David Grynspan

Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is the most common undifferentiated ovarian malignancy in women under 40 years of age. We sequenced the exomes of six individuals from three families with SCCOHT. After discovering segregating deleterious germline mutations in SMARCA4 in all three families, we tested DNA from a fourth affected family, which also carried a segregating SMARCA4 germline mutation. All the familial tumors sequenced harbored either a somatic mutation or loss of the wild-type allele. Immunohistochemical analysis of these cases and additional familial and non-familial cases showed loss of SMARCA4 (BRG1) protein in 38 of 40 tumors overall. Sequencing of cases with available DNA identified at least one germline or somatic deleterious SMARCA4 mutation in 30 of 32 cases. Additionally, the SCCOHT cell line BIN-67 had biallelic deleterious mutations in SMARCA4. Our findings identify alterations in SMARCA4 as the major cause of SCCOHT, which could lead to improvements in genetic counseling and new treatment approaches.

Histone H3K36 mutations promote sarcomagenesis through altered histone methylation landscape

An oncohistone deranges inhibitory chromatin Missense mutations (that change one amino acid for another) in histone H3 can produce a so-called oncohistone and are found in a number of pediatric cancers. For example, the lysine-36–to-methionine (K36M) mutation is seen in almost all chondroblastomas. Lu et al. show that K36M mutant histones are oncogenic, and they inhibit the normal methylation of this same residue in wild-type H3 histones. The mutant histones also interfere with the normal development of bone-related cells and the deposition of inhibitory chromatin marks. Science, this issue p. 844 The lysine-36–to–methionine mutation in histone H3 is oncogenic and interferes with inhibitory chromatin marks. Several types of pediatric cancers reportedly contain high-frequency missense mutations in histone H3, yet the underlying oncogenic mechanism remains poorly characterized. Here we report that the H3 lysine 36–to–methionine (H3K36M) mutation impairs the differentiation of mesenchymal progenitor cells and generates undifferentiated sarcoma in vivo. H3K36M mutant nucleosomes inhibit the enzymatic activities of several H3K36 methyltransferases. Depleting H3K36 methyltransferases, or expressing an H3K36I mutant that similarly inhibits H3K36 methylation, is sufficient to phenocopy the H3K36M mutation. After the loss of H3K36 methylation, a genome-wide gain in H3K27 methylation leads to a redistribution of polycomb repressive complex 1 and de-repression of its target genes known to block mesenchymal differentiation. Our findings are mirrored in human undifferentiated sarcomas in which novel K36M/I mutations in H3.1 are identified.

Unsupervised Placental Gene Expression Profiling Identifies Clinically Relevant Subclasses of Human Preeclampsia

Preeclampsia (PE) is a complex, hypertensive disorder of pregnancy, demonstrating considerable variability in maternal symptoms and fetal outcomes. Unfortunately, prior research has not accounted for this variability, resulting in a lack of robust biomarkers and effective treatments for PE. Here, we created a large (N=330) clinically relevant human placental microarray data set, consisting of 7 previously published studies and 157 highly annotated new samples from a single BioBank. Applying unsupervised clustering to this combined data set identified 3 clinically significant probable etiologies of PE: “maternal”, with healthy placentas and term deliveries; “canonical”, exhibiting expected clinical, ontological, and histopathologic features of PE; and “immunologic” with severe fetal growth restriction and evidence of maternal antifetal rejection. Moreover, these groups could be distinguished using a small quantitative polymerase chain reaction panel and demonstrated varying influence of maternal factors on PE development. An additional subclass of PE placentas was also revealed to form because of chromosomal abnormalities in these samples, supported by array-based comparative genomic hybridization analysis. Overall, our findings represent a new paradigm in our understanding of the origins and maternal–placental contributions to the pathology of PE. The study of PE represents a unique opportunity to access human tissue associated with a complex hypertensive disorder, and our novel approach could be applied to other hypertensive and heterogeneous human diseases.

DICER1 mutations in an adolescent with cervical embryonal rhabdomyosarcoma (cERMS)

To the Editor: Embryonal rhabdomyosarcomas of the cervix (cERMS) (“cervical sarcoma botryoides”) are rare embryonal tumors, usually diagnosed in childhood or adolescence, with a world literature of uterine/cervical ERMS limited to 115 cases [1]. The association of cERMSwith germlineDICER1mutations was first established in three families by Foulkes in 2011, and subsequently reported by Dehner et al., although the coexistence of cERMS and ovarian Sertoli-Leydig cell tumors (OSLCT) had previously been recognized [2–4]. In 2012, Doros et al. [5] reported germline DICER1 mutations in 2/52 (3.8%) sporadic ERMS, including 7 uterine/vaginal/pelvic cases.

Maternal floor infarction: Management of an underrecognized pathology

Maternal floor infarction is a relatively rare condition characterized clinically by severe early onset fetal growth restriction with features of uteroplacental insufficiency. It has a very high recurrence rate and carries a significant risk or fetal demise. Pathological characteristics include massive and diffuse fibrin deposition along the decidua basalis and the perivillous space of the basal plate. We present a case of recurrent maternal floor infarction and propose diagnostic clues as well as potential therapeutic options.

Gene expression profiling in necrotizing enterocolitis reveals pathways common to those reported in Crohn's disease

BackgroundNecrotizing enterocolitis (NEC) is the most frequent life-threatening gastrointestinal disease experienced by premature infants in neonatal intensive care units. The challenge for neonatologists is to detect early clinical manifestations of NEC. One strategy would be to identify specific markers that could be used as early diagnostic tools to identify preterm infants most at risk of developing NEC or in the event of a diagnostic dilemma of suspected disease. As a first step in this direction, we sought to determine the specific gene expression profile of NEC.MethodsDeep sequencing (RNA-Seq) was used to establish the gene expression profiles in ileal samples obtained from preterm infants diagnosed with NEC and non-NEC conditions. Data were analyzed with Ingenuity Pathway Analysis and ToppCluster softwares.ResultsData analysis indicated that the most significant functional pathways over-represented in NEC neonates were associated with immune functions, such as altered T and B cell signaling, B cell development, and the role of pattern recognition receptors for bacteria and viruses. Among the genes that were strongly modulated in neonates with NEC, we observed a significant degree of similarity when compared with those reported in Crohn’s disease, a chronic inflammatory bowel disease.ConclusionsGene expression profile analysis revealed a predominantly altered immune response in the intestine of NEC neonates. Moreover, comparative analysis between NEC and Crohn’s disease gene expression repertoires revealed a surprisingly high degree of similarity between these two conditions suggesting a new avenue for identifying NEC biomarkers.

MeCP2 in the enteric nervous system

Rett syndrome (RTT) is an intellectual deficit and movement disorder that develops during early childhood in girls. Affected children are normal until 6–18 months of age, after which symptoms begin to appear. Most cases of RTT are due to mutations in the MeCP2 gene leading to disruption of neuronal communication in the central nervous system. In addition, RTT patients show peripheral ailments such as gastrointestinal (GI), respiratory, and cardiac dysfunction. The etiology of intestinal dysfunction in RTT is not well‐understood. Reports on the presence of MeCP2 in the peripheral nervous system are scant. As such we examined the levels of MeCP2 in human and murine GI tissue and assessed MeCP2 expression at various developmental stages.

Metastatic signet ring cell adenocarcinoma of the bladder: responsive to treatment?

Signet ring cell variant of mucinous adenocarcinoma of the urinary bladder is an exceptionally rare urologic malignancy, generally felt to be resistant to chemotherapy and radiotherapy. We describe a case of this malignancy with unusual sites of metastasis and an unexpectedly good response to treatment.

Atypical fibrodysplasia ossificans progressiva diagnosed by whole‐exome sequencing

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by congenital malformations of the great toes and progressive heterotopic ossification of connective tissue that begins during the first decade of life. Our patient presented with intrauterine growth retardation, respiratory distress, neonatal onset soft tissue masses, bilateral hallux valgus, and congenital anomalies of the thyroid and uterus. She was initially diagnosed with atypical infantile myofibromatosis based on clinical and pathological findings. She underwent whole‐exome sequencing (WES) as part of the FORGE study to identify the gene for infantile myofibromatosis; however a de novo dominant mutation in ACVR1 (NM_001105.4:c.617G>A) revised the diagnosis to FOP. This patient highlights the utility of WES as an early diagnostic tool in the investigation of patients with unusual presentations of rare diseases, thereby providing clinicians with accurate molecular diagnoses and the opportunity to tailor clinical management to improve patient care.

Radiographic features in a rare case of sphenoid sinus extramedullary hematopoeisis in sickle cell disease.

Sickle cell disease is a common hematologic disorder with some uncommon clinical manifestations. While there are an abundance of described disease manifestations of the head and neck, extramedullary hematopoesis within the paranasal sinuses is exceedingly rare. Here, we present a case of a young boy with known sickle cell disease who presented to hospital with headaches of new onset. Imaging demonstrated an expansile mass lesion occupying the sphenoid sinus and on biopsy was found to be active hematopoetic bone marrow. A description of the case and review of subtle but characteristic radiographic findings follow.