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Monosomy 7 mosaicism in metastatic choroidal melanoma
Cancer Genetics and Cytogenetics 177 (2007) 70e72
Short communication
Monosomy 7 mosaicism in metastatic choroidal melanoma Hande Taylana, Hayyam Kiratlia,*, Dilek Aktasb b
a Department of Ophthalmology Department of Genetics, Hacettepe University, Sihhiye, Ankara 06100, Turkey
Received 6 March 2007; received in revised form 24 April 2007; accepted 9 May 2007
Abstract
Uveal melanoma is the most common primary intraocular malignancy in adults. Several cytogenetic studies on uveal melanoma cells have revealed that the majority of these cells harbor alterations in chromosomes 3, 6, and 8. This report describes the results of cytogenetic analysis performed on a fresh choroidal melanoma tissue sample from a patient with cerebellar metastasis. Monosomy 7 mosaicism was observed. To our knowledge, monosomy 7 has not been reported in patients with uveal melanoma. We suggest that observation of monosomy 7 may be related to an aggressive clinical behavior and unusual cerebellar metastasis in uveal melanoma. Further data are necessary to define the exact role of monosomy 7 in the pathogenesis and evolution of uveal melanoma. Ó 2007 Elsevier Inc. All rights reserved.
1. Introduction Uveal melanoma is the most common primary intraocular malignancy and is believed to arise from neuroectodermally derived melanocytes present in the choroid, ciliary body, or iris [1,2]. Metastasis is the most important factor affecting survival in uveal melanoma, and overall mortality is approximately 50% in 10 years because of the development of liver metastasis [3]. Despite advances in the diagnosis and treatment of uveal melanoma, patient survival still has not improved significantly. Several cytogenetic studies on uveal melanoma revealed that abnormalities of chromosomes 3, 6, and 8 do not occur randomly [4e8]. Monosomy 3 is the first and still most common chromosomal abnormality found in choroidal melanoma. It has been detected in nearly half of uveal melanoma cases with poor prognosis and has been linked strongly to metastatic disease [7,9,10]. Extra copies of 6p are found in approximately one fourth of uveal melanoma cases and have been correlated with better prognosis [9,11,12]. Loss of 6q has also been observed in uveal melanoma and has been described more commonly in metastasizing tumors [5]. Furthermore, gain of 8q has been found in uveal melanoma and is strongly related with metastasis, similar to monosomy 3 [11,13]. In addition, loss of 1p, 9p, and 13q, as well as gain of chromosome 21, have been reported [8,9,11,14]. We herein report the results of * Corresponding author. Tel.: þ90-312-305-1777; fax: þ90-312-3094101. E-mail address: [email protected] (H. Kiratli). 0165-4608/07/$ e see front matter Ó 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.cancergencyto.2007.05.004
cytogenetic analysis on a fresh intraocular uveal melanoma tissue sample from a patient with cerebellar metastasis.
2. Case report An otherwise healthy 64-year-old man complained of decreased vision and pain in his right eye and was referred to our center. Upon examination, his visual acuity was no light perception in the right eye and 20/20 in the left. Biomicroscopic examination of the right eye showed upper and lower eyelid edema, chemosis, a dark brown subconjunctival mass in the inferior fornix, corneal edema, shallow anterior chamber, rubeosis iridis, and nuclear cataract. Right intraocular pressure was 68 mmHg. Cranial and orbital MRI studies suggested extraocular extension of an intraocular tumor, the signal characteristics of which were compatible with uveal melanoma. There was also evidence of cerebellar metastasis. Because of massive orbital spread and no prospect for useful vision, exenteration of the right orbit was performed. The histopathologic diagnosis was mixed cell type choroidal melanoma with optic nerve invasion and filling of 50% of the orbital cavity. The patient refused further treatment and died of metastatic disease a year later. To perform cytogenetic analysis, fresh tumor samples were obtained from within the eye portion of the exenterated specimen. The tumor tissue was then mechanically minced and treated with collagenase. Cytogenetic analysis was performed on short-term cultures of the primary tumor sample and harvested. GTG banding was performed using routine methods. The karyotypes were described in
H. Taylan et al. / Cancer Genetics and Cytogenetics 177 (2007) 70e72
accordance with ISCN 2005 [15]. The karyotype was found to be 46,XY[14]/45,XY,-7 [6], indicating monosomy 7 mosaicism (Fig. 1).
3. Discussion Advances in cytogenetics have been instrumental in the identification of chromosomal alterations in uveal melanomas and have provided some insight into the pathogenesis of disease. Monosomy 3 has been detected in a number of metastasizing melanomas and has been correlated with tumor diameter, ciliary body involvement, the presence of epithelial cells, and closed PAS-positive loops [7]. Among patients with uveal melanoma, monosomy 3 has been associated with a reduction of the 5-year survival probability from 100 to 50% [10]. Prescher et al. [5] proposed that monosomy 3 could be the early event in tumor development. Furthermore, gains of chromosome 8 have also been related with reduced survival probability [13]. In addition, loss of chromosome 3 and gains of chromosome 8 tend to occur together [16]. Monosomy 7 has been detected in many types of cancer and has been associated with progression in meningioma [17] and hemophagocytic syndrome [18]. By using allelotyping analysis, at least three distinct regions on the loci 7q22, 7q31.1, and 7q31.2 were observed in patients with myelodysplastic syndrome (MDS) and acute myelogeneous leukemia associated with monosomy 7 [19,20]. A newly described deletion affecting the tumor supressor gene DOCK4, localized within the 7q31 interval, was present in human prostate and ovarian cancers [21]. Monosomy 7
71
or partial loss of 7q in pediatric MDS was recently associated with poor prognosis and progression to ALL or to AML [22]. Monosomy 7 has also been observed in a case with common melanocytic nevi [23]. To the best of our knowledge, this is the first patient in whom monosomy 7 mosaicism has been documented in fresh intraocular melanoma tissue. Uveal melanomas arise from the melanocytes of the uveal, and skin melanomas are derived from epidermal melanocytes. Structural rearrangements of chromosome 1, loss of 9p, 6p, and 10q, as well as gain of chromosome 7, are the most common chromosomal abnormalities involved in skin melanomas [24]. Further statistical analysis suggested that 3 might be more specific for uveal melanoma and 10 for cutaneous melanomas, adding that both were very common in both types of melanomas [24]. It is noteworthy that 3 and þ6p imbalances were found to represent alternative starting cytogenetic pathways leading to karyotypic evolution present again in both cutaneous and uveal melanomas [24]. These two early and initializing imbalances are often followed by secondary changes involving þ8q, 8p, and 1p after 3 and 6q, 16, 9p, or 10 after þ6p [24]. Uveal melanomas tend to metastasize via the bloodstream to distant sites, predominantly to the liver, in 70e90% of patients with metastatic disease [25,26]. Brain metastasis is rare and accounts for 5e11% of all metastatic uveal melanoma cases [25e27]. Cerebellar metastasis is exceedingly rare and portends the same overall dismal prognosis compared to metastatic loci discovered at other sites [27,28]. Monosomy 7 mosaicism in our patient may be related to an aggressive clinical course, as evidenced by the massive orbital invasion and the highly unusual cerebellar
Fig.1. The karyotype of the patient with choroidal melanoma having monosomy 7.
72
H. Taylan et al. / Cancer Genetics and Cytogenetics 177 (2007) 70e72
metastases. Further studies are necessary to determine the exact contribution of monosomy 7 to the pathogenesis and progression of choroidal melanoma.
References [1] Singh AD, Topham A. Incidence of uveal melanoma in United States: 1973e1997. Ophthalmology 2003;110:956e61. [2] Diener-West M, Hawkins BS, Markowitz JA, Schachat AP. A review of mortality from choroidal melanoma. II. A meta-analysis of 5-year mortality rates following enucleation, 1966 through 1988. Arch Ophthalmol 1992;110:245e50. [3] Bergman L, Seregard S, Nilsson B, Lundell G, Ringborg U, Ragnarsson-Olding B. Uveal melanoma survival in Sweden from 1960 to 1998. Invest Ophthalmol Vis Sci 2003;44:3282e7. [4] Sisley K, Cottam DW, Rennie IG, Parsons MA, Potter AM, Potter CW, Rees RC. Non-random abnormalities of chromosomes 3, 6 and 8 associated with posterior uveal melanoma. Genes Chromosomes Cancer 1990;5:197e200. [5] Prescher G, Bornfeld N, Becher R. Nonrandom chromosomal abnormalities in primary uveal melanoma. J Natl Cancer Inst 1990;82: 1765e9. [6] Singh AD, Boghosian-Sell L, Wary KK, Shields CL, De Potter P, Donoso LA, Shields JA, Cannizzaro LA. Cytogenetic findings in primary uveal melanoma. Cancer Genet Cytogenet 1994;72:109e15. [7] Scholes AGM, Damato BE, Nunn J, Hiscott P, Grierson I, Field JK. Monosomy 3 in uveal melanoma: correlation with clinical and histologic predictors of survival. Invest Ophthalmol Vis Sci 2003;44:1008e11. [8] Sisley K, Parsons MA, Garnham J, Potter AM, Curtis D, Rees RC, Rennie IG. Association of specific chromosome alterations with tumour phenotype in posterior uveal melanoma. Br J Cancer 2000;82:330e8. [9] Aalto Y, Eriksson L, Seregard S, Larsson O, Knuutila S. Concomitant loss of chromosome 3 and whole arm losses and gains of chromosome 1,6 or 8 in metastasizing primary uveal melanoma. Invest Ophthalmol Vis Sci 2001;42:313e7. [10] Prescher G, Bornfeld N, Hirche, Horsthemke B, Jockel KH, Becher R. Prognostic implications of monosomy 3 in uveal melanoma. Lancet 1996;347:1222e5. [11] Prescher G, Bornfeld N, Friedrichs W, Seeber S, Becher R. Cytogenetics of twelve cases of uveal melanoma and patterns of nonrandom anomalies and isochromosome formation. Cancer Genet Cytogenet 1995;80:40e6. [12] Parrella P, Sidransky D, Merbs SL. Allelotype of posterior uveal melanoma: implications for a bifurcated tumour progression pathway. Cancer Res 1999;59:3032e7. [13] Sisley K, Rennie IG, Parsons MA, Jacques R, Hammond DW, Bell SM, Potter AM, Rees RC. Abnormalities of chromosomes 3
[14]
[15] [16] [17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25] [26]
[27]
[28]
and 8 in posterior uveal melanoma correlate with prognosis. Genes Chromosomes Cancer 1997;19:22e8. Scholes AG, Liloglou T, Maloney P, Hagan S, Nunn J, Hiscott P, Damato BE, Grierson I, Field JK. Loss of heterozygosity on chromosomes 3, 9, 13 and 17, including the retinoblastoma locus, in uveal melanoma. Invest Ophthalmol Vis Sci 2000;42:2472e7. ISCN. An International System for Human Cytogenetic Nomenclature. Basel: S. Karger, 2005. Singh AD, Damato B, Howard P, Harbour JW. Uveal melanoma: genetic aspects. Ophthalmol Clin N Am 2005;85e97. Henn W, Niedermayer I, Ketter R, Reichardt S, Freiler A, Zang KD. Monosomy 7p in meningioma: a rare constituent of tumour progression. Cancer Genet Cytogenet 2003;144:65e8. Tadmor T, Vadazs Z, Dar H, Laor R, Attias D. Hemophagocytic syndrome preceding acute myeloid leukemia with der t (7,17) (q12-q11), monosomy, 17 and 5p-. J Pediatr Hematol Oncol 2006;28:544e6. Liang H, Fairman J, Claxton DF, Nowell PC, Green ED, Nagarajan L. Molecular anatomy of chromosome 7q deletions in myeloid neoplasms evidence for multiple critical loci. Proc Natl Acad Sci USA 1998;95:3781e5. Le Beau MM, Espinosa R 3rd, Davis EM, Eisenbart JD, Larson RA, Green ED. Cytogenetic and molecular delineation of a region of chromosome 7 commonly deleted in malignant myeloid diseases. Blood 1996;88:1930e5. Yajnik V, Paulding C, Sordella R, McClatchey AI, Saito M, Wahrer DC, Reynolds P, Bell DW, Lake R, van den Heuvel S, Settleman J, Haber DA. DOCK4, a GTPase activator, is disrupted during tumourigenesis. Cell 2003;112:673e84. Aktas D, Tuncbilek E. Myelodysplastic syndrome associated with monosomy 7 in childhood: a retrospective study. Cancer Genet Cytogenet 2006;171:72e5. Casorzo L, Luzzi C, Nardacchione A, Picciotto F, Pisacane A, Risio M. Fluorescence in situ hybridization evaluation of chromosomes 6, 7, 9, and 10 throughout human melanocytic tumorigenesis. Melanoma Res 2005;15:155e60. Ho¨glund M, Gisselsson D, Hansen GB, White VH, Sall T, Mitelman F, Horsman D. Dissecting karyotypic patterns in malignant melanomas: temporal clustering of losses and gains in melanoma karyotypic evolution. Int J Cancer 2004;108:57e65. Singh AD, Bray J, Borden EC. Uveal malignant melanoma: metastasis. Philadelphia, PA: Elsevier, 2007. Lorigan JG, Wallace S, Mavligit GM. The prevalence and location of metastases from ocular melanoma: imaging study in 110 patients. AJR Am J Roentgenol 1991;157:1279e81. Midena E, de Belvis V, dei Tos AP, Antonini C. Isolated brain metastasis of malignant choroidal melanoma 27 years after enucleation. Arch Ophthalmol 1999;117:1553s6. Van Wiltenburg R, Sevick RJ, Clark AW, Burger PC, LeBlanc FE. Choroidal melanoma metastasis as a rare cause of cerebellopontine angle lesion: 2 case reports. Can Assoc Radiol J 1998;49:185e9.
Short communication
Monosomy 7 mosaicism in metastatic choroidal melanoma Hande Taylana, Hayyam Kiratlia,*, Dilek Aktasb b
a Department of Ophthalmology Department of Genetics, Hacettepe University, Sihhiye, Ankara 06100, Turkey
Received 6 March 2007; received in revised form 24 April 2007; accepted 9 May 2007
Abstract
Uveal melanoma is the most common primary intraocular malignancy in adults. Several cytogenetic studies on uveal melanoma cells have revealed that the majority of these cells harbor alterations in chromosomes 3, 6, and 8. This report describes the results of cytogenetic analysis performed on a fresh choroidal melanoma tissue sample from a patient with cerebellar metastasis. Monosomy 7 mosaicism was observed. To our knowledge, monosomy 7 has not been reported in patients with uveal melanoma. We suggest that observation of monosomy 7 may be related to an aggressive clinical behavior and unusual cerebellar metastasis in uveal melanoma. Further data are necessary to define the exact role of monosomy 7 in the pathogenesis and evolution of uveal melanoma. Ó 2007 Elsevier Inc. All rights reserved.
1. Introduction Uveal melanoma is the most common primary intraocular malignancy and is believed to arise from neuroectodermally derived melanocytes present in the choroid, ciliary body, or iris [1,2]. Metastasis is the most important factor affecting survival in uveal melanoma, and overall mortality is approximately 50% in 10 years because of the development of liver metastasis [3]. Despite advances in the diagnosis and treatment of uveal melanoma, patient survival still has not improved significantly. Several cytogenetic studies on uveal melanoma revealed that abnormalities of chromosomes 3, 6, and 8 do not occur randomly [4e8]. Monosomy 3 is the first and still most common chromosomal abnormality found in choroidal melanoma. It has been detected in nearly half of uveal melanoma cases with poor prognosis and has been linked strongly to metastatic disease [7,9,10]. Extra copies of 6p are found in approximately one fourth of uveal melanoma cases and have been correlated with better prognosis [9,11,12]. Loss of 6q has also been observed in uveal melanoma and has been described more commonly in metastasizing tumors [5]. Furthermore, gain of 8q has been found in uveal melanoma and is strongly related with metastasis, similar to monosomy 3 [11,13]. In addition, loss of 1p, 9p, and 13q, as well as gain of chromosome 21, have been reported [8,9,11,14]. We herein report the results of * Corresponding author. Tel.: þ90-312-305-1777; fax: þ90-312-3094101. E-mail address: [email protected] (H. Kiratli). 0165-4608/07/$ e see front matter Ó 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.cancergencyto.2007.05.004
cytogenetic analysis on a fresh intraocular uveal melanoma tissue sample from a patient with cerebellar metastasis.
2. Case report An otherwise healthy 64-year-old man complained of decreased vision and pain in his right eye and was referred to our center. Upon examination, his visual acuity was no light perception in the right eye and 20/20 in the left. Biomicroscopic examination of the right eye showed upper and lower eyelid edema, chemosis, a dark brown subconjunctival mass in the inferior fornix, corneal edema, shallow anterior chamber, rubeosis iridis, and nuclear cataract. Right intraocular pressure was 68 mmHg. Cranial and orbital MRI studies suggested extraocular extension of an intraocular tumor, the signal characteristics of which were compatible with uveal melanoma. There was also evidence of cerebellar metastasis. Because of massive orbital spread and no prospect for useful vision, exenteration of the right orbit was performed. The histopathologic diagnosis was mixed cell type choroidal melanoma with optic nerve invasion and filling of 50% of the orbital cavity. The patient refused further treatment and died of metastatic disease a year later. To perform cytogenetic analysis, fresh tumor samples were obtained from within the eye portion of the exenterated specimen. The tumor tissue was then mechanically minced and treated with collagenase. Cytogenetic analysis was performed on short-term cultures of the primary tumor sample and harvested. GTG banding was performed using routine methods. The karyotypes were described in
H. Taylan et al. / Cancer Genetics and Cytogenetics 177 (2007) 70e72
accordance with ISCN 2005 [15]. The karyotype was found to be 46,XY[14]/45,XY,-7 [6], indicating monosomy 7 mosaicism (Fig. 1).
3. Discussion Advances in cytogenetics have been instrumental in the identification of chromosomal alterations in uveal melanomas and have provided some insight into the pathogenesis of disease. Monosomy 3 has been detected in a number of metastasizing melanomas and has been correlated with tumor diameter, ciliary body involvement, the presence of epithelial cells, and closed PAS-positive loops [7]. Among patients with uveal melanoma, monosomy 3 has been associated with a reduction of the 5-year survival probability from 100 to 50% [10]. Prescher et al. [5] proposed that monosomy 3 could be the early event in tumor development. Furthermore, gains of chromosome 8 have also been related with reduced survival probability [13]. In addition, loss of chromosome 3 and gains of chromosome 8 tend to occur together [16]. Monosomy 7 has been detected in many types of cancer and has been associated with progression in meningioma [17] and hemophagocytic syndrome [18]. By using allelotyping analysis, at least three distinct regions on the loci 7q22, 7q31.1, and 7q31.2 were observed in patients with myelodysplastic syndrome (MDS) and acute myelogeneous leukemia associated with monosomy 7 [19,20]. A newly described deletion affecting the tumor supressor gene DOCK4, localized within the 7q31 interval, was present in human prostate and ovarian cancers [21]. Monosomy 7
71
or partial loss of 7q in pediatric MDS was recently associated with poor prognosis and progression to ALL or to AML [22]. Monosomy 7 has also been observed in a case with common melanocytic nevi [23]. To the best of our knowledge, this is the first patient in whom monosomy 7 mosaicism has been documented in fresh intraocular melanoma tissue. Uveal melanomas arise from the melanocytes of the uveal, and skin melanomas are derived from epidermal melanocytes. Structural rearrangements of chromosome 1, loss of 9p, 6p, and 10q, as well as gain of chromosome 7, are the most common chromosomal abnormalities involved in skin melanomas [24]. Further statistical analysis suggested that 3 might be more specific for uveal melanoma and 10 for cutaneous melanomas, adding that both were very common in both types of melanomas [24]. It is noteworthy that 3 and þ6p imbalances were found to represent alternative starting cytogenetic pathways leading to karyotypic evolution present again in both cutaneous and uveal melanomas [24]. These two early and initializing imbalances are often followed by secondary changes involving þ8q, 8p, and 1p after 3 and 6q, 16, 9p, or 10 after þ6p [24]. Uveal melanomas tend to metastasize via the bloodstream to distant sites, predominantly to the liver, in 70e90% of patients with metastatic disease [25,26]. Brain metastasis is rare and accounts for 5e11% of all metastatic uveal melanoma cases [25e27]. Cerebellar metastasis is exceedingly rare and portends the same overall dismal prognosis compared to metastatic loci discovered at other sites [27,28]. Monosomy 7 mosaicism in our patient may be related to an aggressive clinical course, as evidenced by the massive orbital invasion and the highly unusual cerebellar
Fig.1. The karyotype of the patient with choroidal melanoma having monosomy 7.
72
H. Taylan et al. / Cancer Genetics and Cytogenetics 177 (2007) 70e72
metastases. Further studies are necessary to determine the exact contribution of monosomy 7 to the pathogenesis and progression of choroidal melanoma.
References [1] Singh AD, Topham A. Incidence of uveal melanoma in United States: 1973e1997. Ophthalmology 2003;110:956e61. [2] Diener-West M, Hawkins BS, Markowitz JA, Schachat AP. A review of mortality from choroidal melanoma. II. A meta-analysis of 5-year mortality rates following enucleation, 1966 through 1988. Arch Ophthalmol 1992;110:245e50. [3] Bergman L, Seregard S, Nilsson B, Lundell G, Ringborg U, Ragnarsson-Olding B. Uveal melanoma survival in Sweden from 1960 to 1998. Invest Ophthalmol Vis Sci 2003;44:3282e7. [4] Sisley K, Cottam DW, Rennie IG, Parsons MA, Potter AM, Potter CW, Rees RC. Non-random abnormalities of chromosomes 3, 6 and 8 associated with posterior uveal melanoma. Genes Chromosomes Cancer 1990;5:197e200. [5] Prescher G, Bornfeld N, Becher R. Nonrandom chromosomal abnormalities in primary uveal melanoma. J Natl Cancer Inst 1990;82: 1765e9. [6] Singh AD, Boghosian-Sell L, Wary KK, Shields CL, De Potter P, Donoso LA, Shields JA, Cannizzaro LA. Cytogenetic findings in primary uveal melanoma. Cancer Genet Cytogenet 1994;72:109e15. [7] Scholes AGM, Damato BE, Nunn J, Hiscott P, Grierson I, Field JK. Monosomy 3 in uveal melanoma: correlation with clinical and histologic predictors of survival. Invest Ophthalmol Vis Sci 2003;44:1008e11. [8] Sisley K, Parsons MA, Garnham J, Potter AM, Curtis D, Rees RC, Rennie IG. Association of specific chromosome alterations with tumour phenotype in posterior uveal melanoma. Br J Cancer 2000;82:330e8. [9] Aalto Y, Eriksson L, Seregard S, Larsson O, Knuutila S. Concomitant loss of chromosome 3 and whole arm losses and gains of chromosome 1,6 or 8 in metastasizing primary uveal melanoma. Invest Ophthalmol Vis Sci 2001;42:313e7. [10] Prescher G, Bornfeld N, Hirche, Horsthemke B, Jockel KH, Becher R. Prognostic implications of monosomy 3 in uveal melanoma. Lancet 1996;347:1222e5. [11] Prescher G, Bornfeld N, Friedrichs W, Seeber S, Becher R. Cytogenetics of twelve cases of uveal melanoma and patterns of nonrandom anomalies and isochromosome formation. Cancer Genet Cytogenet 1995;80:40e6. [12] Parrella P, Sidransky D, Merbs SL. Allelotype of posterior uveal melanoma: implications for a bifurcated tumour progression pathway. Cancer Res 1999;59:3032e7. [13] Sisley K, Rennie IG, Parsons MA, Jacques R, Hammond DW, Bell SM, Potter AM, Rees RC. Abnormalities of chromosomes 3
[14]
[15] [16] [17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25] [26]
[27]
[28]
and 8 in posterior uveal melanoma correlate with prognosis. Genes Chromosomes Cancer 1997;19:22e8. Scholes AG, Liloglou T, Maloney P, Hagan S, Nunn J, Hiscott P, Damato BE, Grierson I, Field JK. Loss of heterozygosity on chromosomes 3, 9, 13 and 17, including the retinoblastoma locus, in uveal melanoma. Invest Ophthalmol Vis Sci 2000;42:2472e7. ISCN. An International System for Human Cytogenetic Nomenclature. Basel: S. Karger, 2005. Singh AD, Damato B, Howard P, Harbour JW. Uveal melanoma: genetic aspects. Ophthalmol Clin N Am 2005;85e97. Henn W, Niedermayer I, Ketter R, Reichardt S, Freiler A, Zang KD. Monosomy 7p in meningioma: a rare constituent of tumour progression. Cancer Genet Cytogenet 2003;144:65e8. Tadmor T, Vadazs Z, Dar H, Laor R, Attias D. Hemophagocytic syndrome preceding acute myeloid leukemia with der t (7,17) (q12-q11), monosomy, 17 and 5p-. J Pediatr Hematol Oncol 2006;28:544e6. Liang H, Fairman J, Claxton DF, Nowell PC, Green ED, Nagarajan L. Molecular anatomy of chromosome 7q deletions in myeloid neoplasms evidence for multiple critical loci. Proc Natl Acad Sci USA 1998;95:3781e5. Le Beau MM, Espinosa R 3rd, Davis EM, Eisenbart JD, Larson RA, Green ED. Cytogenetic and molecular delineation of a region of chromosome 7 commonly deleted in malignant myeloid diseases. Blood 1996;88:1930e5. Yajnik V, Paulding C, Sordella R, McClatchey AI, Saito M, Wahrer DC, Reynolds P, Bell DW, Lake R, van den Heuvel S, Settleman J, Haber DA. DOCK4, a GTPase activator, is disrupted during tumourigenesis. Cell 2003;112:673e84. Aktas D, Tuncbilek E. Myelodysplastic syndrome associated with monosomy 7 in childhood: a retrospective study. Cancer Genet Cytogenet 2006;171:72e5. Casorzo L, Luzzi C, Nardacchione A, Picciotto F, Pisacane A, Risio M. Fluorescence in situ hybridization evaluation of chromosomes 6, 7, 9, and 10 throughout human melanocytic tumorigenesis. Melanoma Res 2005;15:155e60. Ho¨glund M, Gisselsson D, Hansen GB, White VH, Sall T, Mitelman F, Horsman D. Dissecting karyotypic patterns in malignant melanomas: temporal clustering of losses and gains in melanoma karyotypic evolution. Int J Cancer 2004;108:57e65. Singh AD, Bray J, Borden EC. Uveal malignant melanoma: metastasis. Philadelphia, PA: Elsevier, 2007. Lorigan JG, Wallace S, Mavligit GM. The prevalence and location of metastases from ocular melanoma: imaging study in 110 patients. AJR Am J Roentgenol 1991;157:1279e81. Midena E, de Belvis V, dei Tos AP, Antonini C. Isolated brain metastasis of malignant choroidal melanoma 27 years after enucleation. Arch Ophthalmol 1999;117:1553s6. Van Wiltenburg R, Sevick RJ, Clark AW, Burger PC, LeBlanc FE. Choroidal melanoma metastasis as a rare cause of cerebellopontine angle lesion: 2 case reports. Can Assoc Radiol J 1998;49:185e9.