Delphine Kerob

A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma

So far, no common environmental and/or phenotypic factor has been associated with melanoma and renal cell carcinoma (RCC). The known risk factors for melanoma include sun exposure, pigmentation and nevus phenotypes; risk factors associated with RCC include smoking, obesity and hypertension. A recent study of coexisting melanoma and RCC in the same patients supports a genetic predisposition underlying the association between these two cancers. The microphthalmia-associated transcription factor (MITF) has been proposed to act as a melanoma oncogene; it also stimulates the transcription of hypoxia inducible factor (HIF1A), the pathway of which is targeted by kidney cancer susceptibility genes. We therefore proposed that MITF might have a role in conferring a genetic predisposition to co-occurring melanoma and RCC. Here we identify a germline missense substitution in MITF (Mi-E318K) that occurred at a significantly higher frequency in genetically enriched patients affected with melanoma, RCC or both cancers, when compared with controls. Overall, Mi-E318K carriers had a higher than fivefold increased risk of developing melanoma, RCC or both cancers. Codon 318 is located in a small-ubiquitin-like modifier (SUMO) consensus site (ΨKXE) and Mi-E318K severely impaired SUMOylation of MITF. Mi-E318K enhanced MITF protein binding to the HIF1A promoter and increased its transcriptional activity compared to wild-type MITF. Further, we observed a global increase in Mi-E318K-occupied loci. In an RCC cell line, gene expression profiling identified a Mi-E318K signature related to cell growth, proliferation and inflammation. Lastly, the mutant protein enhanced melanocytic and renal cell clonogenicity, migration and invasion, consistent with a gain-of-function role in tumorigenesis. Our data provide insights into the link between SUMOylation, transcription and cancer.

Allele variations in the OCA2 gene (pink-eyed-dilution locus) are associated with genetic susceptibility to melanoma

The occuloalbinism 2 (OCA2) gene, localized at 15q11, encodes a melanosomal transmembrane protein that is involved in the most common form of human occulo-cutaneous albinism, a human genetic disorder characterized by fair pigmentation and susceptibility to skin cancer. We wondered whether allele variations at this locus could influence susceptibility to malignant melanoma (MM). In all, 10 intragenic single-nucleotide polymorphisms (SNPs) were genotyped in 113 patients with melanomas and in 105 Caucasian control subjects with no personal or family history of skin cancer. By comparing allelic distribution between cases and controls, we show that MM and OCA2 are associated (p value=0.030 after correction for multiple testing). Then, a recently developed strategy, the ‘combination test’ enabled us to show that a combination formed by two SNPs was most strongly associated to MM, suggesting a possible interaction between intragenic SNPs. In addition, the role of OCA2 on MM risk was also detected using a logistic model taking into account the presence of variants of the melanocortin 1 receptor gene (MC1R, a key pigmentation gene) and all pigmentation characteristics as melanoma risk factors. Our data demonstrate that a second pigmentation gene, in addition to MC1R, is involved in genetic susceptibility to melanoma.

Imatinib Mesylate as a Preoperative Therapy in Dermatofibrosarcoma: Results of a Multicenter Phase II Study on 25 Patients

Aims: The treatment of dermatofibrosarcoma protuberans (DFSP) involves wide local excision with frequent need for reconstructive surgery. A t(17;22) translocation resulting in COL1A1-PDGFB fusion is present in >95% of cases. Certain patient observations and a report on nine patients suggest that imatinib mesylate, targeting platelet-derived growth factor receptor β, has clinical potential in DFSP. The primary aim of this phase II multicenter study was to define the percentage of clinical responders (Response Evaluation Criteria in Solid Tumors) to a 2-month preoperative daily administration of 600 mg of imatinib mesylate before wide local excision. The secondary aims were to determine tolerance, objective response from imaging results (ultrasound and magnetic resonance imaging), and pathologic responses observed in sequential tissue specimens. Patients and Methods: A two-stage flexible design was used with interim analysis after the recruitment of six patients. Twenty-five adults suffering from primary or recurrent DFSP were included from July 2004 to May 2006. Results: The COL1A1-PDGFB fusion gene was detected in 21 out of 25 patients following fluorescence in situ hybridization analysis (two cases were noninformative). A clinical response was achieved in nine (36%) patients (95% confidence interval, 18.9-57.5). The median relative tumoral decrease was 20.0% (range, −12.5 to 100). Apart from expected grade 1 or 2 side effects, we observed one grade 3 neutropenia, one grade 3 maculopapular rash, and one grade 4 transient transaminitis. Conclusion: Our results support the use of imatinib in a neoadjuvant setting in nonresectable DFSP, or when surgery is difficult or mutilating. These results will be useful for setting hypotheses in the evaluation of new drugs to treat primary or secondary resistance to imatinib. Clin Cancer Res; 16(12); 3288–95. ©2010 AACR.

Fetal Microchimeric Cells Participate in Tumour Angiogenesis in Melanomas Occurring during Pregnancy

Melanoma is a major malignancy in younger individuals that accounts for 8% of all neoplasias associated with gestation. During pregnancy, a small number of fetal cells enter the maternal circulation. These cells persist and then migrate to various maternal tissues where they may engraft and differentiate, particularly if there is organ damage, adopting the phenotype of the host organ. To understand the relationship between melanoma and pregnancy, we analyzed these tumors in both humans and mice. Fetal cells were detected in 63% of human primary melanomas versus 12% in nevi during pregnancy (P = 0.034) and in 57% of B16 melanomas in pregnant mice but never in normal skin (P = 0.000022). More than 50% of these fetal cells expressed the CD34, CD31, or von Willebrand factor endothelial cell markers. In addition, the Lyve-1 lymphatic antigen was expressed by more than 30% of fetal cells in mice. In conclusion, we show that melanomas during pregnancy frequently harbor fetal cells that have an endothelial phenotype. Further studies are needed to assess whether the fetal contribution to lymphangiogenesis may alter the prognosis of the maternal tumor.

PTCH mutations and deletions in patients with typical nevoid basal cell carcinoma syndrome and in patients with a suspected genetic predisposition to basal cell carcinoma: a French study

The patched (PTCH) mutation rate in nevoid basal cell carcinoma syndrome (NBCCS) reported in various studies ranges from 40 to 80%. However, few studies have investigated the role of PTCH in clinical conditions suggesting an inherited predisposition to basal cell carcinoma (BCC), although it has been suggested that PTCH polymorphisms could predispose to multiple BCC (MBCC). In this study, we therefore performed an exhaustive analysis of PTCH (mutations detection and deletion analysis) in 17 patients with the full complement of criteria for NBCCS (14 sporadic and three familial cases), and in 48 patients suspected of having a genetic predisposition to BCC (MBCC and/or age at diagnosis ⩽40 years and/or familial BCC). Eleven new germline alterations of the PTCH gene were characterised in 12 out of 17 patients harbouring the full complement of criteria for the syndrome (70%). These were frameshift mutations in five patients, nonsense mutations in five patients, a small inframe deletion in one patient, and a large germline deletion in another patient. Only one missense mutation (G774R) was found, and this was in a patient affected with MBCC, but without any other NBCCS criterion. We therefore suggest that patients harbouring the full complement of NBCCS criteria should as a priority be screened for PTCH mutations by sequencing, followed by a deletion analysis if no mutation is detected. In other clinical situations that suggest genetic predisposition to BCC, germline mutations of PTCH are not common.

Kaposi's sarcoma in HIV-negative men having sex with men.

Background:Four epidemiologic forms of Kaposis sarcoma have been described, all of which are associated with the human herpesvirus-8. In western countries, human herpesvirus-8 is more prevalent in homosexual men than in the general population, and anecdotal cases of Kaposis sarcoma in HIV-negative homosexual men have been reported. Patients and methods:We included HIV-negative homosexual and bisexual male patients with histologically proven Kaposis sarcoma in a retrospective study. Clinical data were collected using a standardized form. Risk factors for human herpesvirus-8 infection and for the development of Kaposis sarcoma were systematically recorded. Results:Between 1995 and 2007, 28 men met the defined inclusion criteria. Mean age at first symptoms of Kaposis sarcoma was 53 years. Clinical presentation resembled classical Kaposis sarcoma, with limited disease in most patients. No cellular or humoral immunodeficiency was observed. Serologic tests for human herpesvirus-8 (latent immunofluorescence assay) were positive in 88% of patients, and only two patients displayed human herpesvirus-8 viremia at the time of Kaposis sarcoma diagnosis. Three patients developed lymphoproliferative disorders (Castleman disease, follicular lymphoma and Burkitt lymphoma). In this population, α-interferon was well tolerated and gave a complete response, but most patients require only local treatment, if any. Conclusion:Kaposis sarcoma may develop in homosexual or bisexual men without HIV infection. This type of Kaposis sarcoma has clinical features in common with classical Kaposis sarcoma but occurs in younger patients. Its prognosis is good, as Kaposis sarcoma is generally limited, but clinicians should be aware of the association with lymphoproliferative diseases, which may affect prognosis.

Pregnancy Promotes Melanoma Metastasis through Enhanced Lymphangiogenesis

The relationships of pregnancy and melanoma have been debatable. Our aim was to assess the influence of gestation on the course of melanoma in a classic murine model of tumor progression and in women. B16 mouse melanoma cells were injected in nonpregnant or pregnant mice on day 5 of gestation. Animals were evaluated for tumor progression, metastases, and survival. Tumor sections were analyzed for lymphatic and blood vessel number and relative surface and expression of angiogenic growth factors. Finally, primary melanomas from pregnant and nonpregnant women, matched for age and tumor thickness, were also considered. Tumor growth, metastasis, and mortality were increased in B16-injected pregnant mice. Tumors displayed an increase in intratumoral lymphangiogenesis during gestation. This increased lymphatic angiogenesis was not observed in normal skin during gestation, showing its specificity to the tumor. An analysis of melanoma from pregnant and matched nonpregnant women showed a similar increase in lymphatic vessels. Tumors from pregnant mice had increased expression of vascular endothelial growth factor A at the RNA and protein levels. The increased vascular endothelial growth factor A production by melanoma cells could be reproduced in culture using pregnant mouse serum. In conclusion, pregnancy results in increased lymphangiogenesis and subsequent metastasis. Caution should be applied in the management of patients with advanced-stage melanoma during gestation.

Value of Cytogenetic Analysis in the Treatment of Dermatofibrosarcoma Protuberans

A 23-year-old female patient with a long history of relapsingdermatofibrosarcoma protuberans (DFSP) despite iterative sur-gery presented in April 2006 with rapidly relapsing tumor unre-sectable because of massive involvement of the hemifacial andperiorbitalregion.Thelesionpresentedasrapidlyevolving,painfultumors more than 10 centimeters large, deeply infiltrating the fatand muscle (Fig 1). Histology confirmed the diagnosis of grade 3fibrosarcoma arising on DFSP. Translocation t(17;22) was con-firmedusingcaryotypeshowingasupernumeraryringchromosome(Fig 2, A), and fluorescent in situ hybridization (FISH) analysis oninterphase cell nuclei showing the merged green-red signals corre-sponding to collagen 1A1 promoter (

A retrospective analysis of thalidomide therapy in non-HIV-related Kaposi's sarcoma

Background: Thalidomide has antiangiogenic and immunomodulatory properties and has recently been used in the management of human malignancies. Several studies have suggested its interest for treating AIDS-related Kaposi’s sarcoma. Objectives: This study aimed to assess the efficacy and toxicity of thalidomide, an antiangiogenic agent, for the treatment of non-HIV-related Kaposi’s sarcoma. Methods: Eleven patients were included in this retrospective study conducted in the Department of Dermatology of Saint Louis, Paris, between 2000 and 2003. Among them, 2 were immunosuppressed (1 renal transplant recipient and 1 patient with microscopic polyangiitis treated by oral steroids) with stable immunosuppressive regimens during the past 6 months. The median daily thalidomide dosage was 100 mg and the median duration of drug treatment was 16 weeks. Results: Three patients achieved a partial response and 4 had a stable disease. Although no grade 3 or 4 was observed, 3 (27%) out of 11 patients prematurely discontinued thalidomide because of grade 1 sensory neuropathy (paresthesia) and vertigo. Conclusions: Our results show a true although modest interest of thalidomide in non-HIV-related Kaposi’s sarcoma and prompt us to evaluate less toxic thalidomide analogues for this indication.

Idiopathic Systemic Capillary Leak Syndrome: Cutaneous Involvement Can Be Misleading

Background: Systemic capillary leak syndrome (SCLS) is a severe disorder characterized by unexplained rapid transfer of considerable volumes of plasma from the intravascular to the extravascular compartment. For some cases of SCLS, no aetiology is evident and these cases are reported as idiopathic (ISCLS). Objectives: To describe the cutaneous findings in 3 patients with ISCLS. Results: Cutaneous involvement consisted in sclerosis, livedo, purpura and photodistributed maculopapular erythematous rash. Dermal mucinosis was proven by biopsy in 1 patient. No underlying disease was diagnosed during follow-up. Conclusion: The above-mentioned cutaneous findings can be present during acute attacks of ISCLS. They seem specifically related to the ISCLS and not indicative of an underlying disease.