Prospective risk of cancer in CDKN2A germline mutation carriers.

BACKGROUND: The CDKN2A gene is the major known high-risk melanoma susceptibility gene. Susceptibility to other cancers has also been suggested. However, most studies examining the risks of other cancers classified individuals according to the family's CDKN2A mutation rather than determining individual mutation status. For non-population-based studies, risks could also be biased because of cancer occurrence prior to family ascertainment. METHODS: We examined the risk of non-melanoma cancer in 117 mutation-positive and 136 mutation-negative members from 15 families that had at least two first degree relatives with melanoma and CDKN2A mutations restricting the analysis to the period after the families were ascertained (that is, the prospective period) and using individual mutation data. The families have been followed prospectively for 4-26 years starting in the 1970s. RESULTS: Overall, there was no significant association for mutation-negative subjects (Obs/Exp = 0.3, 95% confidence interval (CI) 0.0 to 1.2) although this group had only two observed cancers. In contrast, mutation-positive subjects had a significantly increased risk for all cancers combined (Obs/Exp = 12/5.5 = 2.2, 95% CI 1.1 to 3.8) primarily because of digestive system tumours, particularly pancreatic cancer. No other organ systems or individual tumour sites showed significantly increased risks. CONCLUSIONS: Differences in CDKN2A-non-melanoma cancer associations across studies may result from variation in genetic backgrounds, insufficient follow up, misclassification of mutation carriers, or the presence of other genetic and/or environmental risk factors in both CDKN2A mutation carriers and non-carriers. Larger sample sizes, prospective follow up, and individual mutation data will be required to understand these differences.

Genotype-phenotype relationships in U.S. melanoma-prone families with CDKN2A and CDK4 mutations.

BACKGROUND: Two genes have been implicated in the development of cutaneous malignant melanoma (CMM). CDK4 (the gene encoding cyclin-dependent kinase 4, an oncogene) has exhibited germline mutations found in only three melanoma-prone families to date. CDKN2A is a tumor suppressor gene that encodes p16 (which inhibits activity of the cyclin D1-CDK4 complex) with germline mutations detected in 10%-25% of melanoma-prone families, some of whom are also prone to pancreatic cancer. METHODS: We compared 104 CMM patients from 17 CDKN2A families and 12 CMM case subjects from two CDK4 families. We used nonparametric statistics to test for differences in median age at first CMM diagnosis, numbers of CMMs, and numbers of nevi. The three recurrent mutations were haplotyped. All P values were two-sided. RESULTS: The median age at CMM diagnosis (P =.70) and the median numbers of CMMs (P =.73) did not differ between CMM case subjects from CDKN2A versus CDK4 families. Assessment of CMM case subjects from CDKN2A families with and without pancreatic cancer revealed no statistically significant differences in median age at diagnosis (P =.80) or in tumor number (P =.24). There was, however, a statistically significant difference in age-adjusted median numbers of nevi (P =.004), and CMM case subjects from CDKN2A families without pancreatic cancer had greater numbers of nevi. Recurrent CDKN2A mutations were a change from valine to aspartic acid at codon 126 (n = 3) and from glycine to tryptophan at codon 101 (n = 3). Six CDKN2A families had pancreatic cancer. Both CDK4 families carried a mutation resulting in an arginine-to-cysteine substitution at codon 24. Analyses of recurrent CDKN2A and CDK4 mutations suggested common haplotypes. CONCLUSIONS: The recurrent CDKN2A mutations were observed in families with and without pancreatic cancer, which suggests that other factors may be involved in the development of pancreatic cancer. Despite hypothetical differences in the mechanisms of action between CDKN2A and CDK4, clinical factors were indistinguishable between CMM case subjects from CDKN2A versus CDK4 families.

The National Cancer Program.

OBJECTIVES: To provide an understanding of the history, progress, and future of the National Cancer Program. DATA SOURCES: Published articles, reports, book chapters, and the National Cancer Institute (NCI) web site. CONCLUSIONS: The NCI is the largest agency for cancer research. The cancer incidence and burden remains significant in spite of many advances. Oncology nurses can contribute to the prevention and cure of cancer through an enhanced understanding of the NCI's program. IMPLICATIONS FOR NURSING PRACTICE: The NCI provides many opportunities for oncology nurses. Nurses can conduct NCI-sponsored research trials, serve on NCI advisory boards, and participate in clinical research. Nurses can advise patients and the public of the many resources available to patients from the NCI and assist patients with informed decision making.

High prevalence of antibodies against HERV-K10 in patients with testicular cancer but not with AIDS.

Human endogenous retrovirus K10 (HERV-K10) env and gag expression has been detected in placenta, embryonic tissue, and cell lines. By transfection, these sequences have been expressed in insect cells and developed into serological assays, revealing HERV-K10 antibodies in patients with testicular cancer. Patients with AIDS are at an increased risk for testicular cancer and frequently reactivate latent infections. We postulated that HERV-K10 seroprevalence might be increased with HIV infection or AIDS. Stored, frozen serum samples from 52 patients with testicular cancer (8 patients with HIV and 30 patients with samples near the time of diagnosis) and 84 controls (40 patients with HIV) were diluted 1:40 and tested by immunofluorescence against SF158 cells transfected with HERV-K10 env [ENV1.9(+)] or gag (pACGAG). Seroprevalence rates were compared cross-sectionally in cases and controls, excluding those with indeterminate results (3 of 30 cases and 7 of 84 controls), and also were examined longitudinally in the cases before or after diagnosis of testicular cancer. Seroprevalence to HERV-K10 Env or Gag was 17 of 27 testicular cancer patients (63%) around the time of diagnosis, compared to 4 of 77 controls (5%; P < 0.0001). Seroprevalence was similar (50% to 60%) with seminoma, teratocarcinoma, or embryonal carcinoma, and it was not increased with HIV infection in either cases (33%) or controls (3%). HERV-K10 antibodies were detected in 12 of 19 cases (63%) more than 6 months before seminoma diagnosis, as well as in four cases with residual or recurrent malignancy more than 1 month after initial diagnosis. Thus, HERV-K10 antibodies are detected frequently with testicular cancer and seem to resolve rapidly with effective therapy of the malignancy. Antibody reactivity also occurs in approximately 5% of controls, perhaps because of nonspecific or cross-reactive epitopes. HIV and AIDS were not associated with HERV-K10 antibodies, thus, leaving their higher risk of testicular cancer unexplained.

The genetics of melanoma.

OBJECTIVES: To review the current status and recent advances of genetic epidemiology research in familial melanoma, and the implications for primary and secondary prevention of melanoma. DATA SOURCES: Research studies, review articles, and book chapters pertaining to melanoma susceptibility factors. CONCLUSION: Molecular genetic studies examining candidate genes for melanoma are being pursued vigorously. Considering the complexities and heterogeneity in the genetics of familial melanoma, predictive testing is not currently recommended as an established method for identifying individuals with a genetic predisposition to melanoma. IMPLICATIONS FOR NURSING PRACTICE: An understanding of the genetics of melanoma will help oncology nurses in translating the appropriate clinical implications for primary and secondary prevention related to melanoma.

Apparent anticipation in familial melanoma.

Genetic anticipation refers to progressively earlier age at diagnosis (AAD) and/or increasing severity of a disorder in successive generations. Previous examination of 23 familial melanoma kindreds revealed evidence for a dramatic reduction in AAD in successive generations. To further evaluate evidence for anticipation, we examined the AAD, number of tumours, and tumour thickness in affected parent-offspring (P-O) pairs from these 23 kindreds. Number of tumours and tumour thickness were also evaluated by generation. There were statistically significant intergenerational differences for AAD and number of tumours in the 47 affected P-O pairs. Median AAD decreased from 48 years to 28 years. The median AAD in the offspring (AADo) of a parent with CMM (median 28, mean 29.3 +/- 10.1 years, n = 51) was significantly different from the median AADo of a parent without CMM (42, 42.3 +/- 13.9 years, n = 55) (P < 0.001). In addition, parents with AAD less than the median of 48 years had offspring with a median AAD (26, 25.8 +/- 8.5 years, n = 21) significantly different from those of parents with AAD > or = 48 years (32, 34.5 +/- 10.2 years, n = 26) (P = 0.005). Ninety-four percent (44/47) of the P-O pairs showed positive anticipation, with 62% showing anticipation of > 15 years. There was little difference based on the affected parent's sex. In the 106 CMM cases there were no significant differences in tumour number (P = 0.08) or tumour thickness (P = 0.85) by generation. Number of tumours was however significantly different in cases with AAD < 34 years (n = 52, median 1.5, mean 2.3 +/- 2.4) vs cases with AAD > or = 34 years (n = 54, 1.0, 1.6 +/- 1.7) (P < 0.001). Thus these 23 familial melanoma kindreds showed evidence for anticipation as defined by a decrease in AAD in successive generations. Although increased surveillance may partly explain the results, additional studies should evaluate melanoma risk factors, genetic and/or environmental, across generations to examine the reasons for the apparent anticipation.

Increased risk of pancreatic cancer in melanoma-prone kindreds with p16INK4 mutations.

BACKGROUND: A gene on chromosome 9p, p16INK4, has been implicated in the pathogenesis of cutaneous malignant melanoma in 19 melanoma-prone families. In 10 of these kindreds mutations that impaired the function of the p16INK4 protein (p16M alleles) cosegregated with the disease. By contrast, in the other nine kindreds the mutation did not alter the function of p16INK4 (p16W alleles). We looked for differences in clinical and genetic epidemiologic features in these two groups of families. METHODS: We compared the median ages at diagnosis of melanoma, number of melanomas, thickness of the tumors, and number of nevi in the kindreds. We estimated prospectively the risks of melanoma or other cancers in families followed for 6 to 18 years and the risks of other cancers since 1925 (the entire period) by comparing the number of cancer cases observed with the number expected. RESULTS: The risk of invasive melanoma was increased by a factor of 75 in kindreds with p16M alleles and a factor of 38 in kindreds with p16W alleles. Although this difference was not significant (P = 0.14), there was a striking difference in the risk of other tumors. In kindreds with p16M alleles, the risk of pancreatic cancer was increased by a factor of 13 in the prospective period (2 cases observed, 0.15 expected; standardized incidence ratio, 13.1; 95 percent confidence interval, 1.5 to 47.4) and by a factor of 22 in the entire period (7 cases observed, 0.32 expected; standardized incidence ratio, 21.8; 95 percent confidence interval, 8.7 to 44.8). In contrast, we found no cases of pancreatic cancer in kindred with p16W alleles. CONCLUSIONS: The development of pancreatic cancer in kindreds prone to melanoma may require a p16M mutation. Genetic factors, such as the kind of mutation found in p16INK4, may explain the inconsistent occurrence of other cancers in these kindreds.

Melanocytic nevi, dysplastic nevi, and malignant melanoma in children from melanoma-prone families.

BACKGROUND: Melanocytic nevi, particularly dysplastic nevi (DN), are important markers of increased risk of malignant melanoma in adults, but little is known about their prevalence and relation to melanoma in children. OBJECTIVE: Our purpose was to define the prevalence of DN, number of nevi, and their relation to the risk of melanoma in children younger than 20 years of age from melanoma-prone families. METHODS: One hundred twenty-five persons younger than 20 years of age, from 23 melanoma-prone families, underwent clinical evaluation with nevus counts, photography, and biopsy of suspected melanocytic lesions and were observed for development of DN and melanoma. RESULTS: In melanoma-prone families, 37% of children had DN. The patients were divided into four categories: those with melanoma, DN (without melanoma), indeterminant (largely because of age at examination), and unaffected. The risk of melanoma was assessed by nevus number and presence of DN. High nevus number was strongly correlated with the presence of DN. The risk of the development of melanoma in children from melanoma-prone families appeared most related to the presence of DN (relative risk, 45; 95% confidence intervals, 2.6-786.4) and started at an early age. Of note, all children in whom melanoma developed had DN. CONCLUSION: Family history of melanoma and the presence of DN defines children with a high risk for melanoma developing at an early age.

Age at diagnosis and transmission of invasive melanoma in 23 families with cutaneous malignant melanoma/dysplastic nevi.

BACKGROUND: Familial melanoma patients tend to have an earlier age at first melanoma diagnosis, thinner lesions, a different histologic distribution, and a higher frequency of multiple primary melanomas than patients with nonfamilial melanoma. Previous examination of a large melanoma kindred from Texas suggested that although cutaneous malignant melanoma (CMM) was transmitted in an autosomal dominant fashion, there were sex differences in penetrance and disease expression. PURPOSE: This study further evaluated the age at diagnosis, sex difference in penetrance and disease expression, and segregation of familial CMM. METHODS: We evaluated the age at diagnosis and transmission of CMM in 23 U.S. white families with CMM/dysplastic nevi who had been followed 5-17 years. We estimated the median and mean ages at diagnosis of invasive melanoma for all individuals, for men and women separately, and by generation. Using the computer program BMDP1L, we also estimated the cumulative probability of an offspring developing CMM as a function of age according to whether the mother or father had melanoma. In addition, we used a life-table approach to estimate the probability that offspring of CMM parents were affected with CMM (penetrance). RESULTS: The median age at diagnosis in the 23 kindreds (n = 106) was 33 years, substantially less than that of patients with sporadic melanomas in the U.S. white population. For females, the median age at diagnosis was 29 years; for males, it was 36 years. Nine percent of the case patients developed CMM before age 20 compared with 2% in the general population. There was little difference in the transmission pattern of melanoma between males and females in the 23 families, although sons of CMM parents had a higher risk of CMM than daughters of CMM parents. This difference was, however, based on small numbers and was not statistically significant. The penetrance estimates for CMM were high. They rose rapidly from 6% at age 18 to 85% by age 48. The median age at diagnosis of invasive melanoma decreased dramatically in successive generations; the reduction was 11-16 years per generation and was statistically significant (P < .0001). CONCLUSIONS AND IMPLICATIONS: Although this reduction in median age at diagnosis may result partly from increased surveillance in hereditary melanoma families and the fact that individuals in the younger generations have not yet reached the highest at-risk ages for developing melanoma, the possibility of changes in melanoma risk and risk factors, genetic and/or environmental, across generations should be considered.

Linkage of cutaneous malignant melanoma/dysplastic nevi to chromosome 9p, and evidence for genetic heterogeneity.

We examined the relationship between cutaneous malignant melanoma/dysplastic nevi (CMM/DN) and chromosome 9p in 13 pedigrees with two or more living cases of invasive melanoma. We used two highly informative (CA)n repeats, D9S126 and IFNA, previously implicated in familial malignant melanoma (MLM), to conduct linkage analysis. Three analyses were performed: (1) CMM alone--all individuals without either confirmed melanoma or borderline lesions were considered unaffected (model A); (2) CMM/DN with both variable age at onset and sporadics (model B); and (3) CMM affecteds only--all individuals either without confirmed melanoma or with borderline lesions were designated "unknown" (model C). There was significant evidence for linkage to IFNA in all three models. For CMM alone, the maximum lod score (Zmax) was 4.36 at theta = .10 for model A and 3.39 at theta = .10 for model C. For CMM/DN (model B), Zmax = 3.05 at theta = .20. There was no significant evidence for linkage between CMM alone or CMM/DN and chromosome 9p marker D9S126. In addition, there was significant evidence for heterogeneity when a homogeneity test allowing for linkage to chromosome 9p or chromosome 1p or neither region was used. These results suggest that there is an MLM susceptibility locus on chromosome 9p but that familial melanoma is heterogeneous and not all families with CMM/DN are linked to a locus in this region.

Risk of melanoma and other cancers in melanoma-prone families.

We evaluated the risk of developing melanoma over time in members of 23 melanoma-prone families. All 23 families had dysplastic nevi as well as melanoma. Forty-seven melanomas occurred prospectively, all in family members with dysplastic nevi. The prospective melanomas were markedly thinner than the melanomas diagnosed prior to or at the time of the subject's entry into the study. The cumulative risk of melanoma by age 50 years among people with dysplastic nevi was 48.9% +/- 4.2%. Overall, the relative risk of a prospective melanoma among family members with previous melanoma was 229 (95% confidence interval 110-422). The risk varied by time interval and was 362 in the first 5 years, decreasing to 120 after 5 years. The risk of developing melanoma was 85 times increased (95% confidence interval 41-156) in family members with dysplastic nevi and also declined over time in this group. There was no significant excess of cancers other than melanoma. Close surveillance of these high-risk families has led to diagnosis of melanoma at an earlier developmental stage, which should result in a decrease in mortality over time.

Further evidence for a locus for cutaneous malignant melanoma-dysplastic nevus (CMM/DN) on chromosome 1p, and evidence for genetic heterogeneity.

Assignment of a susceptibility locus for cutaneous malignant melanoma-dysplastic nevus (CMM/DN) to chromosome 1p remains controversial. We examined the relationship between CMM/DN and markers D1S47, PND, and D1S160 on seven new families (set B) plus updated versions of six previously reported families (set A). Three linkage analyses were performed: (1) CMM alone--all individuals without confirmed melanoma or borderline lesions were considered unaffected (model I); (2) CMM/DN with variable age at onset and sporadics (model II); and (3) CMM/DN using the model of Bale et al. (model III). For CMM alone and D1S47, Zmax = 3.12 at theta = .10. For D1S160 and CMM alone, Zmax = 1.76 at theta = .10. PND showed no evidence for linkage to CMM alone. Models II and III showed strong evidence for linkage to D1S47, D1S160, and PND in the set A pedigrees but not in the set B families. We tested for homogeneity of CMM/DN (model II) by splitting families into two groups on the basis of (1) the proportion of CMM/DN cases and (2) the occurrence of immune-related tumors. In group 1 there was significant evidence of heterogeneity with both D1S47 and D1S160, and in group 2 there was significant evidence of heterogeneity with D1S160. Thus, diagnostic, clinical, and genetic heterogeneity are the likely reasons that previous studies have failed to confirm linkage of CMM/DN to chromosome 1p. The results showed significant evidence for a CMM locus linked to D1S47, as well as significant evidence for heterogeneity with only a subset of the families appearing linked to chromosome 1p.

Genodermatoses with profound malignant potential.

There are a number of heritable disorders that have some association with skin cancer. Xeroderma pigmentosum, nevoid basal cell carcinoma syndrome, and familial melanoma and dysplastic nevi are three disorders associated with an extremely high rate of cutaneous malignancy. There is no known cure for these disorders, thus, patients and families need information about the disease process, treatment options, and guidelines aimed at prevention and early detection of skin cancer.

Mapping the gene for hereditary cutaneous malignant melanoma-dysplastic nevus to chromosome 1p.

We used molecular genetic techniques and multipoint linkage analyses to locate the gene responsible for cutaneous malignant melanoma-dysplastic nevus. We evaluated 99 relatives and 26 spouses in six families with a predisposition to melanoma. Thirty-four family members had cutaneous malignant melanoma, and 31 of these 34 also had histologically confirmed dysplastic nevi. Twenty-four family members had dysplastic nevi alone. An analysis of the cosegregation of the cutaneous malignant melanoma-dysplastic nevus trait with 26 polymorphic DNA markers on the short arm of chromosome 1 demonstrated the presence of a gene for susceptibility to melanoma. The gene was located between an anonymous DNA marker (D1S47) and the gene locus for pronatrodilatin, a commonly used reference gene (PND), in chromosome band 1p36. The odds were greater than 260,000:1 in favor of linkage at this location.

Second malignancies following cancer therapy.

In the absence of proper treatment, essentially all patients with disseminated malignancy and a substantial number of those with more localized disease will die of their cancer. Unfortunately, effective cancer therapy usually results in exposure to treatment that, in itself, may be carcinogenic. The long-term risks attributed to such therapy, however, must be balanced against the benefits of therapy for a life-threatening disease. The risk of treatment-related malignancies is under intensive investigation. As the follow-up time increases on various treatment regimens, our knowledge of these late effects will be advanced significantly.

Hereditary melanoma and the dysplastic nevus syndrome: the risk of cancers other than melanoma.

We analyzed the prospective occurrence of cancers other than malignant melanoma in fourteen kindreds with hereditary cutaneous malignant melanoma and the dysplastic nevus syndrome. No significant excess of nonmelanoma cancers was documented, suggesting that hereditary cutaneous malignant melanoma/dysplastic nevus syndrome is not pleiotropic for other tumor types.