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Sancy A Leachman

Publications and source records attributed to Sancy A Leachman.

At least 19 recordsLinked to original sources
PubMed2009

Patterns of photoprotection following CDKN2A/p16 genetic test reporting and counseling.

BACKGROUND: The impact of melanoma genetic testing and counseling on photoprotective behaviors is unknown. OBJECTIVE: To determine if genetic testing and counseling alter compliance with photoprotection recommendations. METHODS: Reported use of sunscreen, protective clothing, and sun avoidance by 59 members of CDKN2A/p16-mutation positive pedigrees was assessed as a function of mutation status and melanoma history, before, immediately after, and 1 month following test reporting. RESULTS: Intentions to practice all photoprotective behaviors increased in all participant groups (P < .0001). At 1 month, 33% of participants reported the adoption of a new photoprotective behavior. Subpopulation analyses identified different patterns of change in photoprotection relative to baseline (P < .005), with no net decline in any group. LIMITATIONS: This initial study of CDKN2A/p16 families is small and awaits replication in a larger sample. CONCLUSION: Melanoma genetic testing and counseling enhanced intentions to implement photoprotective strategies and did not result in reduced compliance in the CDKN2A/p16-subpopulation.

Adult↗
PubMed2006

High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL.

GenoMEL, comprising major familial melanoma research groups from North America, Europe, Asia, and Australia has created the largest familial melanoma sample yet available to characterize mutations in the high-risk melanoma susceptibility genes CDKN2A/alternate reading frames (ARF), which encodes p16 and p14ARF, and CDK4 and to evaluate their relationship with pancreatic cancer (PC), neural system tumors (NST), and uveal melanoma (UM). This study included 466 families (2,137 patients) with at least three melanoma patients from 17 GenoMEL centers. Overall, 41% (n = 190) of families had mutations; most involved p16 (n = 178). Mutations in CDK4 (n = 5) and ARF (n = 7) occurred at similar frequencies (2-3%). There were striking differences in mutations across geographic locales. The proportion of families with the most frequent founder mutation(s) of each locale differed significantly across the seven regions (P = 0.0009). Single founder CDKN2A mutations were predominant in Sweden (p.R112_L113insR, 92% of family's mutations) and the Netherlands (c.225_243del19, 90% of family's mutations). France, Spain, and Italy had the same most frequent mutation (p.G101W). Similarly, Australia and United Kingdom had the same most common mutations (p.M53I, c.IVS2-105A>G, p.R24P, and p.L32P). As reported previously, there was a strong association between PC and CDKN2A mutations (P < 0.0001). This relationship differed by mutation. In contrast, there was little evidence for an association between CDKN2A mutations and NST (P = 0.52) or UM (P = 0.25). There was a marginally significant association between NST and ARF (P = 0.05). However, this particular evaluation had low power and requires confirmation. This GenoMEL study provides the most extensive characterization of mutations in high-risk melanoma susceptibility genes in families with three or more melanoma patients yet available.

Adult↗
PubMed2006

Features associated with germline CDKN2A mutations: a GenoMEL study of melanoma-prone families from three continents.

BACKGROUND: The major factors individually reported to be associated with an increased frequency of CDKN2A mutations are increased number of patients with melanoma in a family, early age at melanoma diagnosis, and family members with multiple primary melanomas (MPM) or pancreatic cancer. METHODS: These four features were examined in 385 families with > or =3 patients with melanoma pooled by 17 GenoMEL groups, and these attributes were compared across continents. RESULTS: Overall, 39% of families had CDKN2A mutations ranging from 20% (32/162) in Australia to 45% (29/65) in North America to 57% (89/157) in Europe. All four features in each group, except pancreatic cancer in Australia (p = 0.38), individually showed significant associations with CDKN2A mutations, but the effects varied widely across continents. Multivariate examination also showed different predictors of mutation risk across continents. In Australian families, > or =2 patients with MPM, median age at melanoma diagnosis < or =40 years and > or =6 patients with melanoma in a family jointly predicted the mutation risk. In European families, all four factors concurrently predicted the risk, but with less stringent criteria than in Australia. In North American families, only > or =1 patient with MPM and age at diagnosis < or =40 years simultaneously predicted the mutation risk. CONCLUSIONS: The variation in CDKN2A mutations for the four features across continents is consistent with the lower melanoma incidence rates in Europe and higher rates of sporadic melanoma in Australia. The lack of a pancreatic cancer-CDKN2A mutation relationship in Australia probably reflects the divergent spectrum of mutations in families from Australia versus those from North America and Europe. GenoMEL is exploring candidate host, genetic and/or environmental risk factors to better understand the variation observed.

Australia↗
PubMed2006

Population-based assessment of non-melanoma cancer risk in relatives of cutaneous melanoma probands.

Using the unique Utah Population Database, which links Utah genealogical data with Utah cancer data, we examined risks for other cancers among relatives of 4,079 melanoma cases. Age- and sex-specific rates for 35 different cancer sites were calculated, and used to estimate relative risks among relatives. In addition to the well-recognized risk for melanoma among first-degree relatives, we found significantly increased risks for prostate, breast, and colon cancers, non-Hodgkin's lymphoma, and multiple myeloma, ranging from 32 to 72% increased risk. Among second-degree relatives, in addition to increased risk for melanoma, we identified significantly increased risks for prostate cancer and multiple myeloma (27 and 53% increase, respectively). Among first-degree relatives of melanoma cases diagnosed before the age of 40 years, we found significantly elevated risks for cutaneous melanoma (380% increase) and prostate cancer (83% increase). Significantly increased risks for prostate cancer and multiple myeloma in both first- and second-degree relatives of melanoma cases are suggestive of heritable cancer syndromes. The increased risks for five additional cancer types in first-degree relatives of melanoma cases suggest that individuals with a family history of melanoma should strictly adhere to recommended screenings for all cancers.

Genes, p16↗
PubMed2006

Activation of dual apoptotic pathways in human melanocytes and protection by survivin.

Apoptosis resistance in melanoma is a primary cause of treatment failure. Apoptotic pathways in melanocytes, from which melanoma arises, are poorly characterized. Human melanocytes were susceptible to apoptosis following exposure to UV radiation (UVB, 24-48 hours), 4-tert-butylphenol (4-TBP, 1-4 hours), and cisplatin (24-48 hours). These responses were associated with Bid cleavage, caspase activation (caspases 3, 8, and 9), mitochondrial depolarization and release of cytochrome c, Smac/DIABLO, and apoptosis-inducing factor (AIF), but not endonuclease G. The apoptotic responses and AIF release were caspase-independent, as they were not blocked by zVal-Ala-Asp(OMe)-fluoromethyl ketone (zVAD-fmk). While RNA interference-mediated knockdown of AIF protected melanocytes against apoptosis induced by serum withdrawal, apoptotic responses to UVB, cisplatin, and 4-TBP were not compromised by AIF knockdown, even in the presence of zVAD-fmk. Finally, adenoviral-mediated expression of Survivin, an inhibitor of apoptosis expressed in melanoma but not melanocytes, protected melanocytes against UVB-induced apoptosis. Survivin expression in melanocytes partially blocked caspase activation and release of mitochondrial release of AIF, cytochrome c, and Smac induced by UVB. These data indicate that multiple stimuli can activate both caspase-dependent and caspase-independent apoptotic pathways in melanocytes, and that endogenous expression of Survivin in melanoma may contribute to apoptosis resistance by multiple mechanisms.

Amino Acid Chloromethyl Ketones↗
PubMed2006

The use of dermatologic drugs in pregnancy and lactation.

Physicians are generally reluctant to prescribe dermatologic drugs to pregnant or nursing women because treatment is often elective and can be harmful to the patient, her fetus, or nursing infant; concerns for potential litigation also give pause. Yet, some effective dermatologic drugs have been determined to be safe during pregnancy and lactation. Of great practicality is an easily accessed reference guide that condenses information on such drugs into a set of tables that list pregnancy and teratogenicity ratings. Indications and contraindications are ordered in relation to the phases and trimesters of pregnancy. A discussion of the necessity of considering stages of childbearing in choosing drug therapies introduces the tables. A summary list of cautions spells out the steps physicians should take in treating women of childbearing age.

Dermatologic Agents↗
PubMed2006

Population-based prevalence of CDKN2A mutations in Utah melanoma families.

Cyclin-dependent kinase inhibitor 2A (CDKN2A or p16) is the major melanoma predisposition gene. In order to evaluate the candidacy for genetic testing of CDKN2A mutations among melanoma prone families, it is important to identify characteristics that predict a high likelihood of carrying a CDKN2A mutation. We primarily used a unique Utah genealogical resource to identify independent melanoma prone families whom we tested for mutations in CDKN2A, cyclin-dependent kinase 4, and alternate reading frame. We sampled 60 families which met the inclusion criteria of two or more affected first-degree relatives. We found four different pathogenic CDKN2A mutations in five families, mutations of uncertain significance in two families, and known polymorphisms in three families. One of the mutations of uncertain significance, 5' untranslated region -25C>T, has not been previously described. Among our population-based set of Utah families, the prevalence of CDKN2A mutations was 8.2% (4/49); the overall prevalence when physician-referred pedigrees were also considered was between 8.3% (5/60) and 10% (6/60). Having four or more first- or second-degree relatives with melanoma, or a family member with > or =3 primary melanomas, correlated strongly with carrying a CDKN2A mutation. We observed a significantly elevated rate of pancreatic cancer in one of four families with a deleterious CDKN2A mutation.

Base Sequence↗
PubMed2006

Melanoma genetics: a review of genetic factors and clinical phenotypes in familial melanoma.

PURPOSE OF REVIEW: The clinical phenotypes of familial melanoma syndromes and genetic and environmental interactions are reviewed to summarize the current status of the field and to identify gaps in molecular and clinical investigations. RECENT FINDINGS: The familial melanoma syndromes are associated with germline mutations in three highly penetrant gene products: p16, alternate reading frame, and cyclin-dependent kinase 4. Certain variants in a low-penetrance gene, MC1R, the melanocortin 1 receptor gene, increase melanoma risk to a lesser extent and act as a genetic modifier when cosegregating with a deleterious p16 gene. The penetrance of these melanoma-predisposing genes is largely influenced by ultraviolet exposure across geographic latitude. Yet cumulative studies are conflicting on whether ultraviolet radiation, including sunburns, early childhood and adolescent sun exposure, and chronic exposure, increases melanoma risk in familial melanoma. To date, the clinical phenotypes of increased number of atypical nevi and nevi body distribution are independent risk factors for melanoma risk, regardless of family history. The atypical mole syndrome cannot reliably predict melanoma germline mutations but increases melanoma risk in p16 mutation carriers. Familial melanoma patients develop melanomas earlier and are prone to developing multiple primary melanomas. Other than these two differences, familial and sporadic melanoma share similar histopathology, prognostic factors, and survival rates. SUMMARY: Familial melanoma is an excellent human model system for the investigation of melanoma. Understanding genotype-phenotype and environmental relationships in familial melanoma will likely lead to improved understanding of pathogenesis for all melanoma patients.

Cyclin-Dependent Kinase 4↗
PubMed2005

Molecular classification of melanoma using real-time quantitative reverse transcriptase-polymerase chain reaction.

BACKGROUND: The early detection and characterization of metastatic melanoma are important for prognosis and management of the disease. Molecular methods are more sensitive in detecting occult lymph node metastases compared with standard histopathology and are reported to have utility in clinical diagnostics. METHODS: Using real-time quantitative reverse transcriptase-polymerase chain reaction ([q]RT-PCR), the authors examined 36 samples (30 melanomas, 4 benign nevi, and 2 reactive lymph nodes) for the expression of 20 melanoma-related genes that function in cell growth and differentiation (epidermal growth factor receptor [EGFR], WNT5A, BRAF, FOS, JUN, MATP, and TMP1), cell proliferation (KI-67, TOP2A, BUB1, BIRC5, and STK6), melanoma progression (CD63, MAGEA3, and GALGT), and melanin synthesis (TYR, MLANA, SILV, PAX3, and MITF). In addition, samples were tested for mutations in BRAF (exons 11 and 15) and NRAS (exons 2 and 3). RESULTS: Hierarchical clustering analysis of the expression data was able to distinguish between the melanoma and nonmelanoma samples and further stratified the melanoma samples into two groups differentiated by high expression of the genes involved in beta-catenin activation (EGFR and WNT5A) and the MAPK/ERK pathway (BRAF, FOS, and JUN). Eighteen of the 28 patients (64%) were found to have mutations in either exon 15 of BRAF (V599 substitution) or codon 61 of NRAS. The mutations were mutually exclusive and did not appear to be associated with the different expression subtypes. CONCLUSIONS: The results of the current study demonstrate that real-time qRT-PCR can be analyzed using hierarchical clustering to identify expression patterns that differentiate between melanomas and other tissue types. Using a supervised analysis of the data, the authors found that the best discriminators for molecularly distinguishing between melanoma, benign nevi, and lymph nodes were MLANA, CD63, and BUB1. These markers could have diagnostic utility for the detection of melanoma micrometastasis in sentinel lymph nodes.

Biomarkers, Tumor↗
PubMed2005

Population-based analysis of prognostic factors and survival in familial melanoma.

PURPOSE: Familial melanoma patients are reported to present with thinner melanomas, to be younger at the time of diagnosis, and to have a greater likelihood of developing multiple primary tumors. We sought to determine whether melanomas that occur in a familial setting demonstrate different prognostic and survival statistics relative to sporadic melanoma. PATIENTS AND METHODS: This population-based study used the Utah Cancer Registry and Utah Population Database to objectively evaluate prognostic and survival statistics of the familial melanoma population. From 1973 to 1999, there were 7,785 cases of invasive melanoma identified through the Utah Cancer Registry. These were linked to the Utah Population Database, resulting in 2,659 subjects with family-history information from which a familiality score could be calculated. Cases scored in the top ninth percentile were assigned as high familial risk, and the remaining 91% were considered low familial risk. RESULTS: Multivariate logistic-regression analysis found no association between sex, Breslow depth, Clark level, or survival and the familial status. Age at first diagnosis of invasive melanoma was slightly lower in the high-familial-risk group (57 v 60 years; P = .03). High-familial-risk subjects had more melanomas diagnosed at age 30 or younger (12% v 6%; P < .001). A significant difference in the overall number of individuals with two or more primary malignant melanomas was not detected among the groups (P = .2). CONCLUSION: These data suggest that melanomas occurring in the context of an underlying inherited susceptibility do not have a significantly different biologic behavior.

Adult↗
PubMed2005

Evaluation of a 7-day continuous intravenous infusion of decitabine: inhibition of promoter-specific and global genomic DNA methylation.

PURPOSE: The nucleoside analog 5-aza-2'-deoxycytidine (5-aza-CdR, decitabine) is a potent inhibitor of DNA methylation in vitro. Cellular treatment with this agent induces the re-expression of methylation-silenced genes. It remains unclear to what extent this compound inhibits DNA methylation in vivo. A clinical study was designed to examine the molecular effects and toxicity of a continuous 1-week intravenous infusion of decitabine in solid tumor patients. METHODS: Ten patients with refractory solid tumors were included in this study. Decitabine was administered at 2 mg/m(2)/d [DOSAGE ERROR CORRECTED] via continuous infusion for 168 hours. Quantitative polymerase chain reaction and high performance liquid chromatography were utilized to measure promoter-specific and global DNA methylation in peripheral-blood cells before and after treatment. RESULTS: Transient grade III/IV neutropenia (two patients) and grade II thrombocytopenia (one patient) was observed at the lowest planned dose step (2 mg/m2/d for 7 days). Nonhematologic toxicities were not observed. Quantitative polymerase chain reaction demonstrated significant MAGE-1 promoter hypomethylation by 14 days after the start of treatment in all 13 treatment cycles examined. Significant genomic DNA hypomethylation was also seen by day 14 in 11 of 13 treatment cycles analyzed. Genomic DNA methylation reverted to baseline levels by 28 to 35 days after the start of treatment, demonstrating that inhibition of DNA methylation by decitabine is transient. CONCLUSION: A 168-hour continuous infusion of decitabine is well tolerated and results in the inhibition of promoter-specific and genomic DNA methylation in vivo. This treatment schedule is suitable for evaluation of decitabine in combination with agents whose activity may be enhanced by the reversal of DNA methylation-mediated gene silencing.

Aged↗
PubMed2005

Melanoma cells express elevated levels of phosphorylated histone H2AX foci.

When human cells sustain a DNA double-strand break (dsb), histone H2AX in chromatin surrounding the DNA break is phosphorylated, marking repair foci. The number of phosphorylated histone H2AX (gammaH2AX) foci approximates the number of dsb present in the cell's nuclear DNA. We observed 0.4 gammaH2AX foci per nucleus in primary human melanocytes. In contrast, in four melanoma cell lines, we detected 7-17 gammaH2AX foci per nucleus, a 17-42 times increase in the basal level of gammaH2AX foci in melanoma cells relative to melanocytes (MC). Thus, untreated melanoma cells express significantly greater numbers of gammaH2AX foci than do untreated MC. Detection and rejoining of ionizing radiation-induced DNA dsb proceeded as rapidly in melanoma cells as in MC. Melanoma cells, however, reduced the number of radiation-induced gammaH2AX foci down only to pre-irradiation levels. Co-localization of the majority of gammaH2AX foci with ataxia telangiectasia mutated, BRCA1, 53BP1, and Nbs1 foci in untreated melanoma cells indicated that the additional foci in melanoma cells were associated with a DNA change that the cells interpret as DNA dsb. Co-localization of gammaH2AX foci with the telomere replication factor 1 protein in untreated melanoma cells indicates that the additional foci in untreated melanoma cells are associated with dysfunctional telomeres that induce a DNA damage stress response.

Apoptosis↗
PubMed2005

Clinical and pathological features of pachyonychia congenita.

Pachyonychia congenita (PC) is a rare genodermatosis affecting the nails, skin, oral mucosae, larynx, hair, and teeth. Pathogenic mutations in keratins K6a or K16 are associated with the PC-1 phenotype whereas K6b and K17 mutations are associated with the PC-2 phenotype. Analysis of clinical, pathological, and genetic data from the literature and two research registries reveal that >97% of PC cases exhibit fingernail and toenail thickening, and painful plantar keratoderma. Prospective evaluation of 57 PC patients from 41 families revealed variable clinical findings: hyperhidrosis (79%), oral leukokeratosis (75%), follicular keratosis (65%), palmar keratoderma (60%), cutaneous cysts (35%), hoarseness or laryngeal involvement (16%), coarse or twisted hair (26%), early primary tooth loss (14%), and presence of natal or prenatal teeth (2%). Stratification of these data by keratin mutation confirmed the increased incidence of cyst formation and natal teeth among PC-2 patients, although cysts were more commonly seen in PC-1 than previously reported (25%-33%). Previously unreported clinical features of PC include development of painful oral and nipple lesions during breastfeeding, copious production of waxy material in ears, and inability to walk without an ambulatory aid (50%). Possible pathogenic mechanisms are discussed with respect to the clinicopathologic and genetic correlations observed.

Darier Disease↗
PubMed2005

Treatment of pachyonychia congenita.

There are currently no specific treatments for pachyonychia congenita (PC). Available treatments generally are directed at specific manifestations of the disorder, and an effective treatment plan must recognize that different patients are more or less troubled by different manifestations of the disease. Treatment for all aspects of PC has been less than completely satisfactory. Very few studies have compared different approaches to treatment, and fewer still have given longitudinal follow-up of efficacy and patient acceptance. This review is essentially a compilation of anecdotes. It was collected from physicians' reports in the literature, from direct communication with physicians currently following patients with PC and from patients who answered a questionnaire on the Pachyonychia Congenita Project web page (http://www.pachyonychia.org/Registry.html).

Darier Disease↗
PubMed2005

The genetic basis of pachyonychia congenita.

In 1994, the molecular basis of pachyonychia congenita (PC) was elucidated. Four keratin genes are associated with the major subtypes of PC: K6a or K16 defects cause PC-1; and mutations in K6b or K17 cause PC-2. Mutations in keratins, the epithelial-specific intermediate filament proteins, result in aberrant cytoskeletal networks which present clinically as a variety of epithelial fragility phenotypes. To date, mutations in 20 keratin genes are associated with human disorders. Here, we review the genetic basis of PC and report 30 new PC mutations. Of these, 25 mutations were found in PC-1 families and five mutations were identified in PC-2 kindreds. All mutations identified were heterozygous amino acid substitutions or small in-frame deletion mutations with the exception of an unusual mutation in a sporadic case of PC-1. The latter carried a 117 bp duplication resulting in a 39 amino acid insertion in the 2B domain of K6a. Also of note was mutation L388P in K17, which is the first genetic defect identified in the helix termination motif of this protein. Understanding the genetic basis of these disorders allows better counseling for patients and paves the way for therapy development.

Base Sequence↗
PubMed2004

Vulvar melanoma: diffuse melanosis and metastasis to the placenta.

Mucocutaneous melanoma, including vulvar melanoma, is rare and has a worse prognosis and higher recurrence rate than traditional cutaneous melanoma. Diffuse cutaneous melanosis is another rare clinical presentation of metastatic melanoma. It is essential for dermatologists to be alerted to rare presentations of melanoma, to facilitate early detection. We present the first case to our knowledge of metastatic vulvar melanoma with diffuse cutaneous melanosis in a pregnant young woman. Despite the occurrence of placental metastasis, a healthy, unaffected baby was born. This case exemplifies the aggressiveness of vulvar melanoma. The genitalia should be included in routine total body skin examinations. Pregnant women with generalized melanosis may be at increased risk for placental metastasis of melanoma. Pregnancy does not alter the incidence or prognosis of melanoma; however, patients with a poor prognosis or high recurrence risk should be informed of potential pregnancy complications associated with melanoma recurrence or metastasis.

Adult↗