Familial Dysplastic Nevus Syndrome Research Articles

On the clinical significance of cutaneous melanoma′s precursors

We can identify three main groups of cutaneous pigmented lesions that could be represented as melanoma precursors: (a) congenital melanocytic nevi, (b) dysplastic or atypical nevi, and (c) acquired melanocytic nevi. The occurrence of melanoma in small and intermediate congenital melanocytic nevi is very uncommon, but there is a high risk in large congenital melanocytic nevi, in particular those arising in the so-called “bathing trunk” distribution. It is very important to distinguish the familial dysplastic nevus syndrome, which is a strong risk factor for cutaneous melanoma, from not familial (sporadic) dysplastic nevus, in which the risk for melanoma would depend on the total number of melanocytic nevi, phototype, and on the relationship to environmental factors.

Risk factors for the development of malignant melanomas

There are numerous risk factors for the development of malignant melanomas. Genetic and environmental aspects have to be considered. The most important genetic risk factor is a mutation in the CDKN2A gene, which is a turmorsuppressor-gene which regulates the cell cycle. In addition, the familial dysplastic nevus syndrome shows a marked risk for the development of malignant melanoma. Patients with xeroderma pigmentosum have an inability to repair UV-induced DNA defects. This constellation leads to early development of epitheliomas and malignant melanomas. Constitutional risk factors are fair-red hair and blue eyes with a high tendency for sunburns. The most important environmental factor is UV-exposition. Sunburns before the age of 15 and the total cumulative UV-dosage are high impact risk factors. The most important preventive measures are to check the whole skin at a regular base in a patient with the familal dysplastic nevus syndrome and in addition all persons should wear a hat, trousers, shirt and glasses. Furthermore direct sun exposure should be avoided during noon time.

Xeroderma Pigmentosum and Related Disorders: Examining the Linkage Between Defective DNA Repair and Cancer

Xeroderma pigmentosum, Cockayne syndrome, the xeroderma pigmentosum-Cockayne syndrome complex, and trichothiodystrophy cells have defects in DNA repair and are associated with clinical and cellular hypersensitivity to ultraviolet radiation (UV). Familial dysplastic nevus syndrome cells have UV hyper-mutability. Although xeroderma pigmentosum and dysplastic nevus syndrome have markedly increased cancer risk, Cockayne syndrome and trichothiodystrophy do not. At the molecular level, these disorders are associated with several different genetic defects as evidenced by the existence of multiple overlapping complementation groups. Recent progress has been made in identifying the chromosomal location and cloning the defective genes in these disorders. Using plasmid shuttle vectors we have shown abnormal repair and mutagenesis of DNA damaged by 254-nm (UVC) or 295-nm (UVB) radiation or the chemical carcinogen aflatoxin in cells from patients with xeroderma pigmentosum. Although xeroderma pigmentosum cells are defective in repair of all photoproducts, Cockayne syndrome cells appear to be defective in repair of cyclobutane dimers and have normal repair of nondimer photoproducts. DNS cells have post UV plasmid hypermutability. These diseases may serve as models for examining molecular mechanisms of carcinogenesis in humans. J Invest Dermatol 103:96-101, 1994

Xeroderma pigmentosum and related disorders: examining the linkage between defective DNA repair and cancer.

Xeroderma pigmentosum, Cockayne syndrome, the xeroderma pigmentosum-Cockayne syndrome complex, and trichothiodystrophy cells have defects in DNA repair and are associated with clinical and cellular hypersensitivity to ultraviolet radiation (UV). Familial dysplastic nevus syndrome cells have UV hypermutability. Although xeroderma pigmentosum and dysplastic nevus syndrome have markedly increased cancer risk. Cockayne syndrome and trichothiodystrophy do not. At the molecular level, these disorders are associated with several different genetic defects as evidenced by the existence of multiple overlapping complementation groups. Recent progress has been made in identifying the chromosomal location and cloning the defective genes in these disorders. Using plasmid shuttle vectors we have shown abnormal repair and mutagenesis of DNA damaged by 254-nm (UVC) or 295-nm (UVB) radiation or the chemical carcinogen aflatoxin in cells from patients with xeroderma pigmentosum. Although xeroderma pigmentosum cells are defective in repair of all photoproducts, Cockayne syndrome cells appear to be defective in repair of cyclobutane dimers and have normal repair of nondimer photoproducts. DNS cells have post UV plasmid hypermutability. These diseases may serve as models for examining molecular mechanisms of carcinogenesis in humans.

Gene-specific DNA repair of UV-induced cyclobutane pyrimidine dimers in some cancer-prone and premature-aging human syndromes

We have examined the gene-specific DNA repair of UV-induced cyclobutane pyrimidine dimers (CPDs) in fibroblasts from the following cancer prone syndromes: familial dysplastic nevus syndrome (DNS), Gardner's syndrome (GS), and Bloom's syndrome (BS). These heritable human syndromes are associated with DNA damage hypersensitivity and have been considered as potentially DNA repair deficient. Previous determinations of DNA repair in these cell strains have been done solely at the level of the overall genome. That approach is not sensitive enough to detect deficiencies in repair at the level of the gene. Defective preferential repair of active genes may impair survival and affect genomic stability. This is exemplified by the disorder Cockayne's syndrome (CS) which is associated with a selective deficiency in the preferential repair of active genes. In this study, we have used a Cockayne's syndrome cell strain and also a normal human fibroblast cell line as a control. Repair was studied in the transcriptionally active gene dihydrofolate reductase (DHFR), the inactive δ globin gene, and in the c-myc protooncogene. In the DNS, GS and BS cell lines, we find preferential repair similar to that in normal cells. In Cockayne's syndrome cells, there is no preferential repair of the DHFR gene.

Melanoma genetics and cytogenetics

It is now well established that cancer has a genetic basis and is accompanied by structural alterations in the chromosomal DNA. Often, these alterations occur in genes playing an important role in the regulation of proliferation and differentiation. The function of these genes is directly related to the process of oncogenic transformation, and therefore these genes are often referred to as oncogenes. 1 Apart from the biochemical and molecular evidence for altered genes in cancer cells, also cytogenetic and classical genetic studies hint at genetic defects that correlate with the development of cancer; in virtually all cancer cells chromosomal defects can be discerned and in a number of human cancer types hereditary defects determining the disease do occur. Often, the inheritance is determined by inactivation of one allele in one of the genes involved in the suppression of cancerous properties, the so-called tumor suppressor genes. 2 In that case cancer becomes manifest when the remaining intact allele of the gene is inactivated by a somatic mutation. A serious complication in establishing the genetic defect in hereditary cancer is that the development of cancer is a multistep process involving more than one gene. 3 So far, no consistent combinations of gene defects have been found in almost any form of human cancer, which makes it difficult to ascertain one particular gene defect that is associated with transmission of the disease. In cutaneous melanoma, about 10% of the cases are familial, and in such cases melanoma is usually associated with an inherited cutaneous phenotype, the familial atypical multiplemole melanoma (FAMMM) syndrome, also called familial dysplastic nevus syndrome (see the article by Bergman and Fusaro in this issue). The atypical nevi can be considered as precursor lesions for melanoma; therefore, the development of melanoma, at least in FAMMM patients, is likely to take place in at least two distinct steps, one leading to atypical melanocytes and the subsequent step correlated with the transition to melanoma. As about half of the patients with sporadic melanoma have atypical moles as compared with only 2 to 9% of the overall population, it seems that sporadic melanoma and familial melanoma have similar genetic defects determining the precursor stage. Also with respect to clinical and histologic features, no differences have been found, indicating that the subsequent genetic alterations leading to melanoma are similar in sporadic melanoma and the FAMMM syndrome. In this article, I briefly exemplify the hereditary features of melanoma and summarize the genetic and cytogenetic defects associated with the FAMMM syndrome and cutaneous melanoma. Furthermore, I review the alterations in tumor suppressor genes and oncogenes in melanoma and discuss their possible role in the various evolutionary steps of this tumor.

Correlation of clinical pigmentary characteristics with histopathologically-confirmed dysplastic nevi in nonfamilial melanoma patients. Studies of melanocytic nevi IX

The dysplastic melanocytic nevus (DMN) is the key clinical marker for the familial dysplastic nevus syndrome and has also been associated with high risk for non-familial melanoma. Characterisations of DMN itself have been qualitative and on a case-by-case basis. In this study, we provided clinical and histological characterisations for each of 150 pigmented lesions from 150 patients with prior malignant melanoma. The steps involved in the study were as follows: (1) The two to four clinicians characterised pigmented lesions on each of 150 patients, and the lesion closest in characteristics to an atypical nevus was quantitatively described based on size, border characteristics and colour characteristics; (2) The lesion was then removed and independently quantified by a single dermatopathologist without knowledge of the clinical features; (3) We computed the correlation between each of the clinical variables and each of the histologic features for each of the 150 patients. Histologic diagnosis of dysplastic nevus was strongly associated with total number of palpable arm nevi, total number of any arm nevi, total number of nevi on the body of any type, and total number of clinically atypical nevi on the body (correlation coefficients 23.2% to 30.4% with P less than 0.01 in each instance). There were also strong correlations between the counts of numbers of nevi and certain types of architectural histologic features, including fusion (bridging of junctional nests), lymphocyte response and fibroplasia of the papillary dermis. Histologic evaluation of solar elastosis was negatively correlated with total numbers of nevi and total number of clinically atypical nevi (P less than 0.01). Freckling on forearm and on shoulders showed no significant positive or negative correlations with any of the histologic features nor with overall diagnosis of dysplastic nevus. We conclude that observations regarding total numbers of nevi (either normal or clinically atypical nevi) are correlated with nuclear and architectural histologic dysplasia on biopsy of the most atypical pigmented lesions.

Ocular melanoma in families with dysplastic nevus syndrome

Five families with the dysplastic nevus syndrome, in each of which one member had ocular melanoma, are reported. These five families were examined within a 3-year period in one medical center. To date only five other families with such a combination have been reported. We suggest a causal relation between ocular melanoma and the familial dysplastic nevus syndrome.

Melanoma in children

Four cases of malignant melanoma in children younger than 17 years of age are presented. Several preexisting conditions increase the risk of development of melanoma during childhood. These include giant congenital melanocytic nevi, the familial dysplastic nevus syndrome, and xeroderma pigmentosum. The role of small congenital lesions and sporadic dysplastic nevi in the development of melanoma in children is less clear. The signs and symptoms associated with melanoma in children are similar to those in adults, as are the histopathologic features, biologic behavior, and treatment of this tumor. The inadequacy of available therapy for metastatic melanoma underscores the necessity for the early diagnosis and prompt surgical treatment of melanomas in children.

Exclusion of the dysplastic nevus syndrome (DNS) locus from the short arm of chromosome 1 by linkage studies in dutch families

Familial dysplastic nevus syndrome (DNS) is an autosomal dominant premalignant condition characterized by multiple large moles of variable size and color and a strongly increased risk for cutaneous malignant melanoma. In order to determine the chromosomal localization of the DNS gene, linkage studies were initiated in six large Dutch families. No support was obtained for linkage between the loci for DNS and the rhesus blood group on chromosome 1. Data from additional markers (DNF15S1, D1Z2, FUCA1, D1S17, D1S57, and PGM1) make it possible to exclude the DNS gene from the short arm of chromosome 1 in these Dutch families.

Bioreduction of 4-nitroquinoline 1-oxide in dysplastic nevus syndrome fibroblasts

Fibroblast strains 3012T and 3072T, derived from normal skin explants of two patients affected with familial dysplastic nevus syndrome (DNS), an hereditary variant of cutaneous malignant melanoma, have been reported to be abnormally sensitive to the cytotoxic and mutagenic effects of the procarcinogen 4-nitroquinoline 1-oxide (4NQO). In this communication we demonstrate that on exposure to a particular concentration of 4NQO, these same two DNS strains sustain an amount of DNA damage which is equal to (3012T) or only ∼ 1.3 times greater than (3072T) that displayed by 8 control fibroblast strains established from clinically normal volunteers. Moreover, cell sonicates of 3072T display ∼ 1.3-fold enhanced capacity to catalyze the reduction of 4NQO to the proximate carcinogen 4-hydroxyaminoquinoline 1-oxide, whereas sonicates of 3012T cells carry out this reaction at a normal rate. Accordingly, our results argue against the postulate that the 4NQO hypersensitivity exhibited by these DNS strains is merely due to an elevated capacity for bioreduction of the inert parent compound to a DNA-reactive derivative.

The familial dysplastic nevus syndrome: Natural history and the impact of screening on prognosis a study of nine families in the Netherlands

Since 1982, nine families with the dysplastic nevus syndrome have been identified in the Leiden area (The Netherlands). A total of 50 primary melanomas were diagnosed in 38 persons. Nineteen of these melanomas had been diagnosed before the start of the screening programme (category I), 11 were detected at the initial examination of the families (category II), and 20 were found during the course of follow-up (category III). To assess the effect of screening, we compared these categories with respect to the developmental stage of the melanomas. One of the 19 melanomas in category I, two of the 11 in category II and seven of the 20 in category III were melanoma in situ. The average thickness of the invasive melanomas in categories I, II and III was 1.75, 0.80 and 0.54 mm respectively. Sixteen of the 19 melanomas in category I (84%) were Clark III or IV, whereas 15 of the 20 melanomas in category III (75%) were Clark I or II. From these findings it may be concluded that screening can lead to the detection of melanomas at an earlier stage, which in turn can permit curative treatment and improvement of both prognosis and life expectancy. The need for supervision based on central registration of affected families to guarantee the continuity of screening is discussed.

Genetic and Epidemiologic Evaluation of Dysplastic Nevi

Dysplastic Nevus Syndrome (DNS) has been defined as that trait characterized by the presence of at least one dysplastic melanocytic nevus. DNS was originally described in kindreds having multiple members with melanoma. Various types DNS have been described in other situations to include individuals with apparently sporadic cases, familial DNS without melanoma and individuals with apparently sporadic DNS with melanoma. These categories are based on historical information in general, and not on examination of family members. In all cases, the presence of dysplastic nevi appear to confer some increased risk of melanoma, which varies between the groups. Similarly cutaneous melanoma is thought to occur in several distinct populations‐random individuals without DNS, individuals with sporadic DNS, and those with familial DNS.Genetic analysis of DNS has been largely confined to the classically ascertained kindreds associated with melanoma. These studies have usually used diagnostic criteria based on pathology of clinically selected material, and that evidence suggests that DNS is inherited as an autosomal dominant trait in these families. Surveys of the general population have detected rates of dysplastic nevi of 5% 20%. In our Utah‐based studies, we have evaluated probands and family members from three groups. These included kindreds with multiple occurrences of melanoma, random individuals with at least one dysplastic nevus, and cases of melanoma with unknown family history. Controls were spouses of study subjects. We sought to determine the percentage of each group associated with dysplastic nevi and/or genetic DNS. The range of phenotype of patients with dysplastic nevi was large with some individuals having few nevi, none of which were clinically atypical, and others having greater than 100 nevi. The prevalence of dysplastic nevi in at least one of two biopsies in Utah population controls is presently Wtimated at 62%. Some probands with melanoma as well as some of their relatives had elevated numbers of nevi, suggesting that this predisposition to melanoma may be inherited.

The Dysplastic Nevus Syndrome

The following constellation of traits constitutes the familial dysplastic nevus syndrome: (1) a distinctive clinical appearance of abnormal melanocytic nevi 1-3 ; (2) unique histologic features, including an abnormal architectural pattern of intraepidermal melanocytes, cytologically atypical intraepidermal melanocytes, connective tissue changes, and a lymphocytic infiltrate 4,5 ; (3) an autosomal dominant inheritance, possibly linked to a susceptibility gene on the short arm of chromosome 1 near the Rh locus 6 ; and (4) hypermutability of fibroblasts and lymphoblasts. (Fibroblasts and lymphoblasts from patients with the dysplastic nevus syndrome and hereditary cutaneous melanoma are abnormally sensitive to ultraviolet radiation damage, simulated sunlight, and exposure to 4-nitroquinoline-1-oxide. 7,8 Their fibroblasts are also hypersensitive to G 2 chromatid radiation damage. 9 ) The syndrome is, in all likelihood, one of the hypermutability disorders. The familial dysplastic nevus syndrome is presently recognized by its clinical and histologic features, but, in due course, it may

The natural history of dysplastic nevi. A case history illustrating their evolution

• A 31-year-old man with familial dysplastic nevus syndrome presented with numerous histologically confirmed dysplastic nevi. Seven years before this, all of his nevi, numbering over 150, had been "prophylactically" removed. Despite the removal of all visible nevi, many new nevocellular nevi and atypical nevi appeared during the subsequent seven years. This case illustrates the natural history of dysplastic nevi and suggests that removal of all nevi to prevent melanoma may be futile. (<i>Arch Dermatol</i>1987;123:1059-1061)

The Natural History of Dysplastic Nevi

A 31-year-old man with familial dysplastic nevus syndrome presented with numerous histologically confirmed dysplastic nevi. Seven years before this, all of his nevi, numbering over 150, had been "prophylactically" removed. Despite the removal of all visible nevi, many new nevocellular nevi and atypical nevi appeared during the subsequent seven years. This case illustrates the natural history of dysplastic nevi and suggests that removal of all nevi to prevent melanoma may be futile.

Dysplastic Nevus Syndrome: Familial and Sporadic Precursors of Cutaneous Melanoma

Familial dysplastic nevus syndrome is an autosomal-dominant precursor of hereditary melanoma in which individuals have clinically and histologically distinctive nevi and a markedly increased risk for development of melanoma. Dysplastic nevi also are found in sporadic forms. Classification of the condition of the patient and proper management including regular examination of nevi can help to determine the risk of melanoma and minimize the potential for neoplastic progression.