Publications by authors named "Christian Ingvar"

132 Publications

The human melanoma proteome atlas-Defining the molecular pathology.

Clin Transl Med 2021 07;11(7):e473

Division of Oncology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.

The MM500 study is an initiative to map the protein levels in malignant melanoma tumor samples, focused on in-depth histopathology coupled to proteome characterization. The protein levels and localization were determined for a broad spectrum of diverse, surgically isolated melanoma tumors originating from multiple body locations. More than 15,500 proteoforms were identified by mass spectrometry, from which chromosomal and subcellular localization was annotated within both primary and metastatic melanoma. The data generated by global proteomic experiments covered 72% of the proteins identified in the recently reported high stringency blueprint of the human proteome. This study contributes to the NIH Cancer Moonshot initiative combining detailed histopathological presentation with the molecular characterization for 505 melanoma tumor samples, localized in 26 organs from 232 patients.
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http://dx.doi.org/10.1002/ctm2.473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255060PMC
July 2021

The Human Melanoma Proteome Atlas-Complementing the melanoma transcriptome.

Clin Transl Med 2021 07;11(7):e451

Division of Oncology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.

The MM500 meta-study aims to establish a knowledge basis of the tumor proteome to serve as a complement to genome and transcriptome studies. Somatic mutations and their effect on the transcriptome have been extensively characterized in melanoma. However, the effects of these genetic changes on the proteomic landscape and the impact on cellular processes in melanoma remain poorly understood. In this study, the quantitative mass-spectrometry-based proteomic analysis is interfaced with pathological tumor characterization, and associated with clinical data. The melanoma proteome landscape, obtained by the analysis of 505 well-annotated melanoma tumor samples, is defined based on almost 16 000 proteins, including mutated proteoforms of driver genes. More than 50 million MS/MS spectra were analyzed, resulting in approximately 13,6 million peptide spectrum matches (PSMs). Altogether 13 176 protein-coding genes, represented by 366 172 peptides, in addition to 52 000 phosphorylation sites, and 4 400 acetylation sites were successfully annotated. This data covers 65% and 74% of the predicted and identified human proteome, respectively. A high degree of correlation (Pearson, up to 0.54) with the melanoma transcriptome of the TCGA repository, with an overlap of 12 751 gene products, was found. Mapping of the expressed proteins with quantitation, spatiotemporal localization, mutations, splice isoforms, and PTM variants was proven not to be predicted by genome sequencing alone. The melanoma tumor molecular map was complemented by analysis of blood protein expression, including data on proteins regulated after immunotherapy. By adding these key proteomic pillars, the MM500 study expands the knowledge on melanoma disease.
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http://dx.doi.org/10.1002/ctm2.451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8299047PMC
July 2021

PTENP1-AS contributes to BRAF inhibitor resistance and is associated with adverse clinical outcome in stage III melanoma.

Sci Rep 2021 05 26;11(1):11023. Epub 2021 May 26.

Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden.

BRAF inhibitors (BRAFi) selectively target oncogenic BRAF and are effective in 80% of advanced cutaneous malignant melanoma cases carrying the V600 mutation. However, the development of drug resistance limits their clinical efficacy. Better characterization of the underlying molecular processes is needed to further improve treatments. We previously demonstrated that transcription of PTEN is negatively regulated by the PTEN pseudogene antisense RNA, PTENP1-AS, and here we investigated the impact of this transcript on clinical outcome and BRAFi resistance in melanoma. We observed that increased expression levels of PTENP1-AS in BRAFi resistant cells associated with enrichment of EZH2 and H3K27me3 at the PTEN promoter, consequently reducing the expression levels of PTEN. Further, we showed that targeting of the PTENP1-AS transcript sensitized resistant cells to BRAFi treatment and that high expression of PTENP1-AS in stage III melanoma correlated with poor survival. Collectively, the data presented here show that PTENP1-AS is a promising target for re-sensitizing cells to BRAFi and also a possible prognostic marker for clinical outcome in stage III melanoma.
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http://dx.doi.org/10.1038/s41598-021-89389-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155038PMC
May 2021

Birth cohort-specific trends of sun-related behaviors among individuals from an international consortium of melanoma-prone families.

BMC Public Health 2021 04 23;21(1):692. Epub 2021 Apr 23.

Department of Dermatology, Leiden University Medical Centre, Leiden, The Netherlands.

Background: Individuals from melanoma-prone families have similar or reduced sun-protective behaviors compared to the general population. Studies on trends in sun-related behaviors have been temporally and geographically limited.

Methods: Individuals from an international consortium of melanoma-prone families (GenoMEL) were retrospectively asked about sunscreen use, sun exposure (time spent outside), sunburns, and sunbed use at several timepoints over their lifetime. Generalized linear mixed models were used to examine the association between these outcomes and birth cohort defined by decade spans, after adjusting for covariates.

Results: A total of 2407 participants from 547 families across 17 centers were analyzed. Sunscreen use increased across subsequent birth cohorts, and although the likelihood of sunburns increased until the 1950s birth cohort, it decreased thereafter. Average sun exposure did not change across the birth cohorts, and the likelihood of sunbed use increased in more recent birth cohorts. We generally did not find any differences in sun-related behavior when comparing melanoma cases to non-cases. Melanoma cases had increased sunscreen use, decreased sun exposure, and decreased odds of sunburn and sunbed use after melanoma diagnosis compared to before diagnosis.

Conclusions: Although sunscreen use has increased and the likelihood of sunburns has decreased in more recent birth cohorts, individuals in melanoma-prone families have not reduced their overall sun exposure and had an increased likelihood of sunbed use in more recent birth cohorts. These observations demonstrate partial improvements in melanoma prevention and suggest that additional intervention strategies may be needed to achieve optimal sun-protective behavior in melanoma-prone families.
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http://dx.doi.org/10.1186/s12889-021-10424-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063451PMC
April 2021

Pre- and Postoperative Circulating IGF-I, IGFBP-3, and IGFBP-7 Levels in Relation to Endocrine Treatment and Breast Cancer Recurrence: A Nested Case-Control Study.

Front Oncol 2021 9;11:626058. Epub 2021 Mar 9.

Department of Clinical Sciences Lund, Oncology, Lund University and Skåne University Hospital, Lund, Sweden.

Insulin-like growth factor-I (IGF-I) and its binding proteins (BPs) have been associated with breast cancer risk, especially high IGF-I concentrations and the biologically active fraction estimated as the IGF-I/IGFBP-3 molar ratio. The relation of circulating IGF-I and IGFBP-3 concentrations with risk of breast cancer recurrence has been less documented. In addition a new member to a sub-group of the IGFBP-superfamily was recently identified, the low affinity IGFBP-7. To date, the role of systemic IGFBP-7 in breast cancer progression has not been investigated. Our purpose was to establish whether circulating IGF-I, IGFBP-3, and IGFBP-7 levels are related to recurrence-risk in breast cancer. A case-control study was nested within the population-based BCBlood cohort of 853 breast cancer patients diagnosed 2002-2010 in Sweden and followed through 2012. In total, 95 patients with recurrence and 170 controls were matched on age and tumor characteristics. Plasma IGF analytes and tumor membrane IGF-I receptor (IGF-IR) positivity were analyzed and recurrence-risk was evaluated with conditional logistic regression. Preoperative tertiles of IGF-I and IGFBP-3 were both positively associated with recurrence-risk, but not IGFBP-7. The trend was of borderline significance for IGF-I, T1:REF, T2 OR:1.6, T3 OR: 2.2 adjusted =0.057 and significant for IGFBP-3 T1:REF, T2 OR:1.2, T3 OR: 2.1 adjusted =0.042. The models were adjusted for age, anthropometric factors, smoking, and treatments. There was a significant interaction between IGFBP-7 and IGF-IR positivity on recurrence, where the highest IGFBP-7 highest IGFBP-7 tertile conferred increased recurrence-risk in patients with IGF-IR positive tumors but not in those with IGF-IR negative tumors ( =0.024). By the 1-year visit, age-adjusted IGF-I levels were reduced by 17% while IGFBP-3 and IGFBP-7 were stable. IGF-I levels were significantly reduced by radiotherapy in all patients and by tamoxifen in patients with ER tumors. Postoperative changes >10% (n=208) in IGF-I, IGFBP-3, IGFBP-7, or the IGF-I/IGFBP-3 ratio did not predict recurrence after adjustment for preoperative levels, age, anthropometric factors, smoking, and treatments. In conclusion, this study suggests that preoperative IGF-I and IGFBP-3 levels, but not postoperative changes, might provide independent prognostic information and influence breast cancer recurrence. The role of IGFBP-7 in breast cancer merits further study.
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http://dx.doi.org/10.3389/fonc.2021.626058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986849PMC
March 2021

Apelin promotes blood and lymph vessel formation and the growth of melanoma lung metastasis.

Sci Rep 2021 Mar 11;11(1):5798. Epub 2021 Mar 11.

Department of Tumor Biology, National Korányi Institute of Pulmonology, Budapest, Hungary.

Apelin, a ligand of the APJ receptor, is overexpressed in several human cancers and plays an important role in tumor angiogenesis and growth in various experimental systems. We investigated the role of apelin signaling in the malignant behavior of cutaneous melanoma. Murine B16 and human A375 melanoma cell lines were stably transfected with apelin encoding or control vectors. Apelin overexpression significantly increased melanoma cell migration and invasion in vitro, but it had no impact on its proliferation. In our in vivo experiments, apelin significantly increased the number and size of lung metastases of murine melanoma cells. Melanoma cell proliferation rates and lymph and blood microvessel densities were significantly higher in the apelin-overexpressing pulmonary metastases. APJ inhibition by the competitive APJ antagonist MM54 significantly attenuated the in vivo pro-tumorigenic effects of apelin. Additionally, we detected significantly elevated circulating apelin and VEGF levels in patients with melanoma compared to healthy controls. Our results show that apelin promotes blood and lymphatic vascularization and the growth of pulmonary metastases of skin melanoma. Further studies are warranted to validate apelin signaling as a new potential therapeutic target in this malignancy.
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http://dx.doi.org/10.1038/s41598-021-85162-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952702PMC
March 2021

Clinical performance of a novel hyperspectral imaging device for cutaneous melanoma and pigmented skin lesions in Caucasian skin.

Skin Res Technol 2021 Sep 2;27(5):803-809. Epub 2021 Mar 2.

Department of Dermatology, Skane University Hospital, Lund University, Lund, Sweden.

Background: The quest for diagnostic tools for the detection of cutaneous malignant melanoma (cMM) is ongoing. A challenge in cMM care is not overlooking cMM at an early stage, while simultaneously avoiding unnecessary biopsies or excisions of benign pigmented skin lesions (PSLs). A novel hyperspectral imaging (HSI) device is shown to have potential for differentiating equivocal PSLs in Asian skin types. Our objective was to assess the accuracy of the HSI device in distinguishing between cMM and benign PSLs in patients with Caucasian skin types.

Methods: Patients with Caucasian skin types (Fitzpatrick I-II), enrolled for excisional biopsies of PSLs were included and examined using the HSI device. The discrimination index (DI) was used to demonstrate the sensitivity (SE) and specificity (SP) in comparison with the re-evaluated histopathology diagnoses.

Results: In 186 patients, 202 pigmented skin lesions were included. The sensitivity to detect cMM was 96.7% (87/90), and the specificity for benign lesions was 42.1% (45/107). The AUC was 0.800 (95% confidence interval (CI): 0.740-0.861).

Conclusions: Our novel HSI device showed a high sensitivity in detecting malignant lesions in patients with Caucasian skin types. Compared with analogous technologies, as multispectral imaging or electrical impedance spectroscopy, our device showed similar or better accuracy in differentiating cMM from benign PSLs. Therefore, it might be a useful clinical tool in skin types I-IV and where further triage of pigmented skin lesions is important.
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http://dx.doi.org/10.1111/srt.13023DOI Listing
September 2021

TRIM study protocol - a prospective randomized multicenter Trial to assess the Role of Imaging during follow-up after radical surgery of stage IIB-C and III cutaneous malignant Melanoma.

BMC Cancer 2020 Dec 7;20(1):1197. Epub 2020 Dec 7.

Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck laboratory, 75185, Uppsala, Sweden.

Background: The incidence of cutaneous malignant melanoma (CMM) is increasing worldwide. In Sweden, over 4600 cases were diagnosed in 2018. The prognosis after radical surgery varies considerably with tumor stage. In recent years, new treatment options have become available for metastatic CMM. Early onset of treatment seems to improve outcome, which suggests that early detection of recurrent disease should be beneficial. Consequently, in several countries imaging is a part of the routine follow-up program after surgery of high risk CMM. However, imaging has drawbacks, including resources required (costs, personnel, equipment) and the radiation exposure. Furthermore, many patients experience anxiety in waiting for the imaging results and investigations of irrelevant findings is another factor that also could cause worry and lead to decreased quality of life. Hence, the impact of imaging in this setting is important to address and no randomized study has previously been conducted. The Swedish national guidelines stipulate follow-up for 3 years by clinical examinations only.

Methods: The TRIM study is a prospective randomized multicenter trial evaluating the potential benefit of imaging and blood tests during follow-up after radical surgery for high-risk CMM, compared to clinical examinations only. Primary endpoint is overall survival (OS) at 5 years. Secondary endpoints are survival from diagnosis of relapse and health-related quality of life (HRQoL). Eligible for inclusion are patients radically operated for CMM stage IIB-C or III with sufficient renal function for iv contrast-enhanced CT and who are expected to be fit for treatment in case of recurrence. The planned number of patients is > 1300. Patients are randomized to clinical examinations for 3 years +/- whole-body imaging with CT or FDG-PET/CT and laboratory tests including S100B protein and LDH. This academic study is supported by the Swedish Melanoma Study Group.

Discussion: This is the first randomized prospective trial on the potential benefit of imaging as a part of the follow-up scheme after radical surgery for high-risk CMM.

Results: The first patient was recruited in June 2017 and as of April 2020, almost 500 patients had been included at 19 centers in Sweden.

Trial Registration: ClinicalTrials.gov , NCT03116412 . Registered 17 April 2017, https://clinicaltrials.gov/ct2/show/study/NCT03116412.
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http://dx.doi.org/10.1186/s12885-020-07632-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720485PMC
December 2020

Automatic diagnosis of melanoma using hyperspectral data and GoogLeNet.

Skin Res Technol 2020 Nov 25;26(6):891-897. Epub 2020 Jun 25.

Department of Biological System Engineering, Graduate School of Biology-Oriented Science and Technology, Kindai University, Wakayama, Japan.

Background: Melanoma is a type of superficial tumor. As advanced melanoma has a poor prognosis, early detection and therapy are essential to reduce melanoma-related deaths. To that end, there is a need to develop a quantitative method for diagnosing melanoma. This paper reports the development of such a diagnostic system using hyperspectral data (HSD) and a convolutional neural network, which is a type of machine learning.

Materials And Methods: HSD were acquired using a hyperspectral imager, which is a type of spectrometer that can simultaneously capture information about wavelength and position. GoogLeNet pre-trained with Imagenet was used to model the convolutional neural network. As many CNNs (including GoogLeNet) have three input channels, the HSD (involving 84 channels) could not be input directly. For that reason, a "Mini Network" layer was added to reduce the number of channels from 84 to 3 just before the GoogLeNet input layer. In total, 619 lesions (including 278 melanoma lesions and 341 non-melanoma lesions) were used for training and evaluation of the network.

Results And Conclusion: The system was evaluated by 5-fold cross-validation, and the results indicate sensitivity, specificity, and accuracy of 69.1%, 75.7%, and 72.7% without data augmentation, 72.3%, 81.2%, and 77.2% with data augmentation, respectively. In future work, it is intended to improve the Mini Network and to increase the number of lesions.
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http://dx.doi.org/10.1111/srt.12891DOI Listing
November 2020

Multiple Primary Melanoma Incidence Trends Over Five Decades: A Nationwide Population-Based Study.

J Natl Cancer Inst 2021 03;113(3):318-328

Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund, Sweden.

Background: Over the past decades, many regions have experienced a steady increase in the incidence of cutaneous melanoma. Here, we report on incidence trends for subsequent primary melanoma.

Methods: In this nationwide population-based study, patients diagnosed with a first primary cutaneous melanoma reported to the Swedish Cancer Registry were followed for up to 10 years for a diagnosis of subsequent primary melanoma. Patients were grouped with patients diagnosed with first melanoma in the same decade (1960s, 1970s, 1980s, 1990s, and 2000s, respectively). Frequencies, incidence rates (IRs), standardized incidence ratios (SIRs), and 95% confidence intervals (CIs) for second melanomas were calculated. All tests of statistical significance were 2-sided.

Results: Of patients with melanoma, 54 884 were included and 2469 were diagnosed, within 10 years, with subsequent melanomas. Over the 5 decades, there was a statistically significant steady increase in the frequency, IR, and SIR for second primary melanoma. For example, in the 1960s cohort, less than 1% (IR = 1.0, 95% CI = 0.5 to 1.7, and IR = 1.1, 95% CI = 0.5 to 1.9 per 1000 person-years in women and men, respectively) had second primary melanoma, and this rose to 6.4% (IR = 7.5, 95% CI = 6.8 to 8.3, per 1000 person-years) in the women and 7.9% (IR = 10.3, 95% CI = 9.3 to 11.2, per 1000 person-years) in the men in the 2000s cohort. This rise was seen independent of age, sex, invasiveness, or site of the melanoma. Further, in patients diagnosed with a second melanoma, the frequency of those having more than 2 melanomas increased statistically significantly and was 0.0% in the 1960s and rose to 18.0% in the 2000s (P < .001).

Conclusions: This is the first study to evaluate and report on a rising trend for subsequent primary melanoma. Additional primary melanomas worsen the patients' survival, and precautions are needed to turn this steep upgoing trend.
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http://dx.doi.org/10.1093/jnci/djaa088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936055PMC
March 2021

Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility.

Nat Genet 2020 05 27;52(5):494-504. Epub 2020 Apr 27.

Department of Dermatology, Instituto Valenciano de Oncología, Valencia, Spain.

Most genetic susceptibility to cutaneous melanoma remains to be discovered. Meta-analysis genome-wide association study (GWAS) of 36,760 cases of melanoma (67% newly genotyped) and 375,188 controls identified 54 significant (P < 5 × 10) loci with 68 independent single nucleotide polymorphisms. Analysis of risk estimates across geographical regions and host factors suggests the acral melanoma subtype is uniquely unrelated to pigmentation. Combining this meta-analysis with GWAS of nevus count and hair color, and transcriptome association approaches, uncovered 31 potential secondary loci for a total of 85 cutaneous melanoma susceptibility loci. These findings provide insights into cutaneous melanoma genetic architecture, reinforcing the importance of nevogenesis, pigmentation and telomere maintenance, together with identifying potential new pathways for cutaneous melanoma pathogenesis.
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http://dx.doi.org/10.1038/s41588-020-0611-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255059PMC
May 2020

The Role of PTEN Loss in Immune Escape, Melanoma Prognosis and Therapy Response.

Cancers (Basel) 2020 Mar 21;12(3). Epub 2020 Mar 21.

Division of Oncology, Department of Clinical Sciences, Lund University, 22381 Lund, Sweden.

Checkpoint blockade therapies have changed the clinical management of metastatic melanoma patients considerably, showing survival benefits. Despite the clinical success, not all patients respond to treatment or they develop resistance. Although there are several treatment predictive biomarkers, understanding therapy resistance and the mechanisms of tumor immune evasion is crucial to increase the frequency of patients benefiting from treatment. The gene is thought to promote immune evasion and is frequently mutated in cancer and melanoma. Another feature of melanoma tumors that may affect the capacity of escaping T-cell recognition is melanoma cell dedifferentiation characterized by decreased expression of the microphtalmia-associated transcription factor () gene. In this study, we have explored the role of PTEN in prognosis, therapy response, and immune escape in the context of expression using immunostaining and genomic data from a large cohort of metastatic melanoma. We confirmed in our cohort that PTEN alterations promote immune evasion highlighted by decreased frequency of T-cell infiltration in such tumors, resulting in a worse patient survival. More importantly, our results suggest that dedifferentiated PTEN negative melanoma tumors have poor patient outcome, no T-cell infiltration, and transcriptional properties rendering them resistant to targeted- and immuno-therapy.
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http://dx.doi.org/10.3390/cancers12030742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140048PMC
March 2020

Protein Expression in Metastatic Melanoma and the Link to Disease Presentation in a Range of Tumor Phenotypes.

Cancers (Basel) 2020 Mar 24;12(3). Epub 2020 Mar 24.

Clinical Protein Science & Imaging, Biomedical Centre, Department of Biomedical Engineering, Lund University, 221 84 Lund, Sweden.

Malignant melanoma is among the most aggressive skin cancers and it has among the highest metastatic potentials. Although surgery to remove the primary tumor is the gold standard treatment, once melanoma progresses and metastasizes to the lymph nodes and distal organs, i.e., metastatic melanoma (MM), the usual outcome is decreased survival. To improve survival rates and life span, advanced treatments have focused on the success of targeted therapies in the MAPK pathway that are based on BRAF (BRAF V600E) and MEK. The majority of patients with tumors that have higher expression of BRAF V600E show poorer prognosis than patients with a lower level of the mutated protein. Based on the molecular basis of melanoma, these findings are supported by distinct tumor phenotypes determined from differences in tumor heterogeneity and protein expression profiles. With these aspects in mind, continued challenges are to: (1) deconvolute the complexity and heterogeneity of MM; (2) identify the signaling pathways involved; and (3) determine protein expression to develop targeted therapies. Here, we provide an overview of the results from protein expression in MM and the link to disease presentation in a variety of tumor phenotypes and how these will overcome the challenges of clinical problems and suggest new promising approaches in metastatic melanoma and cancer therapy.
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http://dx.doi.org/10.3390/cancers12030767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140007PMC
March 2020

Desloratadine and loratadine use associated with improved melanoma survival.

Allergy 2020 08 16;75(8):2096-2099. Epub 2020 Apr 16.

Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund, Sweden.

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http://dx.doi.org/10.1111/all.14273DOI Listing
August 2020

Analysis of DNA methylation patterns in the tumor immune microenvironment of metastatic melanoma.

Mol Oncol 2020 05 21;14(5):933-950. Epub 2020 Mar 21.

Division of Oncology and Pathology, Department of Clinical Sciences, Faculty of Medicine, Lund University, Lund, Sweden.

The presence of immune cells in the tumor microenvironment has been associated with response to immunotherapies across several cancer types, including melanoma. Despite its therapeutic relevance, characterization of the melanoma immune microenvironments remains insufficiently explored. To distinguish the immune microenvironment in a cohort of 180 metastatic melanoma clinical specimens, we developed a method using promoter CpG methylation of immune cell type-specific genes extracted from genome-wide methylation arrays. Unsupervised clustering identified three immune methylation clusters with varying levels of immune CpG methylation that are related to patient survival. Matching protein and gene expression data further corroborated the identified epigenetic characterization. Exploration of the possible immune exclusion mechanisms at play revealed likely dependency on MITF protein level and PTEN loss-of-function events for melanomas unresponsive to immunotherapies (immune-low). To understand whether melanoma tumors resemble other solid tumors in terms of immune methylation characteristics, we explored 15 different solid tumor cohorts from TCGA. Low-dimensional projection based on immune cell type-specific methylation revealed grouping of the solid tumors in line with melanoma immune methylation clusters rather than tumor types. Association of survival outcome with immune cell type-specific methylation differed across tumor and cell types. However, in melanomas immune cell type-specific methylation was associated with inferior patient survival. Exploration of the immune methylation patterns in a pan-cancer context suggested that specific immune microenvironments might occur across the cancer spectrum. Together, our findings underscore the existence of diverse immune microenvironments, which may be informative for future immunotherapeutic applications.
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http://dx.doi.org/10.1002/1878-0261.12663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191190PMC
May 2020

Tertiary lymphoid structures improve immunotherapy and survival in melanoma.

Nature 2020 01 15;577(7791):561-565. Epub 2020 Jan 15.

Department of Clinical Sciences, Division of Oncology and Pathology, Lund University Cancer Center, Lund University, Lund, Sweden.

Checkpoint blockade therapies that reactivate tumour-associated T cells can induce durable tumour control and result in the long-term survival of patients with advanced cancers. Current predictive biomarkers for therapy response include high levels of intratumour immunological activity, a high tumour mutational burden and specific characteristics of the gut microbiota. Although the role of T cells in antitumour responses has thoroughly been studied, other immune cells remain insufficiently explored. Here we use clinical samples of metastatic melanomas to investigate the role of B cells in antitumour responses, and find that the co-occurrence of tumour-associated CD8 T cells and CD20 B cells is associated with improved survival, independently of other clinical variables. Immunofluorescence staining of CXCR5 and CXCL13 in combination with CD20 reveals the formation of tertiary lymphoid structures in these CD8CD20 tumours. We derived a gene signature associated with tertiary lymphoid structures, which predicted clinical outcomes in cohorts of patients treated with immune checkpoint blockade. Furthermore, B-cell-rich tumours were accompanied by increased levels of TCF7 naive and/or memory T cells. This was corroborated by digital spatial-profiling data, in which T cells in tumours without tertiary lymphoid structures had a dysfunctional molecular phenotype. Our results indicate that tertiary lymphoid structures have a key role in the immune microenvironment in melanoma, by conferring distinct T cell phenotypes. Therapeutic strategies to induce the formation of tertiary lymphoid structures should be explored to improve responses to cancer immunotherapy.
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http://dx.doi.org/10.1038/s41586-019-1914-8DOI Listing
January 2020

The Hidden Story of Heterogeneous B-raf V600E Mutation Quantitative Protein Expression in Metastatic Melanoma-Association with Clinical Outcome and Tumor Phenotypes.

Cancers (Basel) 2019 Dec 9;11(12). Epub 2019 Dec 9.

Clinical Protein Science & Imaging, Biomedical Centre, Department of Biomedical, Engineering, Lund University, BMC D13, 221 84 Lund, Sweden.

In comparison to other human cancer types, malignant melanoma exhibits the greatest amount of heterogeneity. After DNA-based detection of the BRAF V600E mutation in melanoma patients, targeted inhibitor treatment is the current recommendation. This approach, however, does not take the abundance of the therapeutic target, i.e., the B-raf V600E protein, into consideration. As shown by immunohistochemistry, the protein expression profiles of metastatic melanomas clearly reveal the existence of inter- and intra-tumor variability. Nevertheless, the technique is only semi-quantitative. To quantitate the mutant protein there is a fundamental need for more precise techniques that are aimed at defining the currently non-existent link between the levels of the target protein and subsequent drug efficacy. Using cutting-edge mass spectrometry combined with DNA and mRNA sequencing, the mutated B-raf protein within metastatic tumors was quantitated for the first time. B-raf V600E protein analysis revealed a subjacent layer of heterogeneity for mutation-positive metastatic melanomas. These were characterized into two distinct groups with different tumor morphologies, protein profiles and patient clinical outcomes. This study provides evidence that a higher level of expression in the mutated protein is associated with a more aggressive tumor progression. Our study design, comprised of surgical isolation of tumors, histopathological characterization, tissue biobanking, and protein analysis, may enable the eventual delineation of patient responders/non-responders and subsequent therapy for malignant melanoma.
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http://dx.doi.org/10.3390/cancers11121981DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966659PMC
December 2019

Tumor genetic heterogeneity analysis of chronic sun-damaged melanoma.

Pigment Cell Melanoma Res 2020 05 23;33(3):480-489. Epub 2019 Dec 23.

Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund University, Lund, Sweden.

Chronic sun-damaged (CSD) melanoma represents 10%-20% of cutaneous melanomas and is characterized by infrequent BRAF V600E mutations and high mutational load. However, the order of genetic events or the extent of intra-tumor heterogeneity (ITH) in CSD melanoma is still unknown. Ultra-deep targeted sequencing of 40 cancer-associated genes was performed in 72 in situ or invasive CMM, including 23 CSD cases. In addition, we performed whole exome and RNA sequencing on multiple regions of primary tumor and multiple in-transit metastases from one CSD melanoma patient. We found no significant difference in mutation frequency in melanoma-related genes or in mutational load between in situ and invasive CSD lesions, while this difference was observed in CSD lesions. In addition, increased frequency of BRAF V600K, NF1, and TP53 mutations (p < .01, Fisher's exact test) was found in CSD melanomas. Sequencing of multiple specimens from one CSD patient revealed strikingly limited ITH with >95% shared mutations. Our results provide evidence that CSD and CSD melanomas are distinct molecular entities that progress via different genetic routes.
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http://dx.doi.org/10.1111/pcmr.12851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217060PMC
May 2020

Participation in a Prospective Cohort Study on Melanoma did not Affect the Incidence and Mortality of the Studied Disease.

Acta Derm Venereol 2020 01 7;100(1):adv00010. Epub 2020 Jan 7.

Department of Clinical Sciences, Cancerepidemiology, SE-221 00 Lund, Sweden.

Prospective observational studies have shown previously that study participants have lower morbidity and mortality than non-participants. The aim of the current study was to determine whether participants in a prospective cohort study on melanoma have a different incidence and mortality of melanoma compared with non-participants and the background population. Information was collected from Swedish National Registers on participants (n = 30,501) and non-participants (n = 10,499) in the "Melanoma In Southern Sweden" (MISS) study and the background population (n = 243,032). Hazard ratios were calculated for overall incidence of cancer and melanoma, and all-cause and melanoma-specific mortality, using Cox regression. Participants had a lower overall incidence of cancer and all-cause mortality than non-participants and the background population. There was no difference in incidence of melanoma or melanoma-specific characteristics between participants and the background population. In conclusion, participants in the MISS study have a slightly better general health, but are a representative sample of the population with regard to studies of melanoma risk factors.
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http://dx.doi.org/10.2340/00015555-3362DOI Listing
January 2020

Novel functional proteins coded by the human genome discovered in metastases of melanoma patients.

Cell Biol Toxicol 2020 06 10;36(3):261-272. Epub 2019 Oct 10.

Clinical Protein Science & Imaging, Biomedical Centre, Department of Biomedical Engineering, Lund University, BMC D13, 221 84, Lund, Sweden.

In the advanced stages, malignant melanoma (MM) has a very poor prognosis. Due to tremendous efforts in cancer research over the last 10 years, and the introduction of novel therapies such as targeted therapies and immunomodulators, the rather dark horizon of the median survival has dramatically changed from under 1 year to several years. With the advent of proteomics, deep-mining studies can reach low-abundant expression levels. The complexity of the proteome, however, still surpasses the dynamic range capabilities of current analytical techniques. Consequently, many predicted protein products with potential biological functions have not yet been verified in experimental proteomic data. This category of 'missing proteins' (MP) is comprised of all proteins that have been predicted but are currently unverified. As part of the initiative launched in 2016 in the USA, the European Cancer Moonshot Center has performed numerous deep proteomics analyses on samples from MM patients. In this study, nine MPs were clearly identified by mass spectrometry in MM metastases. Some MPs significantly correlated with proteins that possess identical PFAM structural domains; and other MPs were significantly associated with cancer-related proteins. This is the first study to our knowledge, where unknown and novel proteins have been annotated in metastatic melanoma tumour tissue.
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http://dx.doi.org/10.1007/s10565-019-09494-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7320927PMC
June 2020

Evaluation of the contribution of germline variants in BRCA1 and BRCA2 to uveal and cutaneous melanoma.

Melanoma Res 2019 10;29(5):483-490

Oncogenomics Group.

Germline mutations of BRCA1 and BRCA2 predispose individuals to a high risk of breast and ovarian cancer, and elevated risk of other cancers, including those of the pancreas and prostate. BRCA2 mutation carriers may have increased risk of uveal melanoma (UM) and cutaneous melanoma (CM), but associations with these cancers in BRCA1 mutation carriers have been mixed. Here, we further assessed whether UM and CM are associated with BRCA1 or BRCA2 by assessing the presence, segregation and reported/predicted pathogenicity of rare germline mutations (variant allele frequency < 0.01) in families with multiple members affected by these cancers. Whole-genome or exome sequencing was performed on 160 CM and/or UM families from Australia, the Netherlands, Denmark and Sweden. Between one and five cases were sequenced from each family, totalling 307 individuals. Sanger sequencing was performed to validate BRCA1 and BRCA2 germline variants and to assess carrier status in other available family members. A nonsense and a frameshift mutation were identified in BRCA1, both resulting in premature truncation of the protein (the first at p.Q516 and the second at codon 91, after the introduction of seven amino acids due to a frameshift deletion). These variants co-segregated with CM in individuals who consented for testing and were present in individuals with pancreatic, prostate and breast cancer in the respective families. In addition, 33 rare missense mutations (variant allele frequency ranging from 0.00782 to 0.000001 in the aggregated ExAC data) were identified in 34 families. Examining the previously reported evidence of functional consequence of these variants revealed all had been classified as either benign or of unknown consequence. Seeking further evidence of an association between BRCA1 variants and melanoma, we examined two whole-genome/exome sequenced collections of sporadic CM patients (total N = 763). We identified one individual with a deleterious BRCA1 variant, however, this allele was lost (with the wild-type allele remaining) in the corresponding CM, indicating that defective BRCA1 was not a driver of tumorigenesis in this instance. Although this is the first time that deleterious BRCA1 mutations have been described in high-density CM families, we conclude that there is an insufficient burden of evidence to state that the increased familial CM or UM susceptibility is because of these variants. In addition, in conjunction with other studies, we conclude that the previously described association between BRCA2 mutations and UM susceptibility represents a rare source of increased risk.
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http://dx.doi.org/10.1097/CMR.0000000000000613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716616PMC
October 2019

2-cm versus 4-cm surgical excision margins for primary cutaneous melanoma thicker than 2 mm: long-term follow-up of a multicentre, randomised trial.

Lancet 2019 08 4;394(10197):471-477. Epub 2019 Jul 4.

Department of Clinical Science and Education, Karolinska Institutet, Stockholm, Sweden; Department of Surgery, Södersjukhuset, Stockholm, Sweden. Electronic address:

Background: The optimal surgical excision margins are uncertain for patients with thick (>2 mm) localised cutaneous melanomas. In our previous report of this multicentre, randomised controlled trial, with a median follow-up of 6·7 years, we showed that a narrow excision margin (2 cm vs 4 cm) did not affect melanoma-specific nor overall survival. Here, we present extended follow-up of this cohort.

Methods: In this open-label, multicentre randomised controlled trial, we recruited patients from 53 hospitals in Sweden, Denmark, Estonia, and Norway. We enrolled clinically staged patients aged 75 years or younger diagnosed with localised cutaneous melanoma thicker than 2 mm, and with primary site on the trunk or upper or lower extremities. Patients were randomly allocated (1:1) to treatment either with a 2-cm or a 4-cm excision margin. A physician enrolled the patients after histological confirmation of a cutaneous melanoma thicker than 2 mm. Some patients were enrolled by a physician acting as responsible for clinical care and as a trial investigator (follow-up, data collection, and manuscript writing). In other cases physicians not involved in running the trial enrolled patients. Randomisation was done by telephone call to a randomisation office, by sealed envelope, or by computer generated lists using permuted blocks. Patients were stratified according to geographical region. No part of the trial was masked. The primary outcome in this extended follow-up study was overall survival and the co-primary outcome was melanoma-specific survival. All analyses were done on an intention-to-treat basis. The study is registered with ClinicalTrials.gov, number NCT03638492.

Findings: Between Jan 22, 1992, and May 19, 2004, 936 clinically staged patients were recruited and randomly assigned to a 4-cm excision margin (n=465) or a 2-cm excision margin (n=471). At a median overall follow-up of 19·6 years (235 months, IQR 200-260), 621 deaths were reported-304 (49%) in the 2-cm group and 317 (51%) in the 4-cm group (unadjusted HR 0·98, 95% CI 0·83-1·14; p=0·75). 397 deaths were attributed to cutaneous melanoma-192 (48%) in the 2-cm excision margin group and 205 (52%) in the 4-cm excision margin group (unadjusted HR 0·95, 95% CI 0·78-1·16, p=0·61).

Interpretation: A 2-cm excision margin was safe for patients with thick (>2 mm) localised cutaneous melanoma at a follow-up of median 19·6 years. These findings support the use of 2-cm excision margins in current clinical practice.

Funding: The Swedish Cancer Society, Stockholm Cancer Society, the Swedish Society for Medical Research, Radiumhemmet Research funds, Stockholm County Council, Wallström funds.
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http://dx.doi.org/10.1016/S0140-6736(19)31132-8DOI Listing
August 2019

The X-Linked DDX3X RNA Helicase Dictates Translation Reprogramming and Metastasis in Melanoma.

Cell Rep 2019 06;27(12):3573-3586.e7

Division of Oncology, Department of Clinical Sciences, Lund University, Lund, Sweden. Electronic address:

The X-linked DDX3X gene encodes an ATP-dependent DEAD-box RNA helicase frequently altered in various human cancers, including melanomas. Despite its important roles in translation and splicing, how DDX3X dysfunction specifically rewires gene expression in melanoma remains completely unknown. Here, we uncover a DDX3X-driven post-transcriptional program that dictates melanoma phenotype and poor disease prognosis. Through an unbiased analysis of translating ribosomes, we identified the microphthalmia-associated transcription factor, MITF, as a key DDX3X translational target that directs a proliferative-to-metastatic phenotypic switch in melanoma cells. Mechanistically, DDX3X controls MITF mRNA translation via an internal ribosome entry site (IRES) embedded within the 5' UTR. Through this exquisite translation-based regulatory mechanism, DDX3X steers MITF protein levels dictating melanoma metastatic potential in vivo and response to targeted therapy. Together, these findings unravel a post-transcriptional layer of gene regulation that may provide a unique therapeutic vulnerability in aggressive male melanomas.
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http://dx.doi.org/10.1016/j.celrep.2019.05.069DOI Listing
June 2019

Sunbed Use Increases Cutaneous Squamous Cell Carcinoma Risk in Women: A Large-scale, Prospective Study in Sweden.

Acta Derm Venereol 2019 Sep;99(10):878-883

Department of Dermatology, Skåne University Hospital, Lasarettsgatan 15, SE-22241 Lund, Sweden.

The incidence of cutaneous squamous cell carcinoma has increased rapidly in Sweden in the past decades. Here, we present a prospective study of the Melanoma in Southern Sweden (MISS)-cohort, with 29,460 participating women in southern Sweden that investigates the risk factors for cutaneous squamous cell carcinoma. Data on the host and skin cancer risk factors were collected through questionnaires and then matched with the National Cancer Registry. Statistical analyses were based on uni- and multivariable Cox proportional hazards models, using age as the time-scale. We found that sunbed use (hazard ratio (HR) 1.2, 95% CI: 1.1-1.4), red and light blond hair (HR 1.6, 95% CI: 1.1-2.3), freckles (HR 1.4, 95% CI: 1.1-1.8) and immunosuppressive medications (HR 2.1, 95% CI: 1.3-4.5) were independent risk factors. Furthermore, we observed a dose-dependent relationship between sunbed use and the development of cutaneous squamous cell carcinoma. Our findings support the idea of integrating dermatological follow-up examinations for immunosuppressed patients and banning the use of sunbeds in order to prevent cutaneous squamous cell carcinoma.
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http://dx.doi.org/10.2340/00015555-3198DOI Listing
September 2019

Improved survival prognostication of node-positive malignant melanoma patients utilizing shotgun proteomics guided by histopathological characterization and genomic data.

Sci Rep 2019 03 26;9(1):5154. Epub 2019 Mar 26.

Lund University, Lund, Sweden.

Metastatic melanoma is one of the most common deadly cancers, and robust biomarkers are still needed, e.g. to predict survival and treatment efficiency. Here, protein expression analysis of one hundred eleven melanoma lymph node metastases using high resolution mass spectrometry is coupled with in-depth histopathology analysis, clinical data and genomics profiles. This broad view of protein expression allowed to identify novel candidate protein markers that improved prediction of survival in melanoma patients. Some of the prognostic proteins have not been reported in the context of melanoma before, and few of them exhibit unexpected relationship to survival, which likely reflects the limitations of current knowledge on melanoma and shows the potential of proteomics in clinical cancer research.
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http://dx.doi.org/10.1038/s41598-019-41625-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435712PMC
March 2019

Clinical protein science in translational medicine targeting malignant melanoma.

Cell Biol Toxicol 2019 08 21;35(4):293-332. Epub 2019 Mar 21.

Department of Dermatology, Semmelweis University, Budapest, Hungary.

Melanoma of the skin is the sixth most common type of cancer in Europe and accounts for 3.4% of all diagnosed cancers. More alarming is the degree of recurrence that occurs with approximately 20% of patients lethally relapsing following treatment. Malignant melanoma is a highly aggressive skin cancer and metastases rapidly extend to the regional lymph nodes (stage 3) and to distal organs (stage 4). Targeted oncotherapy is one of the standard treatment for progressive stage 4 melanoma, and BRAF inhibitors (e.g. vemurafenib, dabrafenib) combined with MEK inhibitor (e.g. trametinib) can effectively counter BRAFV600E-mutated melanomas. Compared to conventional chemotherapy, targeted BRAFV600E inhibition achieves a significantly higher response rate. After a period of cancer control, however, most responsive patients develop resistance to the therapy and lethal progression. The many underlying factors potentially causing resistance to BRAF inhibitors have been extensively studied. Nevertheless, the remaining unsolved clinical questions necessitate alternative research approaches to address the molecular mechanisms underlying metastatic and treatment-resistant melanoma. In broader terms, proteomics can address clinical questions far beyond the reach of genomics, by measuring, i.e. the relative abundance of protein products, post-translational modifications (PTMs), protein localisation, turnover, protein interactions and protein function. More specifically, proteomic analysis of body fluids and tissues in a given medical and clinical setting can aid in the identification of cancer biomarkers and novel therapeutic targets. Achieving this goal requires the development of a robust and reproducible clinical proteomic platform that encompasses automated biobanking of patient samples, tissue sectioning and histological examination, efficient protein extraction, enzymatic digestion, mass spectrometry-based quantitative protein analysis by label-free or labelling technologies and/or enrichment of peptides with specific PTMs. By combining data from, e.g. phosphoproteomics and acetylomics, the protein expression profiles of different melanoma stages can provide a solid framework for understanding the biology and progression of the disease. When complemented by proteogenomics, customised protein sequence databases generated from patient-specific genomic and transcriptomic data aid in interpreting clinical proteomic biomarker data to provide a deeper and more comprehensive molecular characterisation of cellular functions underlying disease progression. In parallel to a streamlined, patient-centric, clinical proteomic pipeline, mass spectrometry-based imaging can aid in interrogating the spatial distribution of drugs and drug metabolites within tissues at single-cell resolution. These developments are an important advancement in studying drug action and efficacy in vivo and will aid in the development of more effective and safer strategies for the treatment of melanoma. A collaborative effort of gargantuan proportions between academia and healthcare professionals has led to the initiation, establishment and development of a cutting-edge cancer research centre with a specialisation in melanoma and lung cancer. The primary research focus of the European Cancer Moonshot Lund Center is to understand the impact that drugs have on cancer at an individualised and personalised level. Simultaneously, the centre increases awareness of the relentless battle against cancer and attracts global interest in the exceptional research performed at the centre.
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http://dx.doi.org/10.1007/s10565-019-09468-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6757020PMC
August 2019

The estrogen receptor coactivator AIB1 is a new putative prognostic biomarker in ER-positive/HER2-negative invasive lobular carcinoma of the breast.

Breast Cancer Res Treat 2019 Jun 22;175(2):305-316. Epub 2019 Feb 22.

Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Medicon Village, 223 81, Lund, Sweden.

Purpose: According to the 2017 St Gallen surrogate definitions of the intrinsic subtypes, Ki67, progesterone receptor (PR) and Nottingham histological grade (NHG) are used for prognostic classification of estrogen receptor (ER) positive/HER2-negative breast cancer into luminal A- or luminal B-like. The aim of the present study was to investigate if additional biomarkers, related to endocrine signaling pathways, e.g., amplified in breast cancer 1 (AIB1), androgen receptor (AR), and G protein-coupled estrogen receptor (GPER), can provide complementary prognostic information in a subset of ER-positive/HER-negative invasive lobular carcinoma (ILC).

Methods: Biomarkers from 224 patients were analyzed immunohistochemically on tissue microarray. The primary endpoint was breast cancer mortality (BCM), analyzed with 10- and 25-year follow-up (FU). In addition, the prognostic value of gene expression data for these biomarkers was analyzed in three publicly available ILC datasets.

Results: AIB1 (high vs. low) was associated to BCM in multivariable analysis (adjusted for age, tumor size, nodal status, NHG, Ki67, luminal-like classification, and adjuvant systemic therapy) with 10-year FU (HR 6.8, 95% CI 2.3-20, P = 0.001) and 25-year FU (HR 3.0, 95% CI 1.1-7.8, P = 0.03). The evidence of a prognostic effect of AIB1 could be confirmed by linking gene expression data to outcome in independent publicly available ILC datasets. AR and GPER were neither associated to BCM with 10-year nor with 25-year FU (P > 0.33). Furthermore, Ki67 and NHG were prognostic for BCM at both 10-year and 25-year FU, whereas PR was not.

Conclusions: AIB1 is a new putative prognostic biomarker in ER-positive/HER2-negative ILC.
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http://dx.doi.org/10.1007/s10549-019-05138-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533234PMC
June 2019

Estimating CDKN2A mutation carrier probability among global familial melanoma cases using GenoMELPREDICT.

J Am Acad Dermatol 2019 Aug 5;81(2):386-394. Epub 2019 Feb 5.

Department of Clinical Sciences, Lund University Hospital Lund, Sweden; Department of Surgery, Lund University Hospital, Lund, Sweden.

Background: Although rare in the general population, highly penetrant germline mutations in CDKN2A are responsible for 5%-40% of melanoma cases reported in melanoma-prone families. We sought to determine whether MELPREDICT was generalizable to a global series of families with melanoma and whether performance improvements can be achieved.

Methods: In total, 2116 familial melanoma cases were ascertained by the international GenoMEL Consortium. We recapitulated the MELPREDICT model within our data (GenoMELPREDICT) to assess performance improvements by adding phenotypic risk factors and history of pancreatic cancer. We report areas under the curve (AUC) with 95% confidence intervals (CIs) along with net reclassification indices (NRIs) as performance metrics.

Results: MELPREDICT performed well (AUC 0.752, 95% CI 0.730-0.775), and GenoMELPREDICT performance was similar (AUC 0.748, 95% CI 0.726-0.771). Adding a reported history of pancreatic cancer yielded discriminatory improvement (P < .0001) in GenoMELPREDICT (AUC 0.772, 95% CI 0.750-0.793, NRI 0.40). Including phenotypic risk factors did not improve performance.

Conclusion: The MELPREDICT model functioned well in a global data set of familial melanoma cases. Adding pancreatic cancer history improved model prediction. GenoMELPREDICT is a simple tool for predicting CDKN2A mutational status among melanoma patients from melanoma-prone families and can aid in directing these patients to receive genetic testing or cancer risk counseling.
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http://dx.doi.org/10.1016/j.jaad.2019.01.079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6634996PMC
August 2019

Interactions Between Genotype and Preoperative Statin Use Impact Clinical Outcomes Among Breast Cancer Patients.

Front Oncol 2018 12;8:428. Epub 2018 Oct 12.

Clinical Sciences in Lund, Oncology and Pathology, Lund University, Lund, Sweden.

Multiple clinical trials investigate statins' effects in breast cancer. The genotype appears to influence statin response and toxicity in the cardiovascular setting. This exploratory study aimed to investigate the interplay between preoperative statin use, genotype, and tumor-specific expression of the statin target 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) in breast cancer. Preoperative statin use, C3435T genotype, and HMGCR expression in relation to outcome were analyzed in 985 primary breast cancer patients from a population-based prospective cohort in Sweden from 2002 to 2012. Preoperative statin use ( = 80) was not associated with C3435T genotype ( = 576), HMGCR expression ( = 848), or clinical outcomes. C3435T TT-carriers had lower risk of breast cancer events than any C-carriers (adjusted hazard ratio (HR) 0.74; 95%CI 0.49, 1.12), but only in non-statin users ( = 0.042). Statin users with TT genotype had higher risk of distant metastasis (HR 4.37; 95%CI 1.20, 15.91; = 0.009) and shorter overall survival than other patients (HR 3.77; 95%CI 1.37, 10.39; = 0.019). In conclusion, there were nominally significant interactions between genotype and preoperative statin use on clinical outcomes, while preoperative statin use was not associated with outcomes. Since this is an exploratory study of the impact of the genotype in relation to statin use and clinical outcomes in the breast cancer setting, the results should be interpreted with caution and warrant replication in an independent cohort, preferably in a randomized setting. Since statin use is common in breast cancer patients, it would be of interest to further elucidate the clinical impact of the genotype in breast cancer.
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http://dx.doi.org/10.3389/fonc.2018.00428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6194198PMC
October 2018
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