National Cancer Institute®
Last Modified: March 1, 2002
UI - 11857383
AU - Iscovich J; Abdulrazik M; Cour C; Fischbein A; Pe'er J; Goldgar DE
TI - Prevalence of the BRCA2 6174 del T mutation in Israeli uveal melanoma patients.
SO - Int J Cancer 2002 Mar 1;98(1):42-4
AD - Selikoff Center for Environmental Health and Human Development and the International Fertility Institute, Ra'anana, Israel. email@example.com
Substantial differences exist in the incidence rates of uveal melanoma (UM) among Israeli Jewish subpopulations: high in immigrants from North America and Europe (Ashkenazic) and low in immigrants from Africa and Asia (Sepharadic). This trend persists in Israeli-born individuals when stratified by their ancestral place of birth. There have been several anecdotal reports of uveal melanoma occurring in breast cancer families with mutations in the BRCA2 gene as well as one systematic study reporting BRCA2 mutations in UM. A single BRCA2 mutation, 6174 del T, occurs in about 1% of the Ashkenazic population and rarely in non-Ashkenazic. To assess the contribution of this germline mutation to uveal melanoma in Jewish Israeli patients, we tested this relationship through analysis of blood samples from a series of UM patients. A total of 153 cases (84 female, 69 male) were available for study, which represents 30% of all cases of UM diagnosed in Israel during the period 1984-1999 (82% for the period 1992-1999). Of the 143 UM patients for which a result could be obtained (4 due to refusals, 6 due to damage to the blood sample), 4 (2.8%, 95% confidence interval [CI] 0-5.6) carried the 6174 del T mutation. Assuming a population frequency of the mutation of 1% as estimated among Ashkenazic Jews in the United States, the probability of observing 4 or more carriers with the 6174 del T mutation, assuming no relationship between uveal melanoma and BRCA2, is 0.057. Although our study confirms the relationship between uveal melanoma and BRCA2, it is clear that the 6174 del T mutation accounts for only a small fraction of all Israeli UM cases. Therefore, BRCA2 mutations are likely to account for an even smaller proportion in populations with low frequencies of BRCA2 alterations. Copyright 2001 Wiley-Liss, Inc.
UI - 11857391
AU - Youl P; Aitken J; Hayward N; Hogg D; Liu L; Lassam N; Martin N; Green A
TI - Melanoma in adolescents: a case-control study of risk factors in Queensland, Australia.
SO - Int J Cancer 2002 Mar 1;98(1):92-8
AD - Queensland Cancer Fund, Brisbane, Australia.
The incidence of melanoma increases markedly in the second decade of life but almost nothing is known of the causes of melanoma in this age group. We report on the first population-based case-control study of risk factors for melanoma in adolescents (15-19 years). Data were collected through personal interviews with cases, controls and parents. A single examiner conducted full-body nevus counts and blood samples were collected from cases for analysis of the CDKN2A melanoma predisposition gene. A total of 201 (80%) of the 250 adolescents with melanoma diagnosed between 1987 and 1994 and registered with the Queensland Cancer Registry and 205 (79%) of 258 age-, gender- and location-matched controls who were contacted agreed to participate. The strongest risk factor associated with melanoma in adolescents in a multivariate model was the presence of more than 100 nevi 2 mm or more in diameter (odds ratio [OR] = 46.5, 95% confidence interval [CI] = 11.4-190.8). Other risk factors were red hair (OR = 5.4, 95%CI = 1.0-28.4); blue eyes (OR = 4.5, 95%CI = 1.5-13.6); inability to tan after prolonged sun exposure (OR = 4.7, 95%CI = 0.9-24.6); heavy facial freckling (OR = 3.2, 95% CI = 0.9-12.3); and family history of melanoma (OR = 4.0, 95%CI = 0.8-18.9). Only 2 of 147 cases tested had germline variants or mutations in CDKN2A. There was no association with sunscreen use overall, however, never/rare use of sunscreen at home under the age of 5 years was associated with increased risk (OR = 2.2, 95%CI = 0.7-7.1). There was no difference between cases and controls in cumulative sun exposure in this high-exposure environment. Factors indicating genetic susceptibility to melanoma, in particular, the propensity to develop nevi and freckles, red hair, blue eyes, inability to tan and a family history of the disease are the primary determinants of melanoma among adolescents in this high solar radiation environment. Lack of association with reported sun exposure is consistent with the high genetic susceptibility in this group. Copyright 2001 Wiley-Liss, Inc.
UI - 11792747
AU - Landi MT; Baccarelli A; Tarone RE; Pesatori A; Tucker MA; Hedayati M;
TI - Grossman L DNA repair, dysplastic nevi, and sunlight sensitivity in the development of cutaneous malignant melanoma.
SO - J Natl Cancer Inst 2002 Jan 16;94(2):94-101
AD - Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892-7236, USA. firstname.lastname@example.org
BACKGROUND: Exposure to UV radiation is associated with cutaneous malignant melanoma (CMM). In mammalian cells, UV radiation induces DNA damage that can be repaired by the nucleotide excision repair system. We designed this case-control study to determine whether DNA repair capacity (DRC) is associated with the risk of CMM and to identify risk factors that may interact biologically with DRC in the development of melanoma. METHODS: Global DRC was measured in lymphocytes with the host-cell reactivation assay. Data were analyzed by use of multiple regression models. All statistical tests were two-sided. RESULTS: DRC could be determined for 132 case patients with incident melanoma and for 145 age- and sex-matched control subjects. No statistically significant association between melanoma risk and DRC by itself was found (odds ratio [OR] = 1.0; 95% confidence interval [CI] = 0.6 to 1.7, adjusted for age, sex, lymphocyte viability, and sample storage time). DRC, however, strongly influenced CMM risk in individuals with a low tanning ability or dysplastic nevi. Individuals with a low tanning ability and a low DRC had a higher risk for CMM (OR = 8.6; 95% CI = 2.7 to 27.5) than individuals with a higher tanning ability and a high DRC. Likewise, individuals with dysplastic nevi and a low DRC had a higher relative risk (OR = 6.7; 95% CI = 2.4 to 18.6) than those lacking dysplastic nevi and having a high DRC. Subjects with dysplastic nevi and a high DRC had an intermediate risk. A likelihood-ratio test gave statistically significant interactions between DRC and tanning response (P =.001) and between DRC and dysplastic nevus status (P =.04), which were independently associated with CMM risk. CONCLUSIONS: DRC may modify the risk for melanoma in the presence of other strong risk factors, such as a low tanning ability and the presence of dysplastic nevi. The occurrence of melanoma in subjects without these risk factors appears to be independent of DRC.
UI - 11604998
AU - Ringhoffer M; Schmitt M; Karbach J; Jager E; Oesch F; Arand M
TI - Quantitative assessment of the expression of melanoma-associated antigens by non-competitive reverse transcription polymerase chain reaction.
SO - Int J Oncol 2001 Nov;19(5):983-9
AD - Third Department of Medicine, University of Ulm, D-89081 Ulm, Germany.
The assessment of tumor-associated antigens (TAA) recognized by T lymphocytes is a prerequisite for diagnosis and immunotherapy of melanoma. Different reverse transcription-polymerase chain reaction (RT-PCR) protocols allowing the quantification of the TAA mRNA expression in the solid tumor or the detection of circulating melanoma cells have been described. We have recently shown a positive correlation between the amount of specific product formed by RT-PCR and the staining intensity in immunohistochemical analysis of the corresponding sample. Here we describe a quantification procedure based on the direct digitization of the PCR products after separation on ethidium bromide-stained agarose gels, followed by computer-assisted densitometry. To standardize our method, we examined the linear range of the densitometric quantification procedure as reflected by the correlation of signal intensity to the amount of the corresponding DNA. As an internal measure for the so-termed cDNA in the different samples after RNA isolation and reverse transcription, a beta-actin PCR was introduced. Subsequently, we chose four sets of primers for the melanoma-associated antigens MAGE1, tyrosinase, Melan A/MART-1 and gp100/Pmel17 and performed PCR analysis over a range of cycle numbers. In each case, the amplification rate remained constant up to at least 26 cycles under the respective conditions. Plotting the logarithm of the amount of product against the cycle number yields a slope that equals the logarithm of the amplification rate. The amount of starting material can be determined from the intercept with the ordinate. In summary, the method introduced in the present work allows the quantification of TAA in melanoma which might be important for the monitoring of disease. Technically the method is sound and sensitive, avoids post-PCR manipulations and can be performed with the standard equipment of a molecular biology laboratory. It can be applied also to other solid tumors and leukemias.
UI - 11844832
AU - Ellerhorst JA; Prieto VG; Ekmekcioglu S; Broemeling L; Yekell S; Chada
TI - S; Grimm EA Loss of MDA-7 expression with progression of melanoma.
SO - J Clin Oncol 2002 Feb 15;20(4):1069-74
AD - Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030-4095, USA. email@example.com
PURPOSE: Ectopic transfer of the melanoma differentiation-associated gene-7 (mda-7) has been shown in vitro to suppress growth and induce apoptosis in a variety of human tumor cell lines; similar effects are not elicited in normal cells. Thus, the mda-7 gene seems to function as a novel tumor suppressor, and there is interest in the potential of mda-7 gene transfer as cancer therapy. The objective of this study was to determine if MDA-7 protein is lost during primary melanoma progression from superficial to invasive stages and from localized to metastatic tumor. As a secondary objective, we analyzed MDA-7 protein expression in primary melanomas for correlation with predictors of outcome and with survival. MATERIALS AND METHODS: MDA-7 protein expression was evaluated by immunohistochemistry in 41 primary melanomas and 41 metastases, including 24 paired samples. Each sample was scored for the percentage of positive cells and the overall intensity of immunolabeling. RESULTS: Significant decreases in MDA-7 immunostaining, reflected in both number and intensity scores, were observed when comparing the intraepidermal and superficially invasive portions with the deeply invasive portions of primary tumors. Significant differences were also observed when comparing primary tumors to paired metastases. CONCLUSION: Downregulation of MDA-7 expression in primary melanomas facilitates progression to invasive and metastatic stages. These data support the development of Ad-mda7 as gene therapy for advanced melanoma.
UI - 11783086
AU - Cai S; Leng X; Wang Y
TI - [Expression of two types of melanoma antigens in hepatocellular carcinoma]
SO - Zhonghua Zhong Liu Za Zhi 2001 May;23(3):205-7
AD - Surgical Department, People's Hospital, Beijing University, Beijing 100044, China.
OBJECTIVE: To investigate the expression of melanoma antigen MAGE-4 and MAGE-10 mRNA in Chinese human hepatocellular carcinoma (HCC). METHODS: The expression of MAGE-4 and MAGE-10 mRNA in HCC tissues and the adjacent non-HCC liver tissues was studied using RT-PCR in 48 samples of HCC. Ten samples of cirrhosis and 10 samples of normal liver tissues were examined. The PCR products were sequenced. RESULTS: Of the 48 HCC samples studied, 15 (31.3%) and 14 (29.2%) expressed MAGE-4 and MAGE-10 mRNA respectively. In contrast, none of the HCC adjacent non-tumorous liver tissues were MAGE-4 and MAGE-10 mRNA detectable. Nor did liver tissues from cirrhosis and normal liver samples. The expression of the two genes in HCC showed no correlation with the serum level of AFP and the tumor size. CONCLUSION: MAGE-4 and MAGE-10 mRNA are specifically expressed in Chinese HCC samples.
UI - 11833005
AU - Kanetsky PA; Swoyer J; Panossian S; Holmes R; Guerry D; Rebbeck TR
TI - A polymorphism in the agouti signaling protein gene is associated with human pigmentation.
SO - Am J Hum Genet 2002 Mar;70(3):770-5
AD - Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA 19104-6021, USA. firstname.lastname@example.org
In mice and humans, binding of alpha-melanocyte--stimulating hormone to the melanocyte-stimulating--hormone receptor (MSHR), the protein product of melanocortin-1 receptor (MC1R) gene, leads to the synthesis of eumelanin. In the mouse, ligation of MSHR by agouti signaling protein (ASP) results in the production of pheomelanin. The role of ASP in humans is unclear. We sought to characterize the agouti signaling protein gene (ASIP) in a group of white subjects, to assess whether ASIP was a determinant of human pigmentation and whether this gene may be associated with increased melanoma risk. We found no evidence of coding-region sequence variation in ASIP, but detected a g.8818A-->G polymorphism in the 3' untranslated region. We genotyped 746 participants in a study of melanoma susceptibility for g.8818A-->G, by means of polymerase chain reaction and restriction fragment--length polymorphism analysis. Among the 147 healthy controls, the frequency of the G allele was.12. Carriage of the G allele was significantly associated with dark hair (odds ratio 1.8; 95% confidence interval [CI] 1.2--2.8) and brown eyes (odds ratio 1.9; 95% CI 1.3--2.8) after adjusting for age, gender, and disease status. ASIP g.8818A-->G was not associated independently with disease status. This is the first report of an association of ASIP with specific human pigmentation characteristics. It remains to be investigated whether the interaction of MC1R and ASIP can enhance prediction of human pigmentation and melanoma risk.
UI - 11579965
AU - Takahashi T; Kazama Y; Shimizu H; Yoshimoto M; Tsujisaki M; Imai K
TI - Brain metastases of malignant melanoma showing unbalanced whole arm chromosomal translocations der (8; 14) (q10; q10) and der (11; 15) (q10; q10) in a Japanese patient.
SO - Intern Med 2001 Sep;40(9):956-60
AD - Second Department of Internal Medicine, Tenshi Hospital, Sapporo.
Since malignant melanoma is a rare malignancy in Japan, little is known about the cytogenetic abnormalities in Japanese patients. We report a case of malignant melanoma showing complex chromosomal abnormalities. A 70-year-old woman was admitted to our hospital because of anorexia, delirium, and right hemiplegia. Cranial CT disclosed several metastatic brain tumors. Multiple subcutaneous and intra-abdominal metastases were also found. A diagnosis of metastatic malignant melanoma was made by biopsy of a subcutaneous tumor. Chromosomal analysis of the tumor cells disclosed complex karyotypic abnormalities including novel unbalanced whole arm translocations der (8; 14) (q10; q10) and der (11; 15) (q10; q10).
UI - 11751501
AU - Indsto JO; Cachia AR; Kefford RF; Mann GJ
TI - X inactivation, DNA deletion, and microsatellite instability in common acquired melanocytic nevi.
SO - Clin Cancer Res 2001 Dec;7(12):4054-9
AD - Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Darcy Road, Westmead, New South Wales 2145, Australia. James_Indsto@wmi.usyd.edu.au
We have investigated several molecular characteristics of common acquired melanocytic nevi to clarify their relationship to malignant melanoma, which is characterized by clonality and the progressive accumulation of DNA deletions. Twenty-four common acquired nevi were subjected to analysis for loss of heterozygosity at four loci on chromosome 9p and six loci on 10q that are commonly deleted in melanoma, but no deletions were seen. X inactivation analysis was performed in lesions from females, using the methylation-sensitive restriction HpaII site in the CAG microsatellite repeat (HUMARA) in exon 1 of the androgen receptor (AR) gene. In 14 melanomas, 11 (92%) were confirmed to have skewed X inactivation, consistent with monoclonality, as were 16 (80%) of 20 benign nevi. One nevus (5%) and 4 (33%) of 12 melanomas also showed loss of heterozygosity at HUMARA. One nevus showed an additional allele, consistent with low level microsatellite instability, at one of the 11 loci that were examined. Common melanocytic nevi, therefore, arise by apparently clonal proliferation, but they do not share chromosomal deletions that are characteristic of melanoma. However, skewed X inactivation patterns were seen in some samples of adjacent microdissected normal epidermis.
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