Genetic Alterations among Korean Melanoma Patients Showing Tumor Heterogeneity: A Comparison between Primary Tumors and Corresponding Metastatic Lesions

213 Background: Pancreatic cancer metastasizes very early, as evidenced by the fact that > 70% of patients with operable disease ultimately develop metastases. Thus, it is likely that the molecular characteristics of primary pancreatic tumors are similar to metastatic lesions. We compared the frequency of genetic alterations and protein expression from primary vs. metastatic pancreatic tumors, and from metastases from different sites. By focusing on actionable genetic and proteomic information, we sought to explore whether targeted therapies could be tailored to patients at metastatic progression based on primary surgical material. Methods: Next generation DNA sequencing (NGS) data of 208 genes and a limited set of protein markers were analyzed from pancreatic tumors of 431 patients enrolled in the Know Your Tumor initiative. Of the 208 genes tested, mutations in 70 were considered potentially actionable based on preclinical and clinical evidence. We compared 146 primary pancreatic tumors against 285 metastatic lesions, and examined subgroups for liver vs. lung vs. other metastatic lesions. Molecular alterations were compared between independent groups for each gene/protein using Fisher’s exact test. Significance was assessed using a false discovery rate adjusted q-value threshold of 0.05. Results: No differences in the specific mutation or expression pattern were observed between primary vs. metastatic lesions, nor across the site of metastasis after correcting for multiple hypotheses. Even the proportion of actionable alterations (including mutations in the homologous recombination DNA repair pathway) was similar across subgroups. Conclusions: Comparison of the muli-omic profile of primary vs. metastatic pancreatic adenocarcinoma reveals that the molecular architecture is very similar, and that actionable alterations are identified at the same frequency. This is unlike the data observed from other solid tumors, (e.g. colon and breast cancer), in which substantial molecular discordance and heterogeneity exists between primary tumors and metastatic sites, but is consistent with the belief that primary pancreatic cancers metastasize early and thus are molecularly indistinguishable from metastatic lesions.

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Inter and intra-tumor heterogeneity of PD-L1 and MET expression in metastatic renal cell carcinoma (mRCC).

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.4569 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 4569-4569 ◽

Cited By ~ 8

Author(s):

Lisa Derosa ◽

Gwenael Le Teuff ◽

Manal Khordahi ◽

Brice Chanez ◽

Emanuelle Zalcman ◽

...

Keyword(s):

Immune Cells ◽

Primary Tumor ◽

Tumor Heterogeneity ◽

Primary Tumour ◽

Predictive Biomarkers ◽

Predictive Biomarker ◽

Clinicopathologic Characteristics ◽

Primary Tumors ◽

Paired Samples ◽

Metastatic Lesions

4569 Background: Although inhibition of PD-1/PD-L1 and MET receptors have clinical efficacy in mRCC, their expression is not a predictive biomarker. Heterogeneity between the sites of disease might be one explanation. The aim of our study was to evaluate PD-L1 and MET expression in primary and metastases (brain (BM)/pancreas (PM)) RCC lesions and their correlation with clinicopathologic characteristics. Methods: RCC specimen from different institutions were collected. Clinicopathologic characteristics were assessed by revision of samples. PD-L1 and MET expression in tumor cells (TC) and immune cells (IC) ( > 1%) were assessed by immunohistochemistry. Results: 180resected RCC specimen were successful collected (42 primary tumors and 138 metastases (87 BM/51 PM)). Overall, 22%, 51% and 23% of patients had at least one specimen expressing PD-L1 TC, IC and MET, respectively. In primary tumours, the proportion was 12%, 50% and 0%, respectively. In metastasis, the proportion of PD-L1 TC was 22% (23% in BM vs 19% in PM, p = 0.631), PD-L1 IC was 48% (47% in BM vs 49% in PM, p = 0.821) and MET was 24% (35% in BM vs 2% in PM, p < 0.001). Comparing paired samples (primary tumour and metastasis) there was discordances of PD-L1 in TC or IC and of MET expression in 30%, 27% and 24% of samples, respectively. These two first disagreements seem varied over time. The discordance in PD-L1 TC or IC and MET between primary tumor and PM (BM) was 15% (40%), 33% (22%) and 0% (67%), respectively. Some correlations were observed between MET and PD-L1 and clinicopathologic characteristics. Conclusions: In this largest analysis, evaluating heterogeneity between primary tumor and metastases (brain/pancreatic lesions) in mRCC, PD-L1 and MET expression suggests that the assessment as predictive biomarkers may require analysis of metastatic lesions. [Table: see text]

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Mutation analysis of mucosal and cutaneous melanomas during progression.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e21047 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e21047-e21047

Author(s):

Giuseppe Palmieri ◽

Maria Colombino ◽

Milena Casula ◽

Amelia Lissia ◽

Gerardo Botti ◽

...

Keyword(s):

Mucosal Melanoma ◽

Braf Mutations ◽

Driver Genes ◽

Primary Tumors ◽

Paired Samples ◽

Metastatic Lesions ◽

Tumor Tissues ◽

Melanoma Patients ◽

Metastatic Sites ◽

Next Generation Sequencing Ngs

e21047 Background: The prevalence of mutations in driver genes during progression in cutaneous and mucosal melanomas remains inconclusive. We investigated the prevalence and distribution of mutations in main candidate genes involved in melanomagenesis among different melanoma tissues using a next-generation sequencing (NGS) approach. Methods: Forty-eight tumor samples from 36 patients with mucosal melanoma (MM) and fifty-two tumor samples from 34 patients with cutaneous melanoma (CM) were collected, after obtaining patients’ written informed consent for tissue sampling. Genomic DNA was isolated from macrodissected tumor tissues containing at least 80% neoplastic cells and analyzed for mutations in 25 most common melanoma-associated oncogenes and tumor suppressor genes, using the IMI Diagnostic Melanoma Panel on the Ion Torrent platform (Life Technologies, USA). Results: A total of 100 tumor tissues from 70 melanoma patients were analyzed. BRAF mutations were detected in 21/34 (62%) CM patients and 13/36 (36%) mm patients. The second most prevalent mutations were found in K-/N-RAS (6/34; 18%) and cKIT (6/36; 17%) genes among CM and mm patients, respectively. No concomitant mutations of BRAF, RAS, and cKIT genes were detected. Among others, mutations were more frequently found in CCND1 (20%), ARID2 (16%), and NF1(12%) genes, considering the entire series of patients. Vast majority of patients who had paired samples of primary and secondary melanomas showed consistent mutation patterns between primary tumors and metastatic lesions. Similar frequencies of mutations in driver genes were seen across metastatic sites. Conclusions: In the era of targeted therapies, assessment of the spectrum and distribution of mutations in main molecular targets among patients with melanoma is needed. Our findings about the prevalence of mutations in driver genes in paired tumor lesions from patients with cutaneous and mucosal melanoma may be useful in the management of such diseases. The Italian Melanoma Intergroup (IMI) includes the following additional members who participated as investigators in this study: Mario Mandalà, Paola Queirolo, Ignazio Stanganelli, Vanna Chiarion Sileni, Pietro Quaglino, Anna Maria Di Giacomo.

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Genetic Determinants for Prediction of Outcome of Patients with Papillary Thyroid Carcinoma

Cancers ◽

10.3390/cancers13092048 ◽

2021 ◽

Vol 13 (9) ◽

pp. 2048

Author(s):

Antónia Afonso Póvoa ◽

Elisabete Teixeira ◽

Maria Rosa Bella-Cueto ◽

Rui Batista ◽

Ana Pestana ◽

...

Keyword(s):

Papillary Thyroid Carcinoma ◽

Thyroid Carcinoma ◽

Patient Outcomes ◽

Genetic Alterations ◽

Papillary Thyroid ◽

Tissue Samples ◽

Primary Tumors ◽

Persistent Disease ◽

Increased Risk ◽

Structural Disease

Papillary thyroid carcinoma (PTC) usually presents an excellent prognosis, but some patients present with aggressive metastatic disease. BRAF, RAS, and TERT promoter (TERTp) genes are altered in PTC, and their impact on patient outcomes remains controversial. We aimed to determine the role of genetic alterations in PTC patient outcomes (recurrent/persistent disease, structural disease, and disease-specific mortality (DSM)). The series included 241 PTC patients submitted to surgery, between 2002–2015, in a single hospital. DNA was extracted from tissue samples of 287 lesions (primary tumors and metastases). Molecular alterations were detected by Sanger sequencing. Primary tumors presented 143 BRAF, 16 TERTp, and 13 RAS mutations. Isolated TERTpmut showed increased risk of structural disease (HR = 7.0, p < 0.001) and DSM (HR = 10.1, p = 0.001). Combined genotypes, BRAFwt/TERTpmut (HR = 6.8, p = 0.003), BRAFmut/TERTpmut (HR = 3.2, p = 0.056) and BRAFmut/TERTpwt (HR = 2.2, p = 0.023) showed increased risk of recurrent/persistent disease. Patients with tumors BRAFwt/TERTpmut (HR = 24.2, p < 0.001) and BRAFmut/TERTpmut (HR = 11.5, p = 0.002) showed increased risk of structural disease. DSM was significantly increased in patients with TERTpmut regardless of BRAF status (BRAFmut/TERTpmut, log-rank p < 0.001; BRAFwt/TERTpmut, log-rank p < 0.001). Our results indicate that molecular markers may have a role in predicting PTC patients’ outcome. BRAFmut/TERTpwt tumors were prone to associate with local aggressiveness (recurrent/persistent disease), whereas TERTpmut tumors were predisposed to recurrent structural disease and DSM.

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Real-life use of talimogene laherparepvec (T-VEC) in melanoma patients in centers in Austria, Switzerland and Germany

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-001701 ◽

2021 ◽

Vol 9 (2) ◽

pp. e001701

Author(s):

Julia Maria Ressler ◽

Matthias Karasek ◽

Lukas Koch ◽

Rita Silmbrod ◽

Joanna Mangana ◽

...

Keyword(s):

Chart Review ◽

Progressive Disease ◽

Overall Response Rate ◽

Real Life ◽

Retrospective Chart Review ◽

Distant Metastases ◽

Complete Response ◽

Talimogene Laherparepvec ◽

Metastatic Lesions ◽

Melanoma Patients

BackgroundTalimogene laherparepvec (T-VEC) is a licensed therapy for use in melanoma patients of stage IIIB-IVM1a with injectable, unresectable metastatic lesions in Europe. Approval was based on the Oncovex Pivotal Trial in Melanoma study, which also included patients with distant metastases and demonstrated an overall response rate (ORR) of 40.5% and a complete response (CR) rate of 16.6%.ObjectivesThe aim of this study was to assess the outcome of melanoma patients treated with T-VEC in a real-life clinical setting.MethodsBased on data from 10 melanoma centers in Austria, Switzerland and southern Germany, we conducted a retrospective chart review, which included 88 patients (44 male, 44 female) with a median age of 72 years (range 36–95 years) treated with T-VEC during the period from May 2016 to January 2020.Results88 patients fulfilled the inclusion criteria for analysis. The ORR was 63.7%. 38 patients (43.2%) showed a CR, 18 (20.5%) had a partial response, 8 (9.1%) had stable disease and 24 (27.3%) patients had a progressive disease. The median treatment period was 19 weeks (range: 1–65), an average of 11 doses (range: 1–36) were applied. 39 (45.3%) patients developed adverse events, mostly mild, grade I (64.1%).ConclusionThis real-life cohort treatment with T-VEC showed a high ORR and a large number of durable CRs.

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Metastatic heterogeneity of the consensus molecular subtypes of colorectal cancer

npj Genomic Medicine ◽

10.1038/s41525-021-00223-7 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Peter W. Eide ◽

Seyed H. Moosavi ◽

Ina A. Eilertsen ◽

Tuva H. Brunsell ◽

Jonas Langerud ◽

...

Keyword(s):

Gene Expression ◽

Colorectal Cancer ◽

Principal Components ◽

Prognostic Value ◽

Tumor Heterogeneity ◽

Molecular Subtypes ◽

R Package ◽

Data Set ◽

Primary Tumors ◽

External Data

AbstractGene expression-based subtypes of colorectal cancer have clinical relevance, but the representativeness of primary tumors and the consensus molecular subtypes (CMS) for metastatic cancers is not well known. We investigated the metastatic heterogeneity of CMS. The best approach to subtype translation was delineated by comparisons of transcriptomic profiles from 317 primary tumors and 295 liver metastases, including multi-metastatic samples from 45 patients and 14 primary-metastasis sets. Associations were validated in an external data set (n = 618). Projection of metastases onto principal components of primary tumors showed that metastases were depleted of CMS1-immune/CMS3-metabolic signals, enriched for CMS4-mesenchymal/stromal signals, and heavily influenced by the microenvironment. The tailored CMS classifier (available in an updated version of the R package CMScaller) therefore implemented an approach to regress out the liver tissue background. The majority of classified metastases were either CMS2 or CMS4. Nonetheless, subtype switching and inter-metastatic CMS heterogeneity were frequent and increased with sampling intensity. Poor-prognostic value of CMS1/3 metastases was consistent in the context of intra-patient tumor heterogeneity.

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Antigenic and Genotypic Similarity between Primary Glioblastomas and Their Derived Neurospheres

Journal of Oncology ◽

10.1155/2011/314962 ◽

2011 ◽

Vol 2011 ◽

pp. 1-16 ◽

Cited By ~ 14

Author(s):

Valentina Caldera ◽

Marta Mellai ◽

Laura Annovazzi ◽

Angela Piazzi ◽

Michele Lanotte ◽

...

Keyword(s):

Stem Cells ◽

Genetic Alterations ◽

Tumor Stem Cells ◽

Primary Tumors ◽

Immunodeficient Mice ◽

Brain Tumor Stem Cells ◽

Tumor Phenotype ◽

Fetal Bovine ◽

Primary Glioblastomas

Formation of neurospheres (NS) in cultures of glioblastomas (GBMs), with self-renewal, clonogenic capacities, and tumorigenicity following transplantation into immunodeficient mice, may denounce the existence of brain tumor stem cells (BTSCs) in vivo. In sixteen cell lines from resected primary glioblastomas, NS showed the same genetic alterations as primary tumors and the expression of stemness antigens. Adherent cells (AC), after adding 10% of fetal bovine serum (FBS) to the culture, were genetically different from NS and prevailingly expressed differentiation antigens. NS developed from a highly malignant tumor phenotype with proliferation, circumscribed necrosis, and high vessel density. Beside originating from transformed neural stem cells (NSCs), BTSCs may be contained within or correspond to dedifferentiated cells after mutation accumulation, which reacquire the expression of stemness antigens.

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