David J. Leffell

Mutations of the Human Homolog of Drosophila patched in the Nevoid Basal Cell Carcinoma Syndrome

The nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by multiple basal cell carcinomas (BCCs), pits of the palms and soles, jaw keratocysts, a variety of other tumors, and developmental abnormalities. NBCCS maps to chromosome 9q22.3. Familial and sporadic BCCs display loss of heterozygosity in this region, consistent with the gene being a tumor suppressor. A human sequence (PTC) with strong homology to the Drosophila segment polarity gene, patched, was isolated from a YAC and cosmid contig of the NBCCS region. Mutation analysis revealed alterations of PTC in NBCCS patients and in related tumors. We propose that a reduction in expression of the patched gene can lead to the developmental abnormalities observed in the syndrome and that complete loss of patched function contributes to transformation of certain cell types.

Developmental defects in gorlin syndrome related to a putative tumor suppressor gene on chromosome 9

Gorlin syndrome is an autosomal dominant disorder that predisposes to basal cell carcinomas of the skin, ovarian fibromas, and medulloblastomas. Unlike other hereditary disorders associated with cancer, it features widespread developmental defects. To investigate the possibility that the syndrome is caused by mutation in a tumor suppressor gene, we searched for loss of heterozygosity in 16 sporadic basal cell carcinomas, 2 hereditary basal cell carcinomas, and 1 hereditary ovarian fibroma and performed genetic linkage studies in five Gorlin syndrome kindreds. Eleven sporadic basal cell carcinomas and all 3 hereditary tumors had allelic loss of chromosome 9q31, and all informative kindreds showed tight linkage between the Gorlin syndrome gene and a genetic marker in this region. Loss of heterozygosity at this chromosomal location, particularly in hereditary tumors, implies that the gene is homozygously inactivated and normally functions as a tumor suppressor. In contrast, hemizygous germline mutations lead to multiple congenital anomalies.

Noninvasive assessment of dermal carotenoids as a biomarker of fruit and vegetable intake

BACKGROUND Resonance Raman spectroscopy (RRS) has been suggested as a feasible method for noninvasive carotenoid measurement of human skin. However, before RRS measures of dermal carotenoids can be used as a biomarker, data on intra- and intersubject variability and validity are needed. OBJECTIVE The purpose of this study was to evaluate the reproducibility and validity of RRS measures of dermal total carotenoids and lycopene in humans. DESIGN In study 1, 74 men and women with diverse skin pigmentation were recruited. RRS measures of the palm, inner arm, and outer arm were obtained at baseline, 1 wk, 2 wk, 1 mo, 3 mo, and 6 mo (to maximize seasonal variation). The RRS device used visible light at 488 nm to estimate total carotenoids and at 514 nm to estimate lycopene. Reproducibility was assessed by intraclass correlation coefficients (ICCs). In study 2, we recruited 28 subjects and assessed dietary carotenoid intake, obtained blood for HPLC analyses, performed RRS measures of dermal carotenoid status, and performed dermal biopsies (3-mm punch biopsy) with dermal carotenoids assessed by HPLC. RESULTS ICCs for total carotenoids across time were 0.97 (palm), 0.95 (inner arm), and 0.93 (outer arm). Total dermal carotenoids assessed by RRS were significantly correlated with total dermal carotenoids assessed by HPLC of dermal biopsies (r = 0.66, P = 0.0001). Similarly, lycopene assessed by RRS was significantly correlated with lycopene assessed by HPLC of dermal biopsies (r = 0.74, P < 0.0001). CONCLUSION RRS is a feasible and valid method for noninvasively assessing dermal carotenoids as a biomarker for studies of nutrition and health.

Novel inactivating mutations of transforming growth factor-β type I receptor gene in head-and-neck cancer metastases

Carcinoma cell lines are frequently refractory to transforming growth factor‐β (TGFβ)‐mediated cell cycle arrest. Whether and how TGFβ signaling is disrupted in the majority of human tumors, however, remains unclear. To investigate whether TGFβ signaling might be disrupted by inactivation of the key signaling molecule, the TGFβ type I (TβR‐I) receptor, and whether or not TβR‐I inactivation is associated with late stage disease, we conducted a comprehensive structural analysis of the TβR‐I gene in fine‐needle aspirates of 23 head‐&‐neck cancer metastases. We encountered 4 different mutations of TβR‐I, 3 of which have not been previously identified. In 1 case, we found a somatic intragenic 4‐bp deletion predicting for a truncation of the receptor protein. This is the first example of a true loss‐of‐function mutation of TβR‐I in a human epithelial neoplasm. In 2 other cases, we identified missense mutations located between the juxtamembrane‐ and serine‐threonine kinase domains. One of these resulted in an alanine‐to‐threonine substitution (A230T), which disrupts receptor signaling activity by causing rapid protein degradation within the endoplasmatic reticulum. This represents a novel mechanism of inactivation of a TGFβ signaling intermediate. Finally, we identified a serine‐to‐tyrosine substitution at codon 387 (S387Y) in a metastasis but not in the corresponding primary tumor. We had previously shown this S387Y mutant to be predominantly associated with breast cancer metastases and to have a diminished ability to mediate TGFβ‐dependent signaling. In aggregate, these findings provide further support for the hypothesis that inactivation of the TGFβ signaling pathway occurs in a significant subset of human cancers.

Indoor tanning and risk of early-onset basal cell carcinoma

BACKGROUND Despite an increase in incidence of basal cell carcinoma (BCC) among young people and the ubiquity of indoor tanning in this population, few epidemiologic studies have investigated this exposure-disease relationship. OBJECTIVE We sought to evaluate the association between indoor tanning and early-onset BCC. METHODS Patients with BCC (n = 376) and control subjects with minor benign skin conditions (n = 390) who were younger than 40 years of age were identified through Yale Dermatopathology. Participants provided information on ever indoor tanning, age of initiation, frequency, duration, burns while tanning, and type of tanning device during an in-person interview. We calculated odds ratios (OR) and 95% confidence intervals (CI) using multivariate logistic regression with never indoor tanners as the referent group. RESULTS Ever indoor tanning was associated with a 69% increased risk of early-onset BCC (95% CI 1.15-2.48). This association was stronger among females (OR 2.14, 95% CI 1.31-3.47), for multiple BCCs (OR 2.16, 95% CI 1.26-3.70), and for BCCs on the trunk and extremities (OR 2.81, 95% CI 1.57-5.02). Risk increased dose dependently with years using regular indoor tanning devices (P trend = .003), number of overall burns (P trend < .001), and burns to biopsy site (P trend < .001) from indoor tanning. Approximately one quarter (27%) of early-onset BCCs (or 43% among women) could be prevented if individuals never tanned indoors. LIMITATIONS Potential recall bias of indoor tanning by patients and generalizability of the control population suggest replication in other studies is warranted. CONCLUSIONS Indoor tanning was a strong risk factor for early-onset BCC, particularly among females. Indoor tanning should continue to be targeted by both policy-based and behavioral interventions, as the impact on BCC-associated morbidity may be substantial.

Tumor Suppressor Gene Mutations and Photocarcinogenesis

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Familial multiple lipomatosis: Report of a case and a review of the literature

Familial multiple lipomatosis is a hereditary syndrome of multiple lipomas occurring in a particular distribution. It is clinically distinct from multiple symmetric lipomatosis with which it is frequently confused in the dermatologic literature. A case of familial multiple lipomatosis is reported and a review of this condition is presented in an effort to resolve the confusion in the literature about familial multiple lipomatosis and multiple symmetric lipomatosis.

Lifetime history of indoor tanning in young people: a retrospective assessment of initiation, persistence, and correlates

BackgroundDespite educational and public health campaigns to convey the risks of indoor tanning, many individuals around the world continue to engage in this behavior. Few descriptive studies of indoor tanning have collected information pertaining to the lifetime history of indoor tanning, thereby limiting our ability to understand indoor tanning patterns and potentially target interventions for individuals who not only initiate, but continue to persistently engage in indoor tanning.MethodsIn-person interviews elicited detailed retrospective information on lifetime history of indoor tanning among white individuals (n = 401) under age 40 seen by a dermatologist for a minor benign skin condition. These individuals were controls in a case-control study of early-onset basal cell carcinoma. Outcomes of interest included ever indoor tanning in both males and females, as well as persistent indoor tanning in females - defined as females over age 31 who tanned indoors at least once in the last three or all four of four specified age periods (ages 11-15, 16-20, 21-30 and 31 or older). Multivariate logistic regression was used to identify sociodemographic and lifestyle correlates of ever and persistent indoor tanning in females.ResultsApproximately three-quarters (73.3%) of females and 38.3% of males ever tanned indoors, with a median age of initiation of 17.0 and 21.5, respectively. Among indoor tanners, 39.3% of females and 21.7% of males reported being burned while indoor tanning. Female ever indoor tanners were younger, had darker color eyes, and sunbathed more frequently than females who never tanned indoors. Using unique lifetime exposure data, 24.7% of female indoor tanners 31 and older persistently tanned indoors starting as teenagers. Female persistent indoor tanners drank significantly more alcohol, were less educated, had skin that tanned with prolonged sun exposure, and sunbathed outdoors more frequently than non-persistent tanners.ConclusionsIndoor tanning was strikingly common in this population, especially among females. Persistent indoor tanners had other high-risk behaviors (alcohol, sunbathing), suggesting that multi-faceted behavioral interventions aimed at health promotion/disease prevention may be needed in this population.

Significant correlations of dermal total carotenoids and dermal lycopene with their respective plasma levels in healthy adults

Carotenoids in skin have been known to play a role in photoprotection against UV radiation. We performed dermal biopsies of healthy humans (N=27) and collected blood samples for pair-wise correlation analyses of total and individual carotenoid content by high performance liquid chromatography (HPLC). The hydrocarbon carotenoids (lycopene and beta-carotene) made up the majority of carotenoids in both skin and plasma, and skin was somewhat enriched in these carotenoids relative to plasma. Beta-cryptoxanthin, a monohydroxycarotenoid, was found in similar proportions in skin as in plasma. In contrast, the dihydroxycarotenoids, lutein and zeaxanthin, were relatively lacking in human skin in absolute and relative levels as compared to plasma. Total carotenoids were significantly correlated in skin and plasma (r=0.53, p<0.01). Our findings suggest that human skin is relatively enriched in lycopene and beta-carotene, compared to lutein and zeaxanthin, possibly reflecting a specific function of hydrocarbon carotenoids in human skin photoprotection.

Melanoma in situ : Part I. Epidemiology, screening, and clinical features

The incidence of melanoma has steadily increased over the past 3 decades, with melanoma in situ comprising a disproportionately high percentage of the rising incidence. Our understanding of melanoma in situ has been shaped by epidemiologic and clinical studies. Central to a review of melanoma in situ is a focus on its epidemiology, pathology, biologic behavior, treatment, and clinical outcome, which may differ significantly from that of malignant melanoma. Part I of this continuing medical education article reviews the epidemiology, risk factors, and clinical features of melanoma in situ; part II covers the histopathology, treatment options, and clinical management.