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This collection, collated by the cancer editorial community of Nature Research journals, presents Research Articles, Reviews,and Disease Primers & PrimeViews across a wide range of rare cancer types, from preclinical and translational work to clinical research. Rare cancers can be defined as cancers with a prevalence of fewer than 5 cases per 100,000 people. These cancers pose particular challenges for researchers, but innovations and advances are discovered daily and here we focus on highlighting the breadth and depth of the research currently taking place across the globe to advance our understanding of these rare cancers.
Simultaneous activation of Wnt and Shh pathways in murine neural precursor cells results in the formation of embryonal tumors with multilayered rosettes (ETMR) that recapitulate the histological and molecular features of human tumors. This novel mouse model represents a platform for evaluating therapeutic approaches for this rare malignant pediatric brain tumor, and provides novel insights into the cell of origin and molecular mechanisms driving the disease.
Chordoma is a rare often incurable malignant bone tumour. Here, the authors investigate driver mutations of sporadic chordoma in 104 cases, revealing duplications in notochordal transcription factor brachyury (T), PI3K signalling mutations, and mutations in LYST, a potential novel cancer gene in chordoma.
Small molecules that perturb chromatin proteins are an emerging focus of current biomedical research. Two groups reporting in this issue have targeted bromodomain-containing BET proteins that bind acetylated lysine residues during gene activation, arriving at cell-permeable small molecule compounds with similar structures based on fused triazole-diazepine rings. James Bradner and colleagues report the development of a compound named JQ1. The BET protein BRD4, with two bromodomains, is implicated in human squamous cell carcinoma. JQ1 inhibits the growth of BRD4-dependent tumours in mouse models. Alexander Tarakhovsky and colleagues' inhibitor, I-BET, is shown to interfere with the binding of certain BET family members to acetylated histones. It inhibits activation of pro-inflammatory genes in macrophages and has immunomodulatory activity in a mouse model of inflammatory disease.
Pineoblastoma is a highly aggressive and rare childhood brain cancer, and the genetic drivers of sporadic pineoblastoma are unknown. Here, the authors genomically interrogated pediatric and adult pineoblastomas and found novel variants including recurrent homozygous deletions of DROSHA.
Jaroslaw Maciejewski, Seishi Ogawa and colleagues examine the clonal dynamics of myelodysplastic syndromes (MDS) by analyzing whole-exome and targeted sequencing data from a large patient collection. They find that progression steps previously defined by pathologic criteria are accompanied by distinct molecular changes, and they show that driver genes can be classified into molecular subtypes differentially associated with low-risk MDS, high-risk MDS or secondary acute myeloid leukemia.
Chordoid glioma is a rare low-grade brain tumor that originates from the anterior wall of the third ventricle where surgical resection is challenging; the clinical outcome of patients after subtotal resection or disease recurrence is poor. Here the authors identify a recurrent missense mutation in PRKCA that may serve as a potential therapeutic target in this uncommon brain cancer.
Genomic and functional analysis of intratumor heterogeneity in pediatric glioma uncovers early clonal divergence and stable spontaneous cooperation between subclonal populations throughout tumor evolution.
Sebaceous carcinomas (SeC) are cutaneous malignancies that sometimes metastasize and cause death. Here the authors perform whole-exome sequencing on 32 SeC and report distinct mutational classes that may explain cancer ontogeny and clinical outcome.
High levels of fumarate or succinate suppress the homologous-recombination DNA-repair pathway in cancer cells that are deficient for FH or SDH, respectively. These tumor cells are vulnerable to PARP inhibitors.
Hepatocellular-cholangiocarcinoma (H-ChC) is a rare subtype of liver cancer with features of hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Here, the authors utilize whole exome sequencing to highlight the monoclonal origin and stemness of H-ChC, as well as substantial intratumoral heterogeneity.
DNA methylation sequencing and bioinformatic analyses uncover an epigenetic disease spectrum in Ewing sarcoma. These characteristic epigenome patterns correlate with state of differentiation and disease aggressiveness, and pave the way for the development of biomarkers.
Elizabeth Perlman and colleagues use genome-wide sequencing, RNA expression, DNA copy number and methylation analyses to characterize the genomic landscape of Wilms tumors. Their integrated analyses implicate two major classes of genetic changes in Wilms tumors that preserve the progenitor state and/or interrupt normal kidney development.
Adult-type granulosa cell tumors of the ovary (aGCTs) are rare and recurrence is difficult to treat. Here, the authors observe in aGCT a novel recurrent somatic truncating mutation of KMT2D, more frequent in recurrent aGCT, and also non-genetic loss of KMT2D expression.
Leila Valanejad et al. report increased expression of modified tumor suppressor proteins (TSPs) with loss of tumor suppressor activity in aggressive, chemotherapy-resistant hepatoblastoma. They find that TSP upregulation occurs via PARP1-mediated chromatin remodeling, leading to activation of multiple cancer-associated pathways.
Franco Locatelli, Dirk Reinhardt, Marry van den Heuvel-Eibrink, C Michel Zwaan, Maarten Fornerod, Tanja Gruber and colleagues report whole-exome and transcriptome sequencing of acute megakaryoblastic leukemia from pediatric and adult patients without Down syndrome (non-DS-AMKL). They find that pediatric non-DS-AMKL can be divided into seven subgroups characterized by chimeric oncogenes with cooperating mutations in epigenetic and kinase signaling genes.
Male breast cancer (MBC) is rare and largely hormonally driven. Here, the authors examine the action of steroid hormone receptors in male and female breast cancers and find gender selective hormone receptor action that associates with the survival of MBC patients.
Granular cell tumors (GCTs) are rare tumors that arise in multiple anatomical locations. Here, the authors investigate the genomics of GCTs, finding inactivating somatic mutations in ATP6AP1 or ATP6AP2 in 72% of the 82 GCTs analyzed. In vitro manipulation of these genes recapitulated GCT phenotypes in cellular models.
Multiregional analysis in 54 childhood cancers highlights four evolutionary patterns of intratumoral variation. Multiple patterns are often found in the same tumor, suggesting that tumors follow different evolutionary strategies concurrently.
Adrenocortical cancer (ACC) is a rarely diagnosed and aggressive cancer whose metastatic form has been scarcely studied. Here, the authors study primary and metastatic ACC to investigate genomic heterogeneity, discovering higher mutation rates in metastatic lesions and novel recurrent mutations.
Tuberous sclerosis complex (TSC) is a rare genetic disease causing multisystem tumour growth. Here the authors analyse 111 TSC-associated tissues for TSC1/TSC2 status, DNA mutations, copy number aberrations, differential gene expression and DNA methylation patterns providing a comprehensive genomic landscape.
Adenomyoepithelioma is a rare tumor of the breast with an unknown genetic basis. Here the authors perform a genomic analysis of adenomyoepitheliomas revealing that their repertoire of somatic mutations vary according to the estrogen receptor (ER) status, and that ER-negative tumors harbor recurrent mutations in HRAS and PI3K pathway genes.
Although anaplastic thyroid carcinoma (ATC) is a rare form of thyroid cancer, the limited efficacy of conventional treatment options and challenges in histological diagnosis make this an almost invariably lethal disease. In this Review, the authors describe the clinical and pathological features of ATC, highlight recent advances in uncovering the genetics and molecular biology of this disease, and discuss both conventional and future treatment modalities.
This Review describes our current understanding of the relationship between genotype and phenotype in myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) and discusses how this knowledge could be used to inform strategies to develop more effective treatments and improve clinical success.
Cholangiocarcinoma, the second most common form of liver cancer after hepatocellular carcinoma, is a heterogeneous disease entity with a near-universal poor prognosis. Our understanding of the epidemiology and biology of cholangiocarcinoma is increasing, and importantly, potentially actionable molecular and immunological targets for novel therapies are increasingly being identified. Herein, the evolving developments in the epidemiology, pathogenesis, and management of cholangiocarcinoma are reviewed.
Osteosarcoma typically occurs during the adolescent growth spurt and is the most common primary cancer of bone. Here, Sharon A. Savage and colleagues discuss how advances in germline and somatic genetics, tumour biology and animal models have enhanced our understanding of osteosarcoma aetiology and could lead to new therapeutic approaches to treat the disease.
Gastrointestinal malignancies are among the most common human cancers. Genomic and transcriptomic analyses have identified recurring molecular subtypes that suggest important biological differences. Here, the authors review the common themes of gastrointestinal cancer subtypes, as well as how they could be implemented into clinical practice.
The Renal Tumour Study Group of the International Society of Paediatric Oncology (SIOP–RTSG) has developed a new protocol for the diagnosis and treatment of childhood renal tumours, the UMBRELLA SIOP–RTSG 2016 (the UMBRELLA protocol). In this Consensus Statement, members of SIOP–RTSG outline the rationale for the recommendations in the protocol.
Marry M. van den Heuvel-Eibrink,
Janna A. Hol ⋯
on behalf of the International Society of Paediatric Oncology — Renal Tumour Study Group (SIOP–RTSG)
Although the aggressive underlying biology of inflammatory breast cancer (IBC) remains largely undefined, the tumour microenvironment (TME) has emerged as a key contributor. This Review discusses intrinsic characteristics of IBC, extrinsic features of the TME and intrinsic–extrinsic communication.
Patients with sarcomas have historically been treated with surgery and/or chemotherapy, although the outcomes achieved with these approaches, especially in advanced-stage disease, are often disappointing. In this Review, the authors describe the opportunities created by selective use of targeted therapies on the basis of the biological characteristics of individual tumours.
Our understanding of mesothelioma pathobiology has increased dramatically in the past 5 years, with an improvement in our knowledge of mesothelioma genetics, epigenetics, tumour microenvironment and immunobiology. This Review discusses these advances and how they might affect therapeutic strategies.
Approximately half of patients diagnosed with oesophageal cancer have metastatic or unresectable disease. Here, the authors discuss the multidisciplinary interventions available to manage dysphagia, improve quality of life and prolong survival in these individuals.
Ginzburg et al. review the evolving role of focal ablative therapies in the management of small renal masses. They describe the techniques, the role of image guidance, pretreatment biopsy, and post-treatment surveillance, as well as data on safety, oncological, and functional outcomes.
Childhood-onset craniopharyngioma is a rare embryonic tumour of low-grade malignancy that has traditionally been treated by radical resection. Here, Müller and colleagues review recent advances in the molecular pathogenesis of the disease and treatment strategies that could lead to novel targeted therapies and more-limited surgeries.
Therapy-related myeloid neoplasms occur as a late complication following chemotherapy and/or radiotherapy administered for a primary condition. In this Review, McNerneyet al. discuss recent studies that have improved our understanding of the aetiology of this disease.
The treatment of pancreatic neuroendocrine tumours (PNETs) in patients with multiple endocrine neoplasia type 1 (MEN1) is challenging. Here, Thakker and colleagues discuss the current and emerging therapies to treat PNETs in patients with or without MEN1.
Despite the considerable detrimental effects associated with penectomy, squamous cell carcinoma (SCC) of the penis is most commonly treated with surgery. However, SCC at other locations can be successfully managed using chemotherapy and radiation. Here, Jonathan Tward makes a case for organ-sparing treatments for penile cancer, based on data from treatment of SCC at other body sites.
Gastric cancer is a deadly malignancy and accumulating evidence suggests that epigenetic abnormalities promote carcinogenesis. Here, the authors summarize the gastric cancer epigenome, highlighting key advances from studies of DNA methylation and histone modifications, and how these findings might lead to therapeutic opportunities.
Outcomes of patients with high-risk, localized renal cancer depend on optimal patient stratification, surgical management, and systemic therapy selection. Blick et al. discuss the current knowledge on these topics and provide an overview of interventions that are currently being investigated in clinical trials.
This Perspective provides an update on targeted therapy development for neuroblastoma and proposes that clinical trial design needs to be rethought in order to provide rigorous, evidence-based assessment of these new therapies in this rare and often deadly paediatric tumour.
Circulating and imaging biomarkers could be useful for the diagnosis of neuroendocrine tumours (NETs). Here, Wouter de Herder and colleagues review the latest research on biomarkers in the NET field and provide clinicians with a comprehensive overview of relevant diagnostic biomarkers.
Leone et al. describe management strategies for patients with penile cancer and metastasis to regional lymph nodes. They review the prognostic factors, indications for lymphadenectomy, surgical techniques and the role of systemic chemotherapy, radiotherapy and new targeted and immunotherapeutic approaches.
Molecular profiling studies are providing novel insights into the biology of hepatocellular carcinoma, although these remain to be translated into novel effective therapies. Nevertheless, therapeutic advances have been made in the past few years, and further advancements are expected in the near future, including biomarker-driven treatments and immunotherapies, as discussed in this Review.
In this Expert Consensus, Grünwald et al. summarize their recommendations for the diagnosis and treatment of patients with renal cell carcinoma and metastasis to the bone. They also outline current challenges and unmet patient needs that should be addressed in the future.
Renal cell carcinomas (RCCs) harbour mutations in genes encoding chromatin modifiers, which have integral roles in genome maintenance and epigenetic regulation. Here, the authors review the mutational landscape and roles of chromatin modifiers as co-drivers in RCC, highlighting therapeutic opportunities.
Treatment protocols for thyroid cancers range from active surveillance to total thyroidectomy followed by radioiodine remnant ablation. In this Review, the authors discuss the strengths and weaknesses of the surveillance tools and follow-up strategies used by clinicians in the treatment of thyroid cancers.
Merkel cell carcinoma (MCC) is a rare and aggressive form of nonmelanoma skin cancer. The availability of immune checkpoint inhibition has improved the outcomes of a subset of patients with MCC, although many unmet needs continue to exist. In this Consensus Statement, the authors summarize developments in our understanding of MCC while also providing consensus recommendations for future research.
Paul W. Harms,
Kelly L. Harms ⋯
on behalf of the International Workshop on Merkel Cell Carcinoma Research (IWMCC) Working Group
TRK fusion proteins are pathognomonic in certain rare tumour types and present in a small subset of diverse cancer types, including some common cancers; TRK inhibitors have promising efficacy in the treatment of these cancers, in a histology-agnostic manner. In this Review, the biology of TRK signalling and TRK fusions, strategies to target these drivers, the unique safety profile of TRK inhibitors and mechanisms of and strategies to overcome acquired resistance to these agents are discussed.
Joosten et al. review the main epigenetic alterations involved in renal carcinogenesis and their effects on key signalling pathways. The authors also discuss the utility of epigenetic aberrations as renal cancer biomarkers and their potential as treatment targets.
Ewing sarcoma is a malignant bone or soft-tissue tumour that mainly affects children, adolescents and young adults. This Primer describes the key characteristic molecular features of and the remaining unanswered research questions in Ewing sarcoma.
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. This Primer highlights RMS epidemiology and disease mechanisms and presents the state of the art in clinical care, including diagnostics, risk-based disease management and prevention of late treatment effects.
Research on the biology of chronic lymphocytic leukaemia (CLL) — a malignancy of CD5+ B cells — has profoundly enhanced the identification of patients who are at high risk of disease progression and the treatment of patients with drugs that target the distinctive features of CLL. This Primer highlights these advances, as well as the epidemiology, genetics and immunobiology of CLL.
Chronic lymphocytic leukaemia (CLL) is a B cell malignancy. This PrimeView focuses on the mechanisms underlying the development of CLL, including genetic alterations, B cell receptor signalling and interactions within the tumour microenvironment.
Kaposi sarcoma is a rare cancer that typically presents with multiple pigmented skin lesions, but may take an aggressive course characterised by lesion ulceration, oedema and visceral organ involvement. This Primer describes the epidemiology, clinical features, cellular mechanisms and management of the main forms of Kaposi sarcoma.