Heterogeneity of monosomy 3 in fine needle aspiration biopsy of choroidal melanoma.

PurposeTo report on the heterogeneity of monosomy 3 in a fine needle aspiration biopsy obtained transsclerally from choroidal melanoma for prognosis.MethodsAll clinical records for patients who had been diagnosed with choroidal melanoma and underwent iodine-125 plaque brachytherapy with intraoperative transscleral fine needle aspiration biopsy from January 2005 to August 20, 2011, and who had a positive result for monosomy 3 according to fluorescence in situ hybridization as reported by clinical cytogenetics testing were collected. Patient age and sex, total number of cells evaluated and number of cells positive for monosomy 3, tumor size, and metastatic outcome were recorded for each patient.ResultsA positive result for monosomy 3 was reported in 93 patients who underwent transscleral fine needle aspiration biopsy. Two patients were lost to follow-up immediately post-operatively, and the remaining 91 patients were included in this study. The mean number of cells evaluated in the biopsy was 273 (range 28 to 520). The mean percentage of cells positive for monosomy 3 was 62.9% (range 4.7%-100%). The mean tumor height was 5.91 mm (range 1.99 to 10.85 mm). Larger tumors were associated with a higher percentage of cells positive for monosomy 3. During the average follow-up interval of 28.9 months (range 3-76 months), choroidal melanoma metastasis developed in 18 (20%) patients. Patients whose tumors had 1%-33% of cells positive for monosomy 3 had a significantly lower risk of metastasis-related death compared to patients whose tumors harbored a higher percentage of monosomy 3 (p = 0.04).ConclusionsCytogenetic heterogeneity of fluorescent in situ hybridization for monosomy 3 exists in a biopsy sample. Larger tumors were more likely to have a higher percentage of monosomy 3 positive cells in the sample. Furthermore, patients whose tumors had more than 33% of cells positive for monosomy 3 had a poorer prognosis than patients whose tumors had lower percentages of monosomy 3

Genomic Alteration Burden in Advanced Prostate Cancer and Therapeutic Implications.

The increasing number of patients with sequenced prostate cancer genomes enables us to study not only individual oncogenic mutations, but also capture the global burden of genomic alterations. Here we review the extent of tumor genome mutations and chromosomal structural variants in various clinical states of prostate cancer, and the related prognostic information. Next, we discuss the underlying mutational processes that give rise to these various alterations, and their relationship to the various molecular subtypes of prostate cancer. Finally, we examine the relationships between the tumor mutation burden of castration-resistant prostate cancer, DNA repair defects, and response to immune checkpoint inhibitor therapy

Targeting Oncogenic BRAF: Past, Present, and Future.

Identifying recurrent somatic genetic alterations of, and dependency on, the kinase BRAF has enabled a "precision medicine" paradigm to diagnose and treat BRAF-driven tumors. Although targeted kinase inhibitors against BRAF are effective in a subset of mutant BRAF tumors, resistance to the therapy inevitably emerges. In this review, we discuss BRAF biology, both in wild-type and mutant settings. We discuss the predominant BRAF mutations and we outline therapeutic strategies to block mutant BRAF and cancer growth. We highlight common mechanistic themes that underpin different classes of resistance mechanisms against BRAF-targeted therapies and discuss tumor heterogeneity and co-occurring molecular alterations as a potential source of therapy resistance. We outline promising therapy approaches to overcome these barriers to the long-term control of BRAF-driven tumors and emphasize how an extensive understanding of these themes can offer more pre-emptive, improved therapeutic strategies

The potential for liquid biopsies in the precision medical treatment of breast cancer.

Currently the clinical management of breast cancer relies on relatively few prognostic/predictive clinical markers (estrogen receptor, progesterone receptor, HER2), based on primary tumor biology. Circulating biomarkers, such as circulating tumor DNA (ctDNA) or circulating tumor cells (CTCs) may enhance our treatment options by focusing on the very cells that are the direct precursors of distant metastatic disease, and probably inherently different than the primary tumor's biology. To shift the current clinical paradigm, assessing tumor biology in real time by molecularly profiling CTCs or ctDNA may serve to discover therapeutic targets, detect minimal residual disease and predict response to treatment. This review serves to elucidate the detection, characterization, and clinical application of CTCs and ctDNA with the goal of precision treatment of breast cancer

Genomic landscape of uveal melanoma

Uveal melanoma (UM) is the most common cancer of the adult eye which can manifest as a highly aggressive form approximately half of the time. Here a comprehensive landscape of genetic alterations in UMs is described. It was identified by integrating copy number alterations (CNAs), and transcriptomic and whole exome sequencing data from 207 primary UMs. Focal copy number analysis with the GISTIC algorithm refined the boundaries of chromosomal segments with chromosomal gains or losses and candidate cancer genes within these segments were identified. Chromosome 8q24.3 was the region most frequently amplified in UMs, being detected in 72% of tumours. A comparison of focal copy gains and losses with that described by a pan-cancer study revealed Plectin 1 as a candidate gene within the 8q24.3 amplicon. Integration of copy number and transcriptomic data also revealed enrichment of genes within pathways leading to activation of NF-kappa B, WNT signaling and RNA splicing. Using a complementary bioinformatics approach, additional novel mutations in known dominant UM driver genes (GNAQ, GNA11, BAP1, SF3B1, EIFIAX and CYSLTR2) were identified and an accurate estimate of the frequencies of mutations in each gene were obtained. Finally, integration of data obtained from CNAs with mutational and transcriptome data reveled homozygous deletions, protein damaging mutations and gene fusions that targeted chromatin modifiers, and specifically genes encoding components of the human SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex. Genes from the BAF complex (ARID1A and ARID1B) and the PBAF complex (PHF10) were subjected to functional loss through CNAs, gene fusions and mutations. Two of these chromatin modifiers (ARID1B and PHF10) map to chromosome 6q whose loss is associated with metastasis in a subset of UMs, and an ARID1B fusion is found in a tumour with a BAP1 mutation that subsequently underwent metastasis. In conclusion, this study provides a comprehensive overview of the landscape of genomic alterations in UM, identifying candidate genes in regions of CNAs and providing further insights into the altered pathways of tumour development and progression.Open Acces