A number sign (#) is used with this entry because heterozygous mutation in the p16 gene (CDKN2A;600160) on chromosome 9p21 increases susceptibility to one form of cutaneous malignant melanoma (CMM2).
Malignant melanoma is a neoplasm of pigment-producing cells called melanocytes that occurs most often in the skin, but may also occur in the eyes, ears, gastrointestinal tract, leptomeninges, and oral and genital mucous membranes (summary byHabif, 2010).
For a discussion of genetic heterogeneity of cutaneous malignant melanoma, see CMM1 (155600).
Bergman et al. (1986) studied extensively affected kindreds in an ancient fishing village in the neighborhood of Leiden, the Netherlands. Autosomal dominant inheritance of dysplastic nevi was confirmed. In 6 pedigrees, 33 patients with melanoma occurred. Fifteen unaffected persons were identified as gene carriers by their position in the pedigrees.
Four independent reports supported the existence of a tumor-suppressor locus on chromosome 9p that is mutated during the early stages of melanoma development (Dracopoli et al., 1987;Cowan et al., 1988;Pedersen and Wang, 1989;Kacker et al., 1990). Rearrangements of this chromosome occur in nearly half of all melanomas, with the most frequently targeted region extending from 9pter to 9q13 (Fountain et al., 1990). The alpha-interferon (147660) and beta-1 interferon (147640) genes are located within this region and are viewed as candidates for involvement in cutaneous melanoma because they have growth-inhibitory properties and, as therapeutic agents, have caused the regression of metastatic melanoma. In addition, interferon-like molecules have been detected in the basal layer of the epidermis, suggesting that they may contribute to the control of normal epidermal growth or regeneration. Also residing in this region of 9p are the tyrosinase-related protein (115501) and the glycoprotein 4-beta-galactosyltransferase (137060) genes which might play a role. Using markers on 9p in studies of loss of heterozygosity,Fountain et al. (1992) identified a small critical region of 2 to 3 Mb on 9p21 in which a putative melanoma tumor-suppressor gene resides. In the course of these studies they excluded IFNB1, the IFNA gene cluster, GGTB2, and TYRP as the site of mutations in melanoma because they are located outside the homozygously deleted regions. In 10 Utah kindreds and 1 Texas kindred with multiple cases of cutaneous malignant melanoma,Cannon-Albright et al. (1992) provided evidence for a locus determining susceptibility in the region 9p13-p22. The markers that determined this location by linkage studies resided in a candidate region on 9p21, previously implicated by the presence of homozygous deletions in melanoma tumors and by the presence of a germline deletion in a person with 8 independent melanomas. Linkage studies placed the susceptibility locus (whichCannon-Albright et al. (1992) symbolized MLM) near IFNA and D9S126 with a maximum lod score of 12.71. The location of a gene predisposing to CMM on 9p was supported by the description of de novo constitutional unbalanced reciprocal translocation involving the short arms of chromosomes 5 and 9 with a cytogenetically visible deletion of one or the other, in a woman with atypical moles and multiple primary melanomas, who lacked a family history of hereditary cutaneous malignant melanoma (Petty et al., 1993). In a second article,Petty et al. (1993) demonstrated deletion of the IFNA locus and several markers located at 9p21. By multipoint linkage analysis using the 9p markers IFNA and D9S126 in 26 Australian melanoma kindreds,Nancarrow et al. (1993) obtained a peak lod score of 4.43, 15 cM centromeric to D9S126; a lod score of 4.13 was also found 15 cM telomeric of IFNA. These data suggest that the CMM2 locus lies outside of the IFNA-D9S126 interval.
In the Dutch pedigree segregating autosomal dominant dysplastic nevi and malignant melanoma described byBergman et al. (1986),Frants et al. (1989) andvan Haeringen et al. (1989) excluded linkage with RH (see111700) on chromosome 1p; indeed, data from additional markers excluded the dysplastic nevus locus from the entirety of chromosome 1p (see CMM1,155600).Bergman et al. (1994) restudied this Dutch pedigree and found linkage to markers on chromosome 9p21: in a linkage analysis in which only melanoma patients were considered as affected, marker D9S171 showed a maximum lod score of 3.11 at theta = 0.0. After introducing family members with 10 or more, or 5 or more, atypical nevi as affected in addition to the melanoma patients, the maximum lod score rose to 4.88 at theta = 0.05 and 3.79 at theta = 0.07, respectively. Interestingly, the sharing of a unique 9p21 haplotype among most melanoma patients in the families from 2 different villages suggested that an old common mutation is present in the Leiden region.
Using 2 highly informative (CA)n repeats, D9S126 and IFNA (147660),Goldstein et al. (1994) performed linkage studies in 13 families previously investigated for linkage to chromosome 1p (Bale et al., 1989;Goldstein et al., 1993). Significant evidence for linkage to IFNA was found. The analyses were performed using CMM alone (all individuals without either confirmed melanoma or borderline lesions were considered unaffected); CMM/DN with both variable age at onset and sporadics; or CMM affecteds only (all individuals either without confirmed melanoma or with borderline lesions were designated 'unknown'). No significant evidence of linkage was found for D9S126 with either CMM alone or CMM/DN. Significant evidence for heterogeneity was found when a homogeneity test allowing for linkage to chromosome 9p or chromosome 1p or neither region was used. Since some families showed linkage to both 1p and 9p, a 2-locus model was being investigated also.
Cannon-Albright et al. (1994) narrowed the assignment of the MLM gene to a 2-cM region that is proximal to D9S736 and distal to D9S171. They commented that 2 of the linkage studies that confirmed the chromosome 9 assignment for malignant melanoma provided no evidence for the existence of genetic heterogeneity (Gruis et al., 1993;Nancarrow et al., 1993). There is evidence both for and against linkage of melanoma to the 1p region as indicated in155600.Cannon-Albright et al. (1994) suggested that the question of genetic heterogeneity for melanoma susceptibility will be best answered when the 9p susceptibility locus has been cloned and tested in multiple kindreds and cases.
Following up on previous linkage analyses of 19 cutaneous malignant melanoma/dysplastic nevi (CMM/DN) kindreds which showed significant evidence of linkage and heterogeneity to both chromosomes 1p and 9p,Goldstein et al. (1996) examined 2-locus hypotheses. The lod scores for CMM alone were highest using the single locus-heterogeneity model. They found much stronger evidence of linkage to 9p than to 1p for CMM alone; the lod scores were approximately 2 times greater on 9p than on 1p. A change in lod scores from an evaluation of CMM alone to CMM/DN suggested to the authors that a chromosome 1p locus contributed to both CMM and CMM/DN, whereas a 9p locus contributed more to CMM alone. For 2-locus models, the lod scores from 1p were greater for CMM/DN than for CMM alone. After conditioning on linkage to the other locus, only the 9p locus consistently showed significant evidence for linkage to CMM alone.
Falchi et al. (2009) conducted a genomewide association study for nevus count (see162900), a known risk factor for cutaneous melanoma, using 297,108 SNPs in 1,524 twins, with validation in an independent cohort of 4,107 individuals.Falchi et al. (2009) identified strongly associated variants in the MTAP gene (156540), which is adjacent to the familial melanoma susceptibility locus CDKN2A on 9p21 (rs4636294, combined P = 3.4 x 10(-15)), as well as in the PLA2G6 gene (603604) on 22q13.1 (rs2284063, combined P = 3.4 x 10(-8)). Variants in these 2 loci also showed association with melanoma risk in 3,131 melanoma cases from 2 independent studies, includingrs10757257 at 9p21 (combined P = 3.4 x 10(-8), odds ratio = 1.23) andrs132985 at 22q13.1 (combined P = 2.6 x 10(-7), odds ratio = 1.23).
Bishop et al. (2009) identified and replicated 3 loci with strong evidence of association with risk for cutaneous melanoma: 16q24 encompassing MC1R (155555) (combined P = 2.54 x 10(27) forrs258322), 11q14-q21 encompassing TYR (606933) (P = 2.41 x 10(-14) forrs1393350), and 9p21 adjacent to MTAP and flanking CDKN2A (P = 4.03 x 10(-7) forrs7023329). MC1R and TYR are associated with pigmentation, freckling, and cutaneous sun sensitivity, well-recognized melanoma risk factors.
The identification of the CDKN2A gene (600160) in melanoma cell lines by study of homozygous deletions for the 9p21 region (Kamb et al., 1994) and the identification of nonsense, missense, and frameshift mutations in those cell lines that had at least one CDKN2 allele present (Kamb et al., 1994) suggested that mutations in this gene may be the basis of familial malignant melanoma in many instances. The mutations in this tumor suppressor gene are involved in many other malignancies, rivaling the p53 gene (191170) in its catholicity.
Weaver-Feldhaus et al. (1994) isolated genomic clones that span a large region in 9p21 surrounding the presumptive tumor suppressor gene(s) thought to be involved in susceptibility to melanoma and to influence progression of certain other tumors. A set of sequence tagged sites in this region were developed. By using these markers and others previously reported, the 9p21 region was studied by physical mapping in 84 melanoma cell lines. Homozygous deletions of the 9p21 region were found in 56% of melanoma tumors tested. A putative tumor suppressor gene was localized to a region of less than 40 kb that lies proximal (centromeric) to the IFNA gene cluster. The results were consistent with previous genetic studies of MLM that mapped the gene to the region between IFNA1 and D9S126.
Puig et al. (1995) presented evidence suggesting the existence of several tumor suppressor genes on 9p that are involved in the predisposition to and/or progression of CMM and excluded p16 from involvement in the early development of some melanoma tumors.
Miller and Mihm (2006) stated that 25 to 40% of melanoma-prone families have mutations in the CDKN2A gene.
Kannengiesser et al. (2007) identified 2 founder mutations in the CDKN2A gene (600160.0017 and600160.0018) among families in southeastern France with cutaneous malignant melanoma.
In affected members of 3 unrelated Italian families with autosomal dominant malignant melanoma,Binni et al. (2010) identified heterozygous mutations in exon 1B of the CDKN2A gene affecting the p14(ARF) isoform (see600160.0020 and600160.0021). These 3 families were from a large cohort of 81 Italian families with melanoma who were negative for CDKN2A mutations affecting the p16(INK4) isoform and mutations in the CDK4 (123829) gene. Mutations affecting exon 1B were not found in any of 58 sporadic cases.
In a population-based study of 35 melanoma patients with CDKN2A mutations, including 22 from the U.K. and 13 from 3 cities in Australia, and their relatives,Cust et al. (2011) estimated that hazard ratios (HR) for melanoma in mutation carriers relative to the general population was 87 in the U.K. and 31 in Australia. However, cumulative risk estimates were not different: 16% of U.K. and 20% of Australian mutation carriers would be diagnosed with melanoma by age 50 years, and 45% and 52%, respectively, by age 80 years. Contrary to the strong association between UV radiation exposure and melanoma risk for the general population, CDKN2A mutation carriers appear to have the same cumulative risk of melanoma irrespective of the ambient UV irradiance of the region in which they live.
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ORPHA: 618; MONDO: 0007964;
| Location | Phenotype | Phenotype MIM number | Inheritance | Phenotype mapping key | Gene/Locus | Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 9p21.3 | {Melanoma, cutaneous malignant, 2} | 155601 | Autosomal dominant | 3 | CDKN2A | 600160 |
A number sign (#) is used with this entry because heterozygous mutation in the p16 gene (CDKN2A; 600160) on chromosome 9p21 increases susceptibility to one form of cutaneous malignant melanoma (CMM2).
Malignant melanoma is a neoplasm of pigment-producing cells called melanocytes that occurs most often in the skin, but may also occur in the eyes, ears, gastrointestinal tract, leptomeninges, and oral and genital mucous membranes (summary by Habif, 2010).
For a discussion of genetic heterogeneity of cutaneous malignant melanoma, see CMM1 (155600).
Bergman et al. (1986) studied extensively affected kindreds in an ancient fishing village in the neighborhood of Leiden, the Netherlands. Autosomal dominant inheritance of dysplastic nevi was confirmed. In 6 pedigrees, 33 patients with melanoma occurred. Fifteen unaffected persons were identified as gene carriers by their position in the pedigrees.
Four independent reports supported the existence of a tumor-suppressor locus on chromosome 9p that is mutated during the early stages of melanoma development (Dracopoli et al., 1987; Cowan et al., 1988; Pedersen and Wang, 1989; Kacker et al., 1990). Rearrangements of this chromosome occur in nearly half of all melanomas, with the most frequently targeted region extending from 9pter to 9q13 (Fountain et al., 1990). The alpha-interferon (147660) and beta-1 interferon (147640) genes are located within this region and are viewed as candidates for involvement in cutaneous melanoma because they have growth-inhibitory properties and, as therapeutic agents, have caused the regression of metastatic melanoma. In addition, interferon-like molecules have been detected in the basal layer of the epidermis, suggesting that they may contribute to the control of normal epidermal growth or regeneration. Also residing in this region of 9p are the tyrosinase-related protein (115501) and the glycoprotein 4-beta-galactosyltransferase (137060) genes which might play a role. Using markers on 9p in studies of loss of heterozygosity, Fountain et al. (1992) identified a small critical region of 2 to 3 Mb on 9p21 in which a putative melanoma tumor-suppressor gene resides. In the course of these studies they excluded IFNB1, the IFNA gene cluster, GGTB2, and TYRP as the site of mutations in melanoma because they are located outside the homozygously deleted regions. In 10 Utah kindreds and 1 Texas kindred with multiple cases of cutaneous malignant melanoma, Cannon-Albright et al. (1992) provided evidence for a locus determining susceptibility in the region 9p13-p22. The markers that determined this location by linkage studies resided in a candidate region on 9p21, previously implicated by the presence of homozygous deletions in melanoma tumors and by the presence of a germline deletion in a person with 8 independent melanomas. Linkage studies placed the susceptibility locus (which Cannon-Albright et al. (1992) symbolized MLM) near IFNA and D9S126 with a maximum lod score of 12.71. The location of a gene predisposing to CMM on 9p was supported by the description of de novo constitutional unbalanced reciprocal translocation involving the short arms of chromosomes 5 and 9 with a cytogenetically visible deletion of one or the other, in a woman with atypical moles and multiple primary melanomas, who lacked a family history of hereditary cutaneous malignant melanoma (Petty et al., 1993). In a second article, Petty et al. (1993) demonstrated deletion of the IFNA locus and several markers located at 9p21. By multipoint linkage analysis using the 9p markers IFNA and D9S126 in 26 Australian melanoma kindreds, Nancarrow et al. (1993) obtained a peak lod score of 4.43, 15 cM centromeric to D9S126; a lod score of 4.13 was also found 15 cM telomeric of IFNA. These data suggest that the CMM2 locus lies outside of the IFNA-D9S126 interval.
In the Dutch pedigree segregating autosomal dominant dysplastic nevi and malignant melanoma described by Bergman et al. (1986), Frants et al. (1989) and van Haeringen et al. (1989) excluded linkage with RH (see 111700) on chromosome 1p; indeed, data from additional markers excluded the dysplastic nevus locus from the entirety of chromosome 1p (see CMM1, 155600). Bergman et al. (1994) restudied this Dutch pedigree and found linkage to markers on chromosome 9p21: in a linkage analysis in which only melanoma patients were considered as affected, marker D9S171 showed a maximum lod score of 3.11 at theta = 0.0. After introducing family members with 10 or more, or 5 or more, atypical nevi as affected in addition to the melanoma patients, the maximum lod score rose to 4.88 at theta = 0.05 and 3.79 at theta = 0.07, respectively. Interestingly, the sharing of a unique 9p21 haplotype among most melanoma patients in the families from 2 different villages suggested that an old common mutation is present in the Leiden region.
Using 2 highly informative (CA)n repeats, D9S126 and IFNA (147660), Goldstein et al. (1994) performed linkage studies in 13 families previously investigated for linkage to chromosome 1p (Bale et al., 1989; Goldstein et al., 1993). Significant evidence for linkage to IFNA was found. The analyses were performed using CMM alone (all individuals without either confirmed melanoma or borderline lesions were considered unaffected); CMM/DN with both variable age at onset and sporadics; or CMM affecteds only (all individuals either without confirmed melanoma or with borderline lesions were designated 'unknown'). No significant evidence of linkage was found for D9S126 with either CMM alone or CMM/DN. Significant evidence for heterogeneity was found when a homogeneity test allowing for linkage to chromosome 9p or chromosome 1p or neither region was used. Since some families showed linkage to both 1p and 9p, a 2-locus model was being investigated also.
Cannon-Albright et al. (1994) narrowed the assignment of the MLM gene to a 2-cM region that is proximal to D9S736 and distal to D9S171. They commented that 2 of the linkage studies that confirmed the chromosome 9 assignment for malignant melanoma provided no evidence for the existence of genetic heterogeneity (Gruis et al., 1993; Nancarrow et al., 1993). There is evidence both for and against linkage of melanoma to the 1p region as indicated in 155600. Cannon-Albright et al. (1994) suggested that the question of genetic heterogeneity for melanoma susceptibility will be best answered when the 9p susceptibility locus has been cloned and tested in multiple kindreds and cases.
Following up on previous linkage analyses of 19 cutaneous malignant melanoma/dysplastic nevi (CMM/DN) kindreds which showed significant evidence of linkage and heterogeneity to both chromosomes 1p and 9p, Goldstein et al. (1996) examined 2-locus hypotheses. The lod scores for CMM alone were highest using the single locus-heterogeneity model. They found much stronger evidence of linkage to 9p than to 1p for CMM alone; the lod scores were approximately 2 times greater on 9p than on 1p. A change in lod scores from an evaluation of CMM alone to CMM/DN suggested to the authors that a chromosome 1p locus contributed to both CMM and CMM/DN, whereas a 9p locus contributed more to CMM alone. For 2-locus models, the lod scores from 1p were greater for CMM/DN than for CMM alone. After conditioning on linkage to the other locus, only the 9p locus consistently showed significant evidence for linkage to CMM alone.
Falchi et al. (2009) conducted a genomewide association study for nevus count (see 162900), a known risk factor for cutaneous melanoma, using 297,108 SNPs in 1,524 twins, with validation in an independent cohort of 4,107 individuals. Falchi et al. (2009) identified strongly associated variants in the MTAP gene (156540), which is adjacent to the familial melanoma susceptibility locus CDKN2A on 9p21 (rs4636294, combined P = 3.4 x 10(-15)), as well as in the PLA2G6 gene (603604) on 22q13.1 (rs2284063, combined P = 3.4 x 10(-8)). Variants in these 2 loci also showed association with melanoma risk in 3,131 melanoma cases from 2 independent studies, including rs10757257 at 9p21 (combined P = 3.4 x 10(-8), odds ratio = 1.23) and rs132985 at 22q13.1 (combined P = 2.6 x 10(-7), odds ratio = 1.23).
Bishop et al. (2009) identified and replicated 3 loci with strong evidence of association with risk for cutaneous melanoma: 16q24 encompassing MC1R (155555) (combined P = 2.54 x 10(27) for rs258322), 11q14-q21 encompassing TYR (606933) (P = 2.41 x 10(-14) for rs1393350), and 9p21 adjacent to MTAP and flanking CDKN2A (P = 4.03 x 10(-7) for rs7023329). MC1R and TYR are associated with pigmentation, freckling, and cutaneous sun sensitivity, well-recognized melanoma risk factors.
The identification of the CDKN2A gene (600160) in melanoma cell lines by study of homozygous deletions for the 9p21 region (Kamb et al., 1994) and the identification of nonsense, missense, and frameshift mutations in those cell lines that had at least one CDKN2 allele present (Kamb et al., 1994) suggested that mutations in this gene may be the basis of familial malignant melanoma in many instances. The mutations in this tumor suppressor gene are involved in many other malignancies, rivaling the p53 gene (191170) in its catholicity.
Weaver-Feldhaus et al. (1994) isolated genomic clones that span a large region in 9p21 surrounding the presumptive tumor suppressor gene(s) thought to be involved in susceptibility to melanoma and to influence progression of certain other tumors. A set of sequence tagged sites in this region were developed. By using these markers and others previously reported, the 9p21 region was studied by physical mapping in 84 melanoma cell lines. Homozygous deletions of the 9p21 region were found in 56% of melanoma tumors tested. A putative tumor suppressor gene was localized to a region of less than 40 kb that lies proximal (centromeric) to the IFNA gene cluster. The results were consistent with previous genetic studies of MLM that mapped the gene to the region between IFNA1 and D9S126.
Puig et al. (1995) presented evidence suggesting the existence of several tumor suppressor genes on 9p that are involved in the predisposition to and/or progression of CMM and excluded p16 from involvement in the early development of some melanoma tumors.
Miller and Mihm (2006) stated that 25 to 40% of melanoma-prone families have mutations in the CDKN2A gene.
Kannengiesser et al. (2007) identified 2 founder mutations in the CDKN2A gene (600160.0017 and 600160.0018) among families in southeastern France with cutaneous malignant melanoma.
In affected members of 3 unrelated Italian families with autosomal dominant malignant melanoma, Binni et al. (2010) identified heterozygous mutations in exon 1B of the CDKN2A gene affecting the p14(ARF) isoform (see 600160.0020 and 600160.0021). These 3 families were from a large cohort of 81 Italian families with melanoma who were negative for CDKN2A mutations affecting the p16(INK4) isoform and mutations in the CDK4 (123829) gene. Mutations affecting exon 1B were not found in any of 58 sporadic cases.
In a population-based study of 35 melanoma patients with CDKN2A mutations, including 22 from the U.K. and 13 from 3 cities in Australia, and their relatives, Cust et al. (2011) estimated that hazard ratios (HR) for melanoma in mutation carriers relative to the general population was 87 in the U.K. and 31 in Australia. However, cumulative risk estimates were not different: 16% of U.K. and 20% of Australian mutation carriers would be diagnosed with melanoma by age 50 years, and 45% and 52%, respectively, by age 80 years. Contrary to the strong association between UV radiation exposure and melanoma risk for the general population, CDKN2A mutation carriers appear to have the same cumulative risk of melanoma irrespective of the ambient UV irradiance of the region in which they live.
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