Laura Schreieder

Genomic events and their timing that grant a primary tumour the competence to disseminate remain poorly defined. We performed sequencing of 247 stage I/II primary cutaneous melanomas (CMs) and 60 matched metastases without intervening therapy from a prospectively followed registry cohort with a median followup of 92 months, integrating copy-number, mutational, protein and spatial-transcriptomic analyses. Relapse was not distinguished by oncogenic point mutations, which were largely shared between primaries and metastases, but by somatic copy-number alterations (SCNAs) and global chromosomal instability. We defined OncoCycle, a six-gene copy-number signature (amplification of CDK4 , MCL1 and CD276 ; biallelic loss of CDKN2A , CDKN2B and TP53BP1 ) that predicted relapse independently of established clinicopathological features in melanoma, and a pan-cancer analysis. In matched pairs, metastatic progression was driven by continued copy-number evolution and reduction in intra-tumoural heterogeneity, rather than by acquired point mutations, and OncoCycle alterations from primary tumours were preserved in metastasis seeding clones. Clonal reconstruction revealed both monoclonal and polyclonal metastasis seeding, and spatial transcriptomics resolved copy-number-defined metastatic subclones occupying and programming distinct immune and stromal niches. Thus, metastatic competence was primed early by focal SCNAs on a background of chromosomal instability, elaborated by continued copy-number evolution during dissemination and spatio-temporal interactions with the tumour-microenvironment.

Cancer cells rely on citrate for multiple metabolic processes, suggesting that limiting the availability of extracellular citrate may represent a novel therapeutic strategy. The plasma membrane citrate transporter (pmCiC) has been implicated in the pathogenesis of several cancers before, and its activity can be inhibited by gluconate. Tissue samples from patients were stained, and pmCiC expression was analysed and correlated with clinical course. Melanoma cells were treated with or without citrate in physiological concentration and with or without gluconate, a pmCiC inhibitor. Cell proliferation rates were subsequently measured. pmCiC expression was observed in 58.2% of primary melanomas and 76.5% of melanoma metastases, but only in 22.2% of benign nevi. However, pmCiC expression did not correlate with the response to novel melanoma‐specific therapies. In the presence of pmCiC, melanoma cells exhibited significantly increased proliferation when exposed to extracellular citrate. This effect was blocked by the addition of gluconate. Extracellular citrate uptake via pmCiC appears to contribute to the pathogenesis of malignant melanoma. Notably, inhibition of pmCiC by gluconate effectively suppressed citrate‐induced proliferation.

Background/Objectives: With regard to excision of pigmented lesions for detection of malignant melanoma (MM), the number needed to treat (NNT) describes the number of melanocytic nevi that need to be biopsied/excised to detect one MM. The aim should be a low NNT. Methods: Single-center data analysis, including dermatohistopathological records of all nevi and MM cases during 2004–2013 at the Department of Dermatology, University Hospital Regensburg (UKR), was performed. We calculated the NNT, correlating it with the patient’s age and referring physician. The MM to MM in situ ratio was calculated to quantify early detection. As a secondary objective, we stratified into a pre- and post-2008 dataset, coinciding with the introduction of statutory skin cancer screening in Germany. Results: The overall NNT of 118,668 pigmented lesions was 17.2. We found a linear decrease in NNT towards older patients (R² = 62%; p < 0.001). The impact of skin cancer screening in 2008 was marked by a reduction in biopsies/excisions, a shift in age distribution, and a decrease in the NNT from 20.3 to 14.7. Office-based dermatologists had an NNT of 22.3, UKR-based dermatologists had an NNT of 8.0, and non-dermatologists had an NNT of 16.5. Conclusions: The age-related decrease in the NNT emphasizes the importance of age stratification for pigmented lesions. The NNT differed between professional settings. The implementation of skin cancer screening in 2008 was associated with a reduced NNT.

(1) Background: Ultraviolet (UV) radiation and sunburns are associated with an increased incidence of acquired nevi and melanomas. However, the data are controversial as to whether chronic UV exposure or high intermittent UV exposure is the major carcinogenic factor in melanocytic tumors. In this study, we compared the degree of actinic elastosis (AE) as a surrogate for lifetime UV exposure in nevi and different clinical melanoma subtypes (i.e., superficial spreading melanoma (SSM), nodular malignant melanoma (NMM), acral lentiginous melanoma (ALM), and lentigo maligna melanoma (LMM)) with respect to clinical variables (age, sex, and body site). (2) Methods: We defined a semi-quantitative score for the degree of AE ranging from 0 = none to 3 = total loss of elastic fibers (basophilic degeneration) and multiplied it by the perilesional vertical extent (depth), measured histometrically (tumor-associated elastosis grade (TEG)). We matched the TEG of n = 595 melanocytic lesions from 559 patients with their clinical variables. (3) Results: The TEG was correlated with age and UV-exposed body sites. Furthermore, the TEG was significantly higher in LMM than in all other types of melanomas and the TEG in NMM was higher than in SSM, irrespective of patient age and tumor site. (4) Conclusions: High cumulative UV exposure is more strongly associated with LMM and NMM than with other melanoma subtypes.