Does the PITSLRE gene complex contribute to the pathogenesis of malignant melanoma of the skin? A study of patient-derived tumor samples

Deletions of the short arm of chromosome 1 are among the most frequent aberrations in many solid tumors including neuroblastoma, breast cancer, and malignant melanoma of the skin [ 1 Heim S. Mitelman F. Cancer cytogenetics. 2nd ed. Wiley-Liss, New York1995 Google Scholar ]. Loss of heterozygosity analysis [ 2 Dracopoli N.C. Harnett P. Bale S.J. Stanger B.Z. Tucker M.A. Housman D.E. Keffort R.F. Loss of alleles from the distal short arm of chromosome 1 occurs late in melanoma tumor progression. Proc Natl Acad Sci USA. 1989; 86: 4614-4618 Crossref PubMed Scopus (210) Google Scholar , 3 Böni R. Matt D. Voetmeyer A. Burg G. Zhuang Z. Chromosomal allele loss in primary cutaneous melanoma is heterogeneous and correlates with proliferation. J Invest Dermatol. 1998; 110: 215-217 Crossref PubMed Scopus (45) Google Scholar ] revealed the subterminal region 1p36 as a deletion hot spot. In our recent fluorescence in situ hybridization (FISH) studies, we were able to demonstrate deletions with a subtelomeric DNA probe hybridizing at the locus D1Z2 (1p36.3) in a surprisingly high percentage of nodular melanoma samples and metastatic melanomas [ 4 Poetsch M. Woenckhaus C. Dittberner T. Pambor M. Lorenz G. Herrmann F.H. Increased frequency of numerical chromosomal abnormalities and 1p36 deletions in isolated cells of paraffin sections of malignant melanoma detected by interphase cytogenetics. Cancer Genet Cytogenet. 1998; 104: 146-152 Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar , 5 Poetsch M. Woenckhaus C. Dittberner T. Pambor M. Lorenz G. Herrmann F.H. Differences in chromosomal aberrations between nodular and superficial spreading malignant melanoma detected by interphase cytogenetics. Lab Invest. 1998; 78: 883-888 PubMed Google Scholar , 6 Poetsch M. Woenckhaus C. Dittberner T. Pambor M. Lorenz G. Herrmann F.H. Significance of the small subtelomeric area of chromosome 1 (p36.3) in the progression of malignant melanoma FISH deletion screening with YAC DNA probes. Virch Archiv. 1999; 435: 105-111 Crossref PubMed Scopus (13) Google Scholar ]. The genetic background of this aberration may be a tumor suppressor gene, for example, the p34cdc2-related PITSLRE protein kinase gene complex (CDC2L) [ 7 Lahti J.M. Valentine M. Xiang J. Jones B. Amann J. Grenet J. Richmond G. Look A.T. Kidd V.J. Alterations in the PITSLRE protein kinase gene complex an chromosome 1p36 in childhood neuroblastoma. Nat Genet. 1994; 7: 370-375 Crossref PubMed Scopus (111) Google Scholar ]. In melanoma cell lines, alterations in the CDC2L1 gene promotor have already been shown [ 8 Nelson M.A. Ariza M.E. Ming Yang J. Thompson F.H. Taetle R. Trent J.M. Wymer J. Massey-Brown K. Broome-Powell M. Easton J. Lahti J.M. Kidd V.J. Abnormalities in the p34cdc2-related PITSLRE protein kinase gene complex (CDC2L) on chromosome band 1p36 in melanoma. Cancer Genet Cytogenet. 1999; 108: 91-99 Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar ] and alterations in PITSLRE gene expression have been suggested to result in loss of apoptotic signaling [ 9 Ariza M.E. Broome-Powell M. Lahti J.M. Kidd V.J. Nelson M.A. Fas-induced apoptosis in human malignant melanoma cell lines is associated with the activation of p34(cdc2)-related PITSLRE protein kinases. J Biol Chem. 1999; 274: 28505-28513 Crossref PubMed Scopus (62) Google Scholar ]; however, the biology of cell lines is not completely comparable to the biologic behavior of neoplastic tissue. To elucidate the possible role of CDC2L in vivo in melanoma cells, we studied 58 malignant melanomas comprising 15 superficial spreading melanomas (SSM), 18 nodular malignant melanomas (NM), and 25 metastatic melanomas by direct sequencing analysis of a part of the CDC2L1 gene promotor with primers described by Nelson et al. [ 8 Nelson M.A. Ariza M.E. Ming Yang J. Thompson F.H. Taetle R. Trent J.M. Wymer J. Massey-Brown K. Broome-Powell M. Easton J. Lahti J.M. Kidd V.J. Abnormalities in the p34cdc2-related PITSLRE protein kinase gene complex (CDC2L) on chromosome band 1p36 in melanoma. Cancer Genet Cytogenet. 1999; 108: 91-99 Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar ]. DNA isolation from paraffin-embedded tissue was performed as previously described [ 10 Poetsch M. Dittberner T. Woenckhaus C. PTEN/MMAC1 in malignant melanoma and its importance for tumor progression. Cancer Genet Cytogenet. 2001; 125: 21-26 Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar ].