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Biogeography of Australasia
Over the last decade, molecular studies carried out on the Australasian biota have revealed a new world of organic structure that exists from submicroscopic to continental scale. Furthermore, in studies of global biogeography and evolution, DNA sequencing has shown that many large groups, such as flowering plants, passerine birds and squamates, have their basal components in this area. Using examples ranging from kangaroos and platypuses to kiwis and birds of paradise, the book examines the patterns of distribution and evolution of Australasian biodiversity and explains them with reference to tectonic and climatic change in the region. The surprising results from molecular biogeography demonstrate that an understanding of evolution in Australasia is essential for understanding the development of modern life on Earth. A milestone in the literature on this subject, this book will be a valuable source of reference for students and researchers in biogeography, biodiversity, ecology and conservation.
eBook
Pulmonary Large-Cell Neuroendocrine Carcinoma: Therapeutic Challenges and Opportunities
Pulmonary large cell neuroendocrine carcinoma (P-LCNEC) is a rare, poorly differentiated, non-small cell malignancy within the spectrum of neuroendocrine tumors (NETs) of the lung. Despite sharing several similarities with small cell lung cancer (SCLC) in their clinical, immunohistopathological, genomic, and prognostic features, it is a distinct and biologically heterogeneous entity with challenging diagnostic and therapeutic requirements. Given the lack of prospective, randomized data to guide management, it is common practice to pursue thoracic surgery for resectable tumors according to the guidelines for non-small cell lung cancer (NSCLC) and implement systemic chemotherapy as early as at stage I, similar to the treatment of SCLC. However, important issues, such as the optimal timing and combination of therapeutic modalities, the most effective type of chemotherapy for advanced-stage disease, and the benefit from prophylactic cranial irradiation, remain debated. Accumulating evidence from retrospective, molecular profiling studies supports the existence of at least two P-LCNEC subtypes, most notably a SCLC-like and a NSCLC-like phenotype, which presumably underlie the observed differential sensitivity to platinum-based regimens and warrant further validation as predictive biomarkers of efficacy. Furthermore, several potentially actionable, driver molecular alterations have been identified, offering implications for personalized treatment approaches, including targeted therapies and immunotherapy. The current review discusses open questions on the diagnosis and management of P-LCNEC, as well as recent advances in its genomic and transcriptomic characterization that create promising therapeutic opportunities.
Journal Article
Genetic alterations of malignant pleural mesothelioma: association with tumor heterogeneity and overall survival
Development of precision medicine for malignant pleural mesothelioma (MPM) requires a deep knowledge of tumor heterogeneity. Histologic and molecular classifications and histo‐molecular gradients have been proposed to describe heterogeneity, but a deeper understanding of gene mutations in the context of MPM heterogeneity is required and the associations between mutations and clinical data need to be refined. We characterized genetic alterations on one of the largest MPM series (266 tumor samples), well annotated with histologic, molecular and clinical data of patients. Targeted next‐generation sequencing was performed focusing on the major MPM mutated genes and the TERT promoter. Molecular heterogeneity was characterized using predictors allowing classification of each tumor into the previously described molecular subtypes and the determination of the proportion of epithelioid‐like and sarcomatoid‐like components (E/S.scores). The mutation frequencies are consistent with literature data, but this study emphasized that TERT promoter, not considered by previous large sequencing studies, was the third locus most affected by mutations in MPM. Mutations in TERT promoter, NF2, and LATS2 were more frequent in nonepithelioid MPM and positively associated with the S.score. BAP1, NF2, TERT promoter, TP53, and SETD2 mutations were enriched in some molecular subtypes. NF2 mutation rate was higher in asbestos unexposed patient. TERT promoter, NF2, and TP53 mutations were associated with a poorer overall survival. Our findings lead to a better characterization of MPM heterogeneity by identifying new significant associations between mutational status and histologic and molecular heterogeneity. Strikingly, we highlight the strong association between new mutations and overall survival.
Our comprehensive genetic characterization of key‐altered genes including TERT promoter in malignant pleural mesothelioma led to the identification of new significant associations between the mutational status and the histological and molecular classifications. Our findings allow a better understanding of the genetic landscape in the context of tumor heterogeneity and highlight the high prognostic value of gene mutations in mesothelioma.
Journal Article
Prognostic Biomarker of Fertility‐Preserving Hormonal Therapy Based on Multigene Panel Testing for Endometrial Cancer
In this study, we identified prognostic biomarkers that predict treatment outcome in patients receiving fertility‐preserving high‐dose medroxyprogesterone acetate (MPA) therapy through comprehensive multigene panel testing. A total of 38 patients (20 atypical endometrial hyperplasia and 18 stage IA G1 without myometrial invasion) who received first‐line MPA therapy were enrolled. Genomic DNA was extracted from formalin‐fixed paraffin‐embedded samples, and PleSSision‐Rapid multigene panel testing was performed. Of the 38 patients, 31 (82%) achieved complete response (CR), 2 (5%) had stable disease (SD), and 5 (13%) had progressive disease (PD) following initial treatment. The median duration to achieve tumor disappearance was 7 months (range: 4–14 months). Following initial treatment, 25 of 32 patients (78%) experienced recurrence, with a median recurrence‐free survival (RFS) of 21 months (range: 2–84 months). The most frequently observed actionable gene mutations were PTEN (68.4%), CTNNB1 (55.2%), and PIK3CA (33.3%). Patients harboring PTEN mutations in EMG1 required a significantly longer duration to achieve tumor disappearance ( p = 0.011). In addition, the presence of PIK3CA mutations in AEH was significantly associated with shorter RFS ( p = 0.048). Molecular classification identified 34 patients (89%) with no specific molecular profile (NSMP), 1 patient (3%) with POLE mutation, and 3 patients (8%) with deficient mismatch repair (d‐MMR). Most patients undergoing MPA therapy were classified as having NSMP. Genetic alterations, specifically mutations in PTEN and PIK3CA , were significantly associated with treatment outcomes, highlighting their potential as prognostic biomarkers.
Journal Article
Dissection of gastric cancer heterogeneity for precision oncology
Gastric cancer (GC) remains the fifth most prevalent cancer worldwide and the third leading cause of global cancer mortality. Comprehensive ‐omic studies have unveiled a heterogeneous GC landscape, with considerable molecular diversity both between and within tumors. Given the complex nature of GC, a long‐sought goal includes effective identification of distinct patient subsets with prognostic and/or predictive outcomes to enable tailoring of specific treatments (“precision oncology”). In this review, we highlight various approaches to molecular classification in GC, covering recent genomic, transcriptomic, proteomic and epigenomic features. We pay special attention to the translational significance of classifier systems and examine potential confounding factors which deserve further investigation. In particular, we discuss recent advancements in our knowledge of intra‐subtype, intra‐patient and intra‐tumor heterogeneity, and the pivotal role of the tumor stromal microenvironment.
Gastric cancer (GC) is a highly heterogeneous disease. This review consolidates the latest developments in the molecular classification of GC, with a keen examination of their translational utility. Furthermore, we pay special attention to the role of tumor heterogeneity and the stromal microenvironment in this era of precision oncology.
Journal Article
Transcriptome-based molecular subtypes and differentiation hierarchies improve the classification framework of acute myeloid leukemia
The current classification of acute myeloid leukemia (AML) relies largely on genomic alterations. Robust identification of clinically and biologically relevant molecular subtypes from nongenomic high-throughput sequencing data remains challenging. We established the largest multicenter AML cohort (n = 655) in China, with all patients subjected to RNA sequencing (RNA-Seq) and 619 (94.5%) to targeted or whole-exome sequencing (TES/WES). Based on an enhanced consensus clustering, eight stable gene expression subgroups (G1–G8) with unique clinical and biological significance were identified, including two unreported (G5 and G8) and three redefined ones (G4, G6, and G7). Apart from four well-known low-risk subgroups including PML::RARA (G1), CBFB::MYH11 (G2), RUNX1::RUNX1T1 (G3), biallelic CEBPA mutations or -like (G4), four meta-subgroups with poor outcomes were recognized. The G5 (myelodysplasia-related/-like) subgroup enriched clinical, cytogenetic and genetic features mimicking secondary AML, and hotspot mutations of IKZF1 (p.N159S) (n = 7). In contrast, most NPM1 mutations and KMT2A and NUP98 fusions clustered into G6–G8, showing high expression of HOXA/B genes and diverse differentiation stages, from hematopoietic stem/progenitor cell down to monocyte, namely HOX-primitive (G7), HOX-mixed (G8), and HOX-committed (G6). Through constructing prediction models, the eight gene expression subgroups could be reproduced in the Cancer Genome Atlas (TCGA) and Beat AML cohorts. Each subgroup was associated with distinct prognosis and drug sensitivities, supporting the clinical applicability of this transcriptome-based classification of AML. These molecular subgroups illuminate the complex molecular network of AML, which may promote systematic studies of disease pathogenesis and foster the screening of targeted agents based on omics.
Journal Article
The biology of uveal melanoma
Uveal melanoma (UM), a rare cancer of the eye, is distinct from cutaneous melanoma by its etiology, the mutation frequency and profile, and its clinical behavior including resistance to targeted therapy and immune checkpoint blockers. Primary disease is efficiently controlled by surgery or radiation therapy, but about half of UMs develop distant metastasis mostly to the liver. Survival of patients with metastasis is below 1 year and has not improved in decades. Recent years have brought a deep understanding of UM biology characterized by initiating mutations in the G proteins GNAQ and GNA11. Cytogenetic alterations, in particular monosomy of chromosome 3 and amplification of the long arm of chromosome 8, and mutation of the BRCA1-associated protein 1, BAP1, a tumor suppressor gene, or the splicing factor SF3B1 determine UM metastasis. Cytogenetic and molecular profiling allow for a very precise prognostication that is still not matched by efficacious adjuvant therapies. G protein signaling has been shown to activate the YAP/TAZ pathway independent of HIPPO, and conventional signaling via the mitogen-activated kinase pathway probably also contributes to UM development and progression. Several lines of evidence indicate that inflammation and macrophages play a pro-tumor role in UM and in its hepatic metastases. UM cells benefit from the immune privilege in the eye and may adopt several mechanisms involved in this privilege for tumor escape that act even after leaving the niche. Here, we review the current knowledge of the biology of UM and discuss recent approaches to UM treatment.
Journal Article
Are We Ready to Implement Molecular Subtyping of Bladder Cancer in Clinical Practice? Part 1: General Issues and Marker Expression
Bladder cancer (BC) is a heterogeneous disease with highly variable clinical and pathological features, and resulting in different outcomes. Such heterogeneity ensues from distinct pathogenetic mechanisms and may consistently affect treatment responses in single patients. Thus, over the last few years, several groups have developed molecular classification schemes for BC, mainly based on their mRNA expression profiles. A “consensus” classification has recently been proposed to combine the published systems, agreeing on a six-cluster scheme with distinct prognostic and predictive features. In order to implement molecular subtyping as a risk-stratification tool in routine practice, immunohistochemistry (IHC) has been explored as a readily accessible, relatively inexpensive, standardized surrogate method, achieving promising results in different clinical settings. The first part of this review deals with the steps resulting in the development of a molecular subtyping of BC, its prognostic and predictive implications, and the main features of immunohistochemical markers used as surrogates to stratify BC into pre-defined molecular clusters.
Journal Article
From Dukes-MAC Staging System to Molecular Classification: Evolving Concepts in Colorectal Cancer
This historical review aimed to summarize the main changes that colorectal carcinoma (CRC) staging systems suffered over time, starting from the creation of the classical Duke’s classification, modified Astler–Coller staging, internationally used TNM (T—primary tumor, N—regional lymph nodes’ status, M—distant metastases) staging system, and ending with molecular classifications and epithelial–mesenchymal transition (EMT) concept. Besides currently used staging parameters, this paper briefly presents the author’s contribution in creating an immunohistochemical (IHC)-based molecular classification of CRC. It refers to the identification of three molecular groups of CRCs (epithelial, mesenchymal and hybrid) based on the IHC markers E-cadherin, β-catenin, maspin, and vimentin. Maspin is a novel IHC antibody helpful for tumor budding assessment, which role depends on its subcellular localization (cytoplasm vs. nuclei). The long road of updating the staging criteria for CRC has not come to an end. The newest prognostic biomarkers, aimed to be included in the molecular classifications, exert predictive roles, and become more and more important for targeted therapy decisions.
Journal Article