Top

Published in:

01-11-2005 | OriginalPaper

Loss of p16 ^INK4A expression is associated with allelic imbalance/loss of heterozygosity of chromosome 9p21 in microdissected synovial sarcomas

Authors: Muna Sabah, Robert Cummins, Mary Leader, Elaine Kay

Published in: Virchows Archiv | Issue 5/2005

Abstract

Deletions of the short arm of chromosome 9 have been observed in many tumours and cell lines. This chromosomal region is frequently targeted during malignant transformation because it contains at least two known tumour suppressor genes: p16 ^INK4 and p15 ^INK4B. p16 ^INK4A acts as a negative cell cycle regulator by inhibiting G₁ cyclin-dependent kinases that phosphorylate the retinoblastoma protein and therefore block the progression of the cell cycle from G₁ to S phase. The role of p16 ^INK4A in the development of synovial sarcoma has not been comprehensively investigated. Ten samples of synovial sarcomas were examined for allelic imbalance/loss of heterozygosity (AI/LOH) of the 9p region and p16 protein expression. DNA was isolated from microdissected sections of normal and tumour cells, amplified by polymerase chain reaction and analysed for AI/LOH by using six microsatellite markers that map to the 9p region. Immunohistochemistry for p16 expression was done. AI/LOH with at least one microsatellite marker on 9p21 was detected in six of ten samples. The most frequent allelic deletions were observed within the coding sequence of p16 ^INK4A. Loss of p16 immunoreactivity was detected in eight samples, six of which showed evidence of alterations at 9p21 region. These findings suggest a possible role of loss of p16 ^INK4A in the development of synovial sarcoma.

Antonescu CR, Leung DH, Dudas M, Ladanyi M, Brennan M, Woodruff JM, Cordon-Cardo C (2000) Alterations of cell cycle regulators in localized synovial sarcoma: a multifactorial study with prognostic implications. Am J Pathol 156:977–983PubMed

Butler D, Collins C, Mabruk M, Barry Walsh C, Leader MB, Kay EW (2000) Deletion of the FHIT gene in neoplastic and invasive cervical lesions is related to high-risk HPV infection but is independent of histopathological features. J Pathol 192:502–510CrossRefPubMed

Cairns P, Mao L, Merlo A, Lee DJ, Schwab D, Eby Y, Tokino K, van der Riet P, Blaugrund JE, Sidransky D (1994) Rates of p16 (MTS1) mutations in primary tumors with 9p loss. Science 265:415–417PubMedCrossRef

Cairns P, Polascik TJ, Eby Y, Tokino K, Califano J, Merlo A, Mao L, Herath J, Jenkins R, Westra W (1995) Frequency of homozygous deletion at p16/CDKN2 in primary human tumours. Nat Genet 11:210–212CrossRefPubMed

Cohen JA, Geradts J (1997) Loss of RB and MTS1/CDKN2 (p16) expression in human sarcomas. Human Pathol 28:893–898CrossRef

Cordon-Cardo C (1995) Mutations of cell cycle regulators. Biological and clinical implications for human neoplasia. Am J Pathol 147:545–560PubMed

Cordon-Cardo C (1997) Molecular biology of sarcomas. In: De Vita VT, Hellman S, Rosenberg SA (eds) Principles and practice of oncology. Lippincott, Philadelphia, pp 1731–1738

dos Santos NR, de Bruijn DR, van Kessel AG (2001) Molecular mechanisms underlying human synovial sarcoma development. Genes Chromosomes Cancer 30:1–14CrossRefPubMed

Golouh R, Stanta G, Bracko M, Bonin S (2001) Correlation of MTS1/p16 and nm23 mRNA expression with survival in patients with peripheral synovial sarcoma. J Surg Oncol 76:83–88CrossRefPubMed

10.

Guillou L, Coindre JM, Bonichon F, Nguyen BB, Terrier P, Collin F, Vilain MO, Mandard AM, Le Doussal V, Leroux A, Jacquemier J, Duplay H, Sastre-Garau X, Costa J (1997) Comparative study of the National Cancer Institute and French Federation of Cancer Centers Sarcoma Group grading systems in a population of 410 adult patients with soft tissue sarcoma. J Clin Oncol 15:350–362PubMed

11.

Hannon GJ, Beach D (1994) p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest. Nature 371:257–261CrossRefPubMed

12.

Kamb A, Gruis NA, Weaver-Feldhaus J, Liu Q, Harshman K, Tavtigian SV, Stockert E, Day RS III, Johnson BE, Skolnick MH (1994) A cell cycle regulator potentially involved in genesis of many tumor types. Science 264:436–440PubMedCrossRef

13.

Merlo A, Herman JG, Mao L, Lee DJ, Gabrielson E, Burger PC, Baylin SB, Sidransky D (1995) 5′ CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers. Nat Med 1:686–692CrossRefPubMed

14.

Nobori T, Miura K, Wu DJ, Lois A, Takabayashi K, Carson DA (1994) Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers. Nature 368:753–756CrossRefPubMed

15.

Nobori T, Takabayashi K, Tran P, Orvis L, Batova A, Yu AL, Carson DA (1996) Genomic cloning of methylthioadenosine phosphorylase: a purine metabolic enzyme deficient in multiple different cancers. Proc Natl Acad Sci U S A 93:6203–6208CrossRefPubMed

16.

Orlow I, Drobnjak M, Zhang ZF, Lewis J, Woodruff JM, Brennan MF, Cordon-Cardo C (1999) Alterations of INK4A and INK4B genes in adult soft tissue sarcomas: effect on survival. J Natl Cancer Inst 91:73–79CrossRefPubMed

17.

Pomerantz J, Schreiber-Agus N, Liegeois NJ, Silverman A, Alland L, Chin L, Potes J, Chen K, Orlow I, Lee HW, Cordon-Cardo C, DePinho RA (1998) The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2's inhibition of p53. Cell 92:713–723CrossRefPubMed

18.

Sabah M, Cummins R, Leader M, Kay E (2004) Loss of heterozygosity of chromosome 9p and loss of p16(INK4A) expression are associated with malignant gastrointestinal stromal tumors. Mod Path 17:1364–1371CrossRef

19.

Sabah M, Cummins R, Leader M, Kay E (2005) Leiomyosarcoma and malignant fibrous histiocytoma share similar allelic imbalance pattern at 9p. Virchows Arch 446:251–258CrossRefPubMed

20.

Sabah M, Cummins R, Leader M, Kay E (2005) Loss of p16INK4A expression is associated with allelic imbalance/loss of heterozygosity in microdissected malignant peripheral nerve sheath tumors. Appl Immunohistochem Mol Morphol (in press)

21.

Schneider-Stock R, Radig K, Roessner A (1997) Loss of heterozygosity on chromosome 9q21 (p16 gene) uncommon in soft-tissue sarcomas. Mol Carcinog 18:63–65CrossRefPubMed

22.

Schneider-Stock R, Walter H, Haeckel C, Radig K, Rys J, Roessner A (1998) Gene alterations at the CDKN2A (p16/MTS1) locus in soft tissue tumors. Int J Oncol 13:325–329PubMed

23.

Schraml P, Muller D, Bednar R, Gasser T, Sauter G, Mihatsch MJ, Moch H (2000) Allelic loss at the D9S171 locus on chromosome 9p13 is associated with progression of papillary renal cell carcinoma. J Pathol 190:457–461CrossRefPubMed

24.

Serrano M, Hannon GJ, Beach D (1993) A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature 366:704–707CrossRefPubMed

25.

Sherr CJ (1996) Cancer cell cycles. Science 274:1672–1677CrossRefPubMed

26.

Skotheim RI, Diep CB, Kraggerud SM, Jakobsen KS, Lothe RA (2001) Evaluation of loss of heterozygosity/allelic imbalance scoring in tumor DNA. Cancer Genet Cytogenet 127:64–70CrossRefPubMed

27.

Sotillo R, Dubus P, Martin J, de la Cueva E, Ortega S, Malumbres M, Barbacid M (2001) Wide spectrum of tumors in knock-in mice carrying a Cdk4 protein insensitive to INK4 inhibitors. EMBO J 20:6637–6647CrossRefPubMed

28.

Trojani M, Contesso G, Coindre JM, Rouesse J, Bui NB, De Mascarel A, Goussot JF, David M, Bonichon F, Lagarde C (1984) Soft-tissue sarcomas of adults; study of pathological prognostic variables and definition of a histopathological grading system. Int J Cancer 33:37–42PubMedCrossRef

29.

Yao J, Pollock RE, Lang A, Tan M, Pisters PW, Goodrich D, El Naggar A, Yu D (1998) Infrequent mutation of the p16/MTS1 gene and overexpression of cyclin-dependent kinase 4 in human primary soft-tissue sarcoma. Clin Cancer Res 4:1065–1070PubMed

30.

Yoo J, Park SY, Kang SJ, Shim SI, Kim BK (2002) Altered expression of G1 regulatory proteins in human soft tissue sarcomas. Arch Pathol Lab Med 126:567–573PubMed

Title: Loss of p16 INK4A expression is associated with allelic imbalance/loss of heterozygosity of chromosome 9p21 in microdissected synovial sarcomas
Authors: Muna Sabah
Robert Cummins
Mary Leader
Elaine Kay
Publication date: 01-11-2005
Publisher: Springer-Verlag
Published in: Virchows Archiv / Issue 5/2005
Print ISSN: 0945-6317
Electronic ISSN: 1432-2307
DOI: https://doi.org/10.1007/s00428-005-0024-1

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Loss of p16 ^INK4A expression is associated with allelic imbalance/loss of heterozygosity of chromosome 9p21 in microdissected synovial sarcomas

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 5/2005

The petrified heart in sepsis

Clear cell mesothelioma presenting as an incarcerated abdominal hernia

Newsletter of the European Society of Pathology

Rhabdomyoma of the head and neck: morphology and differential diagnosis

Molecular cytogenetic characterization of an ins(4;X) occurring as the sole abnormality in an aggressive, poorly differentiated soft tissue sarcoma

Expression of small intestinal and colonic phenotypes in complete intestinal metaplasia of the human stomach