Basal Cell Carcinoma Of Skin Research Articles

Genomic analysis identifies new drivers and progression pathways in skin basal cell carcinoma.

Basal cell carcinoma (BCC) of the skin is the most common malignant neoplasm in humans. BCC is primarily driven by the Sonic Hedgehog (Hh) pathway. However, its phenotypic variation remains unexplained. Our genetic profiling of 293 BCCs found the highest mutation rate in cancer (65 mutations/Mb). Eighty-five percent of the BCCs harbored mutations in Hh pathway genes (PTCH1, 73% or SMO, 20% (P = 6.6 × 10(-8)) and SUFU, 8%) and in TP53 (61%). However, 85% of the BCCs also harbored additional driver mutations in other cancer-related genes. We observed recurrent mutations in MYCN (30%), PPP6C (15%), STK19 (10%), LATS1 (8%), ERBB2 (4%), PIK3CA (2%), and NRAS, KRAS or HRAS (2%), and loss-of-function and deleterious missense mutations were present in PTPN14 (23%), RB1 (8%) and FBXW7 (5%). Consistent with the mutational profiles, N-Myc and Hippo-YAP pathway target genes were upregulated. Functional analysis of the mutations in MYCN, PTPN14 and LATS1 suggested their potential relevance in BCC tumorigenesis.

Imiquimod activates p53-dependent apoptosis in a human basal cell carcinoma cell line

BackgroundThe tumor suppressor p53 controls DNA repair, cell cycle, apoptosis, autophagy and numerous other cellular processes. Imiquimod (IMQ), a synthetic toll-like receptor (TLR) 7 ligand for the treatment of superficial basal cell carcinoma (BCC), eliminates cancer cells by activating cell-mediated immunity and directly inducing apoptosis and autophagy in cancer cells. ObjectiveTo evaluate the role of p53 in IMQ-induced cell death in skin cancer cells. MethodsThe expression, phosphorylation and subcellular localization of p53 were detected by real-time PCR, luciferase reporter assay, cycloheximide chase analysis, immunoblotting and immunocytochemistry. Using BCC/KMC1 cell line as a model, the upstream signaling of p53 activation was dissected by over-expression of TLR7/8, the addition of ROS scavenger, ATM/ATR inhibitors and pan-caspase inhibitor. The role of p53 in IMQ-induced apoptosis and autophagy was assessed by genetically silencing p53 and evaluated by a DNA content assay, immunoblotting, LC3 puncta detection and acridine orange staining. ResultsIMQ induced p53 mRNA expression and protein accumulation, increased Ser15 phosphorylation, promoted nuclear translocation and up-regulated its target genes in skin cancer cells in a TLR7/8-independent manner. In BCC/KMC1 cells, the induction of p53 by IMQ was achieved through increased ROS production to stimulate the ATM/ATR-Chk1/Chk2 axis but was not mediated by inducing DNA damage. The pharmacological inhibition of ATM/ATR significantly suppressed IMQ-induced p53 activation and apoptosis. Silencing of p53 significantly decreased the IMQ-induced caspase cascade activation and apoptosis but enhanced autophagy. Mutant p53 skin cancer cell lines were more resistant to IMQ-induced apoptosis than wildtype p53 skin cancer cell lines. ConclusionIMQ induced ROS production to stimulate ATM/ATR pathways and contributed to p53-dependent apoptosis in a skin basal cell carcinoma cell line BCC/KMC1.

Relation between sonic hedgehog pathway gene polymorphisms and basal cell carcinoma development in the Polish population.

In recent decades, increases have been observed in the incidence of nonmelanoma skin cancers, including basal cell carcinoma (BCC) and squamous cell carcinoma. BCC is the most common neoplasm in Caucasian populations. Sonic hedgehog (Shh) pathway impairment plays a key role in BCC pathogenesis, and there is evidence that Shh pathway genetic variations may predispose to BCC development. We genotyped 22 single-nucleotide polymorphisms (SNPs) in 4 Shh pathway genes: SHH, GLI, SMO, and PTCH. The study group consisted of 142 BCC patients and 142 age-matched, sex-matched healthy subjects (controls). SNPs were assessed using the PCR-RFLP method. The genotype distribution for the polymorphisms in the rs104894049 331 A/T SHH, rs104894040 349 T/C SHH, and rs41303402 385 G/A SMO genes differed significantly between the BCC patients and the controls. The presence of CC genotype in the SHH rs104894040 349 T/C polymorphism was linked to the highest risk of BCC development (OR 87.9, p<0.001). Other genotypes, such as the TT in SHH rs104894049 331 A/T and the GG in SMO rs41303402 385 G/A also statistically raised the risk of BCC, but these associations were weaker. Other investigated polymorphisms showed no statistical differences between patients and controls. The results obtained testify to the importance of the SHH and SMO gene polymorphisms in skin cancerogenesis. These results mainly underline the potential role of SHH3 rs104894040 349 T/C gene polymorphism in the development of skin basal cell carcinomas in patients of Polish origin.

Hypofractionated high-dose-rate plesiotherapy in nonmelanoma skin cancer treatment.

Nonmelanoma skin cancer (NMSC) is the commonest cancer in humans. NMSC treatment currently includes surgery, radiation therapy, and topical approaches. The objective was to analyze and compare the outcomes, toxicity, and cosmesis of NMSC treated by two hypofractionated high-dose-rate (HDR) plesiotherapy techniques. A retrospective institutional clinical study of 134 basal cell or squamous cell skin carcinomas treated at Radiation Oncology Department. Lesions were treated from November 2006 to December 2011 with a moderate hypofractionated HDR plesiotherapy using a fixed applicator or a customized mold. After a median follow-up of 33 months, overall disease-free survival at 3 and 5 years was 95.12% and 93.36%, respectively. For Leipzig applicator, disease-free survival at 3 years was 94.9% and 94.9% at 5 years, for customized mold was 93.1% at 3 years and 88% at 5 years. Complete regression was achieved in 98% of lesions. Two lesions persisted after treatment; both had been treated by a Leipzig applicator. Six lesions suffered local recurrence (five Leipzig applicators and three molds, p = 0.404). Grade <2 acute toxicity noted in 57.3% of patients. Only 2.2% of lesions had Grade 4 acute toxicity. Borderline significant increase of toxicity was associated with customized molds (p = 0.067). Larger tumors were associated with higher acute skin toxicity. The cosmesis outcomes were excellent or good in 82% of patients, fair in 13%, and not available in 5%. Hypofractionated HDR plesiotherapy is an effective and well-tolerated treatment for NMSC with different toxicity levels depending on the plesiotherapy technique used.

Initial Diagnosis of a Common Hematological Malignancy in a Screening Colonoscopy

Extra-medullary (EM) manifestations of chronic lymphocytic leukemia (CLL) are relatively rare. Previous reports of EM-CLL suggest that the skin, CNS, and GI tract are the most commonly affected sites. In the majority of EM-CLL cases, EM involvement by CLL is only discovered after a primary diagnosis of CLL is made. GI involvement in CLL is generally associated with advanced stages of the disease in which the disease has transformed into large B cell lymphoma (i.e. Richter syndrome). Here we report a case of colonic involvement by CLL in a 50-year-old man who presented for a screening colonoscopy. This case is unique as the patient neither had a previous diagnosis of CLL nor experienced any of the associated symptoms. An asymptomatic 50-year-old man presented for his first screening colonoscopy. His past medical history was unremarkable except for prior squamous cell and basal cell skin carcinomas. Colonoscopy revealed grade 1 internal hemorrhoids and a 5 mm non-bleeding sessile polyp in the transverse colon which was resected for histological evaluation. Review of the specimen demonstrated multiple lymphoid aggregates composed of CD20 (+), CD5 (+), CD23 (+), LEF1 (+), Cyclin D1 (-) cells, which is consistent with involvement by CLL/small lymphocytic lymphoma (SLL). Blood counts were essentially normal, and no evidence of lymphoma or other pathologic abnormalities were found in the upper GI tract. A CT scan of the chest, abdomen, and pelvis revealed a small degree of lymphadenopathy above and below the diaphragm. The patient was diagnosed with stage IIIAE CLL/SLL. Further immunohistochemical analysis of the colon specimen indicated that the neoplastic cells did not express ZAP-70. Expression of ZAP-70 by the neoplastic cells is a reliable indication of the unmutated IgVH status in these cells. Considering that the unmutated IgVH status in the neoplastic cells is associated with a more aggressive clinical course of CLL, lack of ZAP-70 expression suggested an indolent course of disease. Immediate treatment was deferred, as the watch-and-wait approach is often the standard of care for low-risk CLL patients. This case is remarkable for at least two reasons: it demonstrates that the possibility of GI involvement in CLL should not be reserved only for later stages of the disease, and it emphasizes the need for the pathologists to remain vigilant for immunophenotype suspicious lymphoid aggregates even in the absence of a known CLL/SLL diagnosis.

Frequent DPH3 promoter mutations in skin cancers.

Recent reports suggested frequent occurrence of cancer associated somatic mutations within regulatory elements of the genome. Based on initial exome sequencing of 21 melanomas, we report frequent somatic mutations in skin cancers in a bidirectional promoter of diphthamide biosynthesis 3 (DPH3) and oxidoreductase NAD-binding domain containing 1 (OXNAD1) genes. The UV-signature mutations occurred at sites adjacent and within a binding motif for E-twenty six/ternary complex factors (Ets/TCF), at -8 and -9 bp from DPH3 transcription start site. Follow up screening of 586 different skin lesions showed that the DPH3 promoter mutations were present in melanocytic nevi (2/114; 2%), melanoma (30/304; 10%), basal cell carcinoma of skin (BCC; 57/137; 42%) and squamous cell carcinoma of skin (SCC; 12/31; 39%). Reporter assays carried out in one melanoma cell line for DPH3 and OXNAD1 orientations showed statistically significant increased promoter activity due to -8/-9CC > TT tandem mutations; although, no effect of the mutations on DPH3 and OXNAD1 transcription in tumors was observed. The results from this study show occurrence of frequent somatic non-coding mutations adjacent to a pre-existing binding site for Ets transcription factors within the directional promoter of DPH3 and OXNAD1 genes in three major skin cancers. The detected mutations displayed typical UV signature; however, the functionality of the mutations remains to be determined.

Exome sequencing in skin neoplasms

In recent years, the incidence of skin neoplasms has been increasing year by year. Environmental factors and genetic susceptibility are considered to be key pathogenic factors of skin neoplasms. Gene mutations are closely related to the occurrence and development of skin neoplasms, which have provided clues to the pathogenesis of skin neoplasms. Numerous novel mutant genes have been found in some skin neoplasms such as malignant melanoma, skin squamous cell carcinoma and skin basal cell carcinoma. As an efficient platform for screening susceptibility genes, exome sequencing has advantages of deep coverage and high accuracy, can detect pathogenic genes and novel candidate genes in skin neoplasms and other diseases, and is of great significance for early diagnosis, treatment and predilection of prognosis of skin neoplasms. Key words: Skin neoplasms; Exome; Multilocus sequence typing; Genes; Mutation

Toxicological evaluation of smokeless tobacco: 2-year chronic toxicity and carcinogenicity feeding study in Wistar Han rats

A comprehensive 2-year oral chronic toxicity/carcinogenicity study was conducted with smokeless tobacco using modern toxicological test methods and well-accepted standards. The study included a 1-year interim subgroup to assess toxicity at that intermediate time point. Test groups consisted of a tobacco blend (B) used in snus, and an aqueous tobacco extract of that tobacco blend (E) administered at 0.2, 2, or 5mgnicotine/kg body weight/day via dosed feed to male and female Wistar Han rats. The dosages were selected to simulate potential exposure in humans ingesting smokeless tobacco or an aqueous extract of smokeless tobacco (the latter intended to simulate a snus extract, to enable bridging these data to snus epidemiology data). The following endpoints were evaluated: clinical observations, body weights, feed consumption (FC), ophthalmic exams, toxicokinetics, clinical pathology, gross pathology, and histopathology. During the 2-year study, clear treatment-related, dose-responsive effects included: (1) increases in plasma nicotine and cotinine (indicating that animals were appropriately exposed to levels relevant to human exposure) and (2) decreases in body weights with some alterations in FC. At the 2-year time point, two tumor types (in the highest B doses) displayed statistically significantly increased incidence trends vs. controls: (1) uterine carcinoma in females and (2) epididymal mesothelioma in males. Three tumor types displayed statistically significantly decreased incidence trends: (1) mammary gland adenomas in females, (2) skin basal cell carcinomas in females, and (3) thyroid follicular cell adenomas in males. These increases (and decreases) in tumor trends were interpreted as not being treatment-related because: (1) there were no preneoplastic or related non-neoplastic histopathological findings in the treated rats at the 1-year or 2-year time points to suggest that any of these neoplastic findings were treatment-related and (2) the tumor morphologies and incidences were generally within the expected range of historical controls for Wistar Han rats. Findings from this study indicate that chronic exposure of male and female Wistar Han rats to either a tobacco blend used in snus, or a tobacco extract of that blend does not lead to increased toxicity or carcinogenicity, based on the specified outcomes measured.

Abstract 874: Personal history of psoriasis and risk of incident cancer among women: the Nurses’ Health Study

Abstract Background: Psoriasis has long been hypothesized to pose an increased risk of cancer due to the chronic, inflammatory state induced by psoriasis. Most prior studies on psoriasis and cancer were based on clinical settings, and the interest has been remarkably focused on the association between systemic therapies, typically only used in moderate-to-severe psoriasis, and risk of psoriasis. The evidence linking psoriasis with cancer is still controversial and few data are available from prospective studies. We systemically examined the association between a personal history of psoriasis and risk of incident cancer (other than skin basal cell carcinoma and squamous cell carcinoma). Methods and Findings: A total of 64,990 participants were included from the Nurses’ Health Study (1996-2012). Diagnoses of cancers were obtained by biannual self-reported questionnaires and all cancers were confirmed. Clinician-diagnosed psoriasis and diagnosis year were collected in 2008 and validated with a supplementary questionnaire. We included 2180 cases with psoriasis and most had mild disease (92%). During 957,359 person-years’ follow-up, 8,348 incident cancers were documented. We did not find an altered risk of total cancer associated with personal history of psoriasis (multivariate-adjusted hazard ratio [HR] = 1.02; 95% CI: 0.89-1.17). However, for individual cancers, a personal history of psoriasis was associated with an increased risk of melanoma (HR = 1.94, 95% CI: 1.20-3.12) and kidney cancer (HR = 2.50, 95% CI: 1.27-4.92). The associations appeared stronger among psoriasis with 1 or more palm body surface area (BSA, P for trend 0.003 for melanoma and 0.0004 for kidney cancer), but remained significant even after exclusion of psoriasis with more than two palms’ BSA involvement. Conclusions: We suggest a positive association between a personal history of psoriasis and risk of melanoma and renal cancer, which appears not be entirely a result of greater medical scrutiny or use of systemic therapies. Personal history of psoriasis and risk of first primary cancerNo psoriasis (935,227 person-years)Psoriasis (22,132 person-years)Age-adjusted RRMultivariable-adjusted RRTotal cancer (other than keratinocyte carcinoma)81392091.06 (0.92-1.21)1.02 (0.89-1.17)Breast cancer4034860.91 (0.73-1.12)0.89 (0.71-1.10)Colorectal cancer697201.19 (0.76-1.86)1.11 (0.71-1.73)Non-Hodgkin lymphoma527131.01 (0.58-1.75)1.03 (0.59-1.78)Endometrial cancer51570.60 (0.28-1.26)0.54 (0.26-1.15)Lung cancer429141.23 (0.72-2.09)1.05 (0.61-1.79)Melanoma380182.00 (1.25-3.21)1.94 (1.20-3.12)Bladder cancer23271.20 (0.57-2.55)1.10 (0.52-2.35)Ovarian Cancer19461.25 (0.55-2.81)1.28 (0.56-2.88)Thyroid cancer15351.37 (0.56-3.33)1.36 (0.56-3.32)Kidney cancer13792.74 (1.40-5.39)2.50 (1.27-4.92)Other Cancers841241.03 (0.69-1.54)0.97 (0.65-1.46) Citation Format: Wen-Qing Li, Jiali Han, Eunyoung Cho, Shaowei Wu, Hongji Dai, Martin Weinstock, Abrar Qureshi. Personal history of psoriasis and risk of incident cancer among women: the Nurses’ Health Study. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 874. doi:10.1158/1538-7445.AM2015-874

Application of laser-assisted transdermal drug delivery in dermatology

Lasers have been widely applied to the clinical setting due to high precision, high controllability and technological maturity. When assisting transdermal drug delivery, lasers can change the skin barrier to increase the amount of drugs permeated and depth of permeation of drugs. Ablative fractional lasers are the first choice for assisting transdermal drug delivery because of small damage, few adverse reactions and definite potential to increase permeability. The effect on transdermal drug delivery is mainly affected by wavelength range and energy density of fractional lasers as well as incubation time and relative molecular mass of drugs. In the dermatology clinic, ablative fractional laser-assisted transdermal drug delivery can improve the therapeutic effect on skin basal cell carcinoma, actinic keratosis and hyperplastic scar, and allow the reduction of methotrexate dosage in treating psoriasis. Both animal experiments and clinical trials have proved the feasibility to treat dermatoses using laser-assisted transdermal drug delivery. Key words: Lasers; Physicochemical phenomena; Osmosis; Neoplasms, basal cell; Keratosis, actinic; Cicatrix; Transdermal drug delivery

Second primary cancers in the Vaud and Neuchâtel Cancer Registries.

An increasing proportion of new cancers is registered in patients who have received a previous cancer diagnosis. As data are inconsistent across studies, we provided information for populations long covered by valid cancer registration. Data were derived from the Swiss cancer Registries of Vaud and Neuchâtel (885,000 inhabitants). Patients diagnosed with a new malignancy (except skin basal and squamous cell carcinomas) during the period 2005-2010 were included. Over the period 2005-2010, 24,859 patients were registered with incident cancer. Of these, 3127 (13%) had multiple primary cancers and 578 (2.3%) were synchronous. Breast, prostate, colorectum, skin, melanomas, and squamous cell carcinomas of the head and neck (SHN) and bladder/ureter were the most common sites of first neoplasms, whereas breast, lung, colorectum, prostate, melanoma, and SHN were the most common sites of second neoplasms. The most common pairing was breast with breast (31% synchronous), followed by the bladder/ureter with the prostate (72% synchronous), prostate with the colorectum, SHN with SHN, and SHN with lung. Five-year crude survival of patients with synchronous cancers (34%) was not significantly lower than that of patients with single neoplasms (39%). This population-based study indicates that about one in eight incident neoplasms in these mature registries are second neoplasms and almost 1/40 patients are diagnosed with synchronous primary cancers. These are related to shared genetic and environmental factors as well as diagnostic and therapeutic procedures. As cancer diagnosis and survival is likely to improve, the proportion of patients with multiple primary cancers will further increase in the future.

Nonmelanoma Skin Cancer in the Population of the City of Belgrade in the Period 1999-2011.

Nonmelanoma skin cancers in the literature are mainly related to basal cell and squamous cell skin carcinoma. The aim of the study was to determine the trend in the incidence of histological types of nonmelanoma skin cancers in the population of the city of Belgrade from 1999 to 2011. From the Serbian National Cancer Registry we extracted all recorded cases of skin cancer in Belgrade from January 1st 1999 to December 31st 2011. Incidence rates were standardized by the method of direct standardization with the world population as the standard population. Trends and annual percentage change (APC) of incidence rate were calculated by performing joinpoint regression analyses. Incidence rate of nonmelanoma skin cancer showed significantly increasing trend between 1999 and 2006 with APC of 8.6% (95% Cl: 5.6-11.7), basal cell carcinoma increased with APC of 8.4% (95% Cl: 5.2-11.6) and squamous cell skin carcinoma with APC of 9.33% (95% Cl: 5.7-13.1). The incidence increased with age for both men and women, especially after the age of 60. Our results showed a continuously increasing incidence trend of both basal cell and squamous cell skin carcinomas in the population of the city of Belgrade between 1999 and 2011. Adequate primary and secondary prevention would certainly be successful in reducing this type of cancer in the future.

Cutaneous Adverse Reactions during Anti-Tnf Alpha Treatment for Inflammatory Bowel Diseases: The Experience of the Dermatology Clinic of Cagliari

Background Anti-tumour necrosis factor alpha are a well-documented class of disease-modifying therapy for inflammatory bowel diseases, including Crohn's disease and ulcerative colitis. The monoclonal anti-TNFα antibody Infliximab and Adalimumab are the current approved drugs in Italy, showing high efficacy, but also variable clinically significant adverse effects. Method From 2012, an observational prospective study was activated at the Dermatology Clinic of Cagliari University, to screen all patients with inflammatory bowel diseases treated with Infliximab and Adalimumab for cutaneous adverse reactions and skin cancers. A basal visit, complete of melanocytic lesions digital image recording was performed in all patients referred from the Gastroenterology Unit of the same University Hospital. Subsequent visits were performed when new lesions or modification of the skin appearance occurred. All cutaneous adverse reactions associated with anti-TNF treatment were reported to the Italian Pharmacovigilance network. Results Ninety-one patients were included in the study: 58 (31 women and 27 men) patients affected by Crohn's disease, (the age range was between 16 and 69 years), and 33 patients with ulcerative colitis (15 women and 17 men; age range between 21 and 68 years). Proportion of patients treated with infliximab (52%) was similar to adalimumab (48%). Cutaneous adverse reactions were observed in 38 patients (42%): 20 were taking Infliximab (52%) and 18 Adalimumab (48%). Adverse reactions observed by frequency included: infections (32%), eczematous dermatitis (23%), infusion systemic reactions and at the injection site (5.7%), psoriasis paradoxical reaction (5.7%), followed by a mixture of different cutaneous reactions, including urticaria, photosensitivity, chronic lupus erythematosus, lichenoid eruption, alopecia areata, hypertrichosis. Benign skin tumors eruption (15%) and basal cell carcinoma (2.8%) occurrence were also noted. Patient with dysplastic melanocytic nevi (10%) at screening were regularly followed with digital dermoscopy, but no one showed changes in the study period. Conclusion Our sample of patients had a high rate of skin adverse reactions (42%), but considering severity, no case required definitive discontinuation of therapy. Dermatologist support might be critical to optimize biological agent management in inflammatory bowel diseases, performing a careful basal screening, strict monitoring of adverse reactions and prompt intervention, as well as educating the patient towards skin cancer prevention, considering the long-term drug exposure.

Gorlin - Goltz Syndrome

Gorlin-Goltz Syndrome (GGS) is known as nevoid basal cell carcinoma syndrome (NBCCS); it is a rare condition with multi-organ involvement. It has an autosomal dominant trait with complete penetrance and variable expressivity. The condition presents with a wide range of pathological features including malignancy of the skin (basal cell carcinoma); its early diagnosis is vital. Odontogenic Keratocyst (OKC) being one of the prominent features and mostly an early one, the dental specialty most often is in a position to identify this condition first.

Vismodegib hedgehog-signaling inhibition and treatment of basal cell carcinomas as well as keratocystic odontogenic tumors in Gorlin syndrome.

Vismodegib hedgehog signaling inhibition treatment has potential for reducing the burden of multiple skin basal cell carcinomas and jaw keratocystic odontogenic tumors. They are major criteria for the diagnosis of Gorlin syndrome, also called nevoid basal cell carcinoma syndrome. Clinical features of Gorlin syndrome are reported, and the relevance of hedgehog signaling pathway inhibition by oral vismodegib for maxillofacial surgeons is highlighted. In summary, progressed basal cell carcinoma lesions are virtually inoperable. Keratocystic odontogenic tumors have an aggressive behavior including rapid growth and extension into adjacent tissues. Interestingly, nearly complete regression of multiple Gorlin syndrome-associated keratocystic odontogenic tumors following treatment with vismodegib. Due to radio-hypersensitivity in Gorlin syndrome, avoidance of treatment by radiotherapy is strongly recommended for all affected individuals. Vismodegib can help in those instances where radiation is contra-indicated, or the lesions are inoperable. The effect of vismodegib on basal cell carcinomas was associated with a significant decrease in hedgehog-signaling and tumor proliferation. Vismodegib, a new and approved drug for the treatment of advanced basal cell carcinoma, is a specific oncogene inhibitor. It also seems to be effective for treatment of keratocystic odontogenic tumors and basal cell carcinomas in Gorlin syndrome, rendering the surgical resections less challenging.

Non-Invasive Treatment of Extensive Eyelid Cancerous Lesion by Photodynamic Therapy: A Case Report

Cancer of the eyelid represents approximately 10% of all skin cancer in the head and neck region, and approximately 5-10% of all skin cancers. Basal cell carcinoma is the most common cutaneous malignancy in the periocular area, accounting for approximately 70-90% of all cases. The standard treatment for eyelid cancer is surgical excision with reconstruction in case of orbital invasion. Such surgery is involved and in some cases can cause irreversible functional damage to the eye, as well as significant aesthetic and emotional distress for the patient. Photodynamic therapy is a wellestablished technique for the treatment of skin basal cell carcinoma. We therefore propose photodynamic therapy as an alternative treatment of non-melanoma skin cancer and are also indicated as principal option for same types of eyelid cancer. This is a case report of an eighty three year old patient with a histopathological diagnosis of basal cell carcinoma located in the left eyelid. The patient was treated by topical photodynamic therapy using a cream application of 20% Methyl-aminolevulic acid, and a fluency of 150 J/cm2. Clinical evaluation of the patient thirty days after treatment showed a significant clinical response with no evidence of scarring. In addition, no signs of recurrence were observed up to 6 months of follow-up. This clinical case thus showed excellent healing and cosmetic result. In summary, photodynamic therapy is a non-surgical treatment alternative that has the potential to become the number one option for eyelid cancer management, in particular for high risk patients or when surgical resection of highly involved areas is required.

Incidence of Secondary Malignancies Following Allogeneic Hematopoietic Cell Transplantation: A Single Center Experience

Late effects occurring post allogeneic hematopoietic cell transplantation (HCT) include the development of secondary malignancies (SM). The purpose of this single-center study was to retrospectively assess the incidence of SM in 2200 patients that consecutively underwent HCT for a variety of hematological conditions between 1970 and 2013, and to investigate parameters associated with occurrence of SM and survival post diagnosis.Median patient age at transplant was 42 years (range 17-71). Graft was bone marrow in 1310 patients (60%), peripheral blood stem cells (PBSC) in 890 patients (40%). Related donors were used in 1624 patients (74%), unrelated in 576 patients (26%). Transplants were performed for acute myeloid leukemia (AML, n=756, 34%), chronic myeloid leukemia (CML, n=486, 22%), acute lymphoblastic leukemia (ALL, n=275, 13%), non-Hodgkin lymphoma (n=174, 8%), myelodysplastic syndrome (n=159, 7%), aplastic anemia (n=128, 6%) and other conditions (n=222, 10%). Conditioning regimen was myeloablative in 1903 patients (87%) and reduced intensity in 297 patients (13%). Concerning total body irradiation (TBI) dose, 556 patients (25%) did not receive TBI, 1060 patients (48%) received 200-500 cGy and 584 patients (27%) received >500 cGy. Median follow-up of survivors was 120 months (range 1-398). SM was observed in 155 patients (7% of total). Of the patients that developed SM, 39 (25% of SM) were with skin malignancy (30 with non-metastatic squamous and basal cell carcinoma), 25 (16%) with gynecological malignancies, 18 (12%) with gastrointestinal, 19 (12%) with hematological, 20 (13%) with oral squamous carcinoma, 14 (9%) with prostate, 6 (4%) with lung, 4 (3%) with thyroid and 10 (6%) with other forms of SM.Excluding patients with non-metastatic squamous and basal cell carcinoma of skin, the remaining 125 patients demonstrated a median time to SM of 99 months (range 1-393). Median time to development of SM was 4, 7 and 12 years for the age groups >55, 41-55 and <41 years of age respectively (p=0.0004). At 5 years post-HCT, 2.5% of patients had developed SM (95%CI 1.9-3.3), at 10 years 3.9% developed SM (95%CI 3.1-4.9) and at 15 years 6.0% of survivors had developed SM (95%CI 4.8-7.3). Analysis was performed for the effect of age at HCT, graft source, donor type, time period transplant was performed, conditioning intensity and TBI dose. In both the univariate and multivariable analysis, none of the aforementioned variables influenced cumulative incidence of SM.Concerning the survival of the 125 patients following diagnosis of SM (excluding non-metastatic squamous and basal cell carcinoma of skin), median follow-up of survivors was 37 months (range 1-344 months), survival at 10 years post-SM was 49% (SE ±6.6%). 25% of patients died of causes related to SM. Univariate analysis demonstrated a significant influence of ECOG score at diagnosis of SM (p<0.0001), while age at SM, coexistence of GvHD at diagnosis, existence of other co-morbidities and time period from HCT to diagnosis of SM did not significantly influence survival. Multivariable analysis demonstrated ECOG score at diagnosis of SM as the only independent predictor of survival post diagnosis, with HR 2.8 for ECOG score 1 and HR 7.0 for ECOG score 2-4 compared to ECOG score 0 (p<0.0001).In conclusion, incidence of SM post-HCT does not seem to be related to dose of TBI or conditioning intensity. Younger patients develop SM significantly later post-HCT, while a higher ECOG score at diagnosis of SM is independently prognostic of poor survival. DisclosuresMessner:Otsuka Pharmaceuticals Inc: Research Funding.

Abstract 37: TP53 coding and noncoding variants in cancer susceptibility: From Li-Fraumeni syndrome to Lynch syndrome

Abstract The present study is to generate a mouse model of a p53 noncoding germline polymorphism that predisposes human carriers to multiple types of cancer. p53, encoded by TP53, is recognized as the guardian of the human genome. Three distinct sets of alterations occur at the TP53 locus, which spans ∼20kb in the human genome: tumor-associated somatic mutations, germline mutations causing Li-Fraumeni syndrome, and germline polymorphisms. The first two types of TP53 mutations occur in the coding sequence (CDS) and produce mutant p53 proteins that lack most or all of the normal tumor suppressive functions and often confer oncogenic properties. By contrast, only a few of the &amp;gt;200 naturally occurring germline variants of TP53 in human populations cause measurable perturbation of p53 function. More than 90% of TP53 germline variants occur in 10 introns alleged to have no cancer-related biological consequences. None of the 20 variants in the TP53 CDS have been reproducibly linked to cancer predisposition. Genome-wide association studies (GWAS) reported no significant association between any germline TP53 polymorphism and any cancer with a P value ≤ 10-7 (a threshold for genome-wide significance) until a single nucleotide polymorphism (SNP) rs78378222 was found to be associated strongly with skin basal cell carcinoma. rs78378222 is located in the fifth nucleotide of the TP53 polyadenylation signal (PAS) that is required for polyadenylation machinery recognition and subsequent cleavage and polyadenylation of mRNA. The risk-associated minor allele is a “C”, resulting in an alternative PAS (AATACA) instead of the canonical PAS (AATAAA). This variant is also associated with an increased risk of colorectal adenoma, prostate cancer, glioma, and esophageal squamous cell carcinoma. It is notable that cancer susceptibility of this p53 noncoding variant does not mirror that of p53 coding germline mutations (patients with Li-Fraumeni syndrome develop predominantly breast cancer, brain tumors, acute leukemia, sarcoma, and adrenal cortical carcinoma). Specifically, carriers with the p53 PAS variant are not predisposed to breast cancer. The p53 PAS variant is uniquely positioned among cancer-susceptibility alleles: (i) low frequency (∼2% in the general populations), (ii) intermediate cancer risk (odds ratio 1.39-3.54), and (iii) predisposing carriers to multiple types of cancer. To mimic this naturally occurring human variant, we have generated a mouse line with a p53 gene carrying the alternative PAS (AATACA) using zinc-finger nuclease technology. The resultant mutant p53 allele is termed p531755C as the 1755th nucleotide of mouse p53 reference mRNA is the ortholog of human rs78378222. We demonstrate that heterozygote p53+/1755C and homozygote p531755C/1755C mice treated with azoxymethane (AOM) and dextran sodium sulfate (DSS) developed more colon tumors than the p53+/+ controls and homozygous mice developed more advanced tumors than heterozygous mice. With data from murine tumorigenesis and human epidemiology, we propose that this p53 noncoding germline variant is a cancer susceptibility allele associated with Lynch syndrome rather than Li-Fraumeni syndrome. Citation Format: Qipan Deng, Yong Li. TP53 coding and noncoding variants in cancer susceptibility: From Li-Fraumeni syndrome to Lynch syndrome. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr 37. doi:10.1158/1538-7445.CANSUSC14-37

Molecular classification of basal cell carcinoma of skin by gene expression profiling.

Non-melanoma skin cancers (NMSC) including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are more common kinds of skin cancer. Although these tumors share common pathological and clinical features, their similarity and heterogeneity at molecular levels are not fully elaborated yet. Here, by performing comparative analysis of gene expression profiling of BCC, SCC, and normal skin tissues, we could classify the BCC into three subtypes of classical, SCC-like, and normal-like BCCs. Functional enrichment and pathway analyses revealed the molecular characteristics of each subtype. The classical BCC showed the enriched expression and transcription signature with the activation of Wnt and Hedgehog signaling pathways, which were well known key features of BCC. By contrast, the SCC-like BCC was enriched with immune-response genes and oxidative stress-related genes. Network analysis revealed the PLAU/PLAUR as a key regulator of SCC-like BCC. The normal-like BCC showed prominent activation of metabolic processes particularly the fatty acid metabolism. The existence of these molecular subtypes could be validated in an independent dataset, which demonstrated the three subgroups of BCC with distinct functional enrichment. In conclusion, we suggest a novel molecular classification of BCC providing insights on the heterogeneous progression of BCC.

Zfx facilitates tumorigenesis caused by activation of the Hedgehog pathway.

The Hedgehog (Hh) signaling pathway regulates normal development and cell proliferation in metazoan organisms, but its aberrant activation can promote tumorigenesis. Hh-induced tumors arise from various tissues and they may be indolent or aggressive, as is the case with skin basal cell carcinoma (BCC) or cerebellar medulloblastoma, respectively. Little is known about common cell-intrinsic factors that control the development of such diverse Hh-dependent tumors. Transcription factor Zfx is required for the self-renewal of hematopoietic and embryonic stem cells, as well as for the propagation of acute myeloid and T-lymphoblastic leukemias. We report here that Zfx facilitates the development of experimental BCC and medulloblastoma in mice initiated by deletion of the Hh inhibitory receptor Ptch1. Simultaneous deletion of Zfx along with Ptch1 prevented BCC formation and delayed medulloblastoma development. In contrast, Zfx was dispensable for tumorigenesis in a mouse model of glioblastoma. We used genome-wide expression and chromatin-binding analysis in a human medulloblastoma cell line to characterize direct, evolutionarily conserved targets of Zfx, identifying Dis3L and Ube2j1 as two targets required for the growth of the human medulloblastoma cells. Our results establish Zfx as a common cell-intrinsic regulator of diverse Hh-induced tumors, with implications for the definition of new therapeutic targets in these malignancies.