fishel R, Rüschoff J (1997) Diagnostic microsatellite instability: definition and correlation with mismatch repair protein expression. Cancer Res 57:4749–4756

    PubMed  CAS  Google Scholar 

  4. Furue M, Kato M, Nakamura K, Nashiro K, Kikuchi K, Okochi H, Miyazono K, Tamaki K (1997) Dysregulated expression of transforming growth factor β and its type-I and type-II receptors in basal-cell carcinoma. Int J Cancer 71:505–509

    Article  PubMed  CAS  Google Scholar 

  5. Giglia-Mari G, Sarasin A (2003) TP53 Mutations in human skin cancers. Hum Mutat 21:217–228

    Article  PubMed  CAS  Google Scholar 

  6. Hardman RA, Afshari CA, Barrett JC (2001) Involvement of mammalian MLH1 in the apoptotic response to peroxide-induced oxidative stress. Cancer Res 61:1392–1397

    PubMed  CAS  Google Scholar 

  7. Hoang J-M, Cottu PH, Thuille B, Salmon RJ, Thomas G, Hamelin R (1997) BAT-26, an indicator of the replication error phenotype in colorectal cancers and cell lines. Cancer Res 57:300–303

    PubMed  CAS  Google Scholar 

  8. Hussein MR, Wood GS (2002) Microsatellite instability and its relevance to cutaneous tumorigenesis. J Cutan Pathol 29:257–267

    Article  PubMed  Google Scholar 

  9. Jass JR, Walsh MD, Barker M, Simms LA, Young J, Legget BA (2002) Distinction between familial and sporadic forms of colorectal cancer showing DNA microsatellite instability. Eur J Cancer 38:858–866

    Article  PubMed  CAS  Google Scholar 

  10. Lane DP (1992) p53, guardian of the genome. Nature 358:15–16

    Article  PubMed  CAS  Google Scholar 

  11. Lawes DA, SenGupta S, Boulos PB (2003) The clinical importance and prognostic implications of microsatellite instability in sporadic cancer. Eur J Surg Oncol 29:201–212

    Article  PubMed  CAS  Google Scholar 

  12. Mellon I, Champe GN (1996) Products of DNA mismatch repair genes mutS and mutL are required for transcription-coupled nucleotide-excision repair of the lactose operon in Escherichia coli. Proc Natl Acad Sci 93:1292–1297

    Article  PubMed  CAS  Google Scholar 

  13. Meyers M, Wagner MW, Hwang HS, Kinsella TJ, Boothman DA (2001) Role of the hMLH1 DNA mismatch repair protein in fluoropyrimidine-mediated cell death and cell cycle responses. Cancer Res 61:5193–5201

    PubMed  CAS  Google Scholar 

  14. Peris K, Magrini F, Keller G, Manente L, D’Alessandro E, Onorati MT, Höfler H, Chimenti S (1997) Analysis of microsatellite instability and loss of heterozygosity in Keratoacanthoma. Arch Dermatol Res 289:185–188

    Article  PubMed  CAS  Google Scholar 

  15. Quinn GA, Healy E, Rehman I, Sikkink S, Rees JL (1995) Microsatellite instability in human non-melanoma and melanoma skin cancer. J Invest Dermatol 104:309–312

    Article  PubMed  CAS  Google Scholar 

  16. Rass K, Gutwein P, Müller SM, Friedrich M, Meineke V, Welter C, Tilgen W, Reichrath J (2000) Immunohistochemical analysis of DNA mismatch repair enzyme hMSH2 in normal human skin and basal cell carcinomas. Histochem J 32:93–97

    Article  PubMed  CAS  Google Scholar 

  17. Rass K, Gutwein P, Welter C, Meineke V, Tilgen W, Reichrath J (2001) DNA mismatch repair enzyme hMSH2 in malignant melanoma: Increased immunoreactivity as compared to acquired melanocytic nevi and strong mRNA expression in melanoma cell lines. Histochem J 33:459–467

    Article  PubMed  CAS  Google Scholar 

  18. Redston M (2001) Carcinogenesis in the GI tract from morphology to genetics and back again. Mod Pathol 4:236–245

    Article  Google Scholar 

  19. Sardi I, Piazzini M, Palleschi G, Pinzi C, Taddei I, Arrigucci S, Guazzelli R, Fabbri P, Moretti S (2000) Molecular detection of microsatellite instability in basal cell carcinoma. Oncol Rep 7:1119–1122

    PubMed  CAS  Google Scholar 

  20. Scherer SJ, Welter C, Zang KD, Dooley S (1996) Specific in vitro binding of p53 to the promoter region of the human mismatch repair gene hMSH2. Biochem Biophys Res Commun 221:722–728

    Article  PubMed  CAS  Google Scholar 

  21. Schmid P, Itin P, Rufli TH (1996) In situ analysis of transforming growth factors-β (TGF-β1, TGF-β2, TGF-β3) and TGF-β type II receptor expression in basal cell carcinomas. Br J Dermatol 134:1044–1051

    Article  PubMed  CAS  Google Scholar 

  22. Staibano S, Lo Muzio L, Pannone G, Somma P, Farronato G, Franco R, Bambini F, Serpico R, De Rosa G (2001) P53 and hMSH2 expression in basal cell carcinomas and malignant melanomas from photoexposed areas of head and neck region. Int J Oncol 19:551–559

    PubMed  CAS  Google Scholar 

  23. Tsai KY, Tsao H (2004) The genetics of skin cancer. Am J Med Genet 131C:82–92

    Article  Google Scholar 

  24. Umar A, Boland CR, Terdiman JP, Syngal S, de la Chapelle A, Ruschoff J, Fishel R, Lindor NM, Burgart LJ, Hamelin R, Hamilton SR, Hiatt RA, Jass J, Lindblom A, Lynch HT, Peltomaki P, Ramsey SD, Rodriguez-Bigas MA, Vasen HF, Hawk ET, Barrett JC, Freedman AN, Srivastava S (2004) Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 96:261–268

    Article  PubMed  CAS  Google Scholar 

  25. Wang Y, Irish J, Macmillan C, Brown D, Xuan Y, Boyington C, Gullane P, Kamel-Reid S (2001) High frequency of microsatellite instability in young patients with head-and-neck squamous-cell carcinoma: lack of involvement of the mismatch repair genes hMLH1 and hMSH2. Int J Cancer 93:353–360

    Article  PubMed  CAS  Google Scholar 

  26. Weihrauch M, Bader M, Lehnert G, Wittekind C, Tannapfel A, Wrbitzky R (2002) Carcinogen-specific mutation pattern in the p53 tumour suppressor gene in UV radiation-induced basal cell carcinoma. Int Arch Occup Environ Health 75:272–276

    Article  PubMed  CAS  Google Scholar 

  27. Zhou X-P, Hoang J-M, Li Y-J, Seruca R, Carneiro F, Sobrino-Simoes M, Gleeson C, Hillary Russel SE, Muzeau F, Flejou J-F, Hoang-Xuan K, Lidereau R, Thomas G, Hamelin R (1998) Determination of the replication error phenotype in human tumours without the requirement for matching normal DNA by analysis of mononucleotide repeat microsatellites. Genes Chromosomes Cancer 21:101–107

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Angelica A. Saetta.

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Saetta, A.A., Aroni, K., Stamatelli, A. et al. Expression of mismatch repair enzymes, hMLH1 and hMSH2 is not associated with microsatellite instability and P53 protein accumulation in basal cell carcinoma. Arch Dermatol Res 297, 99–107 (2005). https://doi.org/10.1007/s00403-005-0580-x

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  • DOI: https://doi.org/10.1007/s00403-005-0580-x

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