Gastrointestinal stromal tumors in children and young adults: a clinicopathologic, molecular, and genomic study of 15 cases and review of the literature

Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors of the intestinal tract that typically occur in adults over the age of 40 years. GISTs in younger patients are rare and not well characterized. The objective was to define the characteristics of GISTs in children and young adults (<30 years old). Clinicopathologic and molecular features, including KIT/PDGFRA genotype, in GISTs from 5 children and 10 young adults were analyzed. Gene expression analysis was performed on 5 gastric tumor samples from 2 children, 2 gastric tumors from young adults, and 10 gastric GISTs from older adults using an U133A Affymetrix platform (22,000 genes). All five pediatric GISTs occurred in girls, involved the stomach as multiple nodules, showed predominantly an epithelioid morphology, often involved lymph nodes, and lacked KIT or PDGFRA mutations. Although all five patients developed recurrence (four in the liver, three in the peritoneum, and two in both sites), four are still alive with disease. Of the 10 GISTs in young adults, half occurred in the small bowel and had spindle cell morphology, and one case had lymph node metastasis. KIT mutations were identified in seven cases, four in exon 11 and three in exon 9. Seven patients developed recurrence, and at last follow-up two patients had died of disease. Gene expression analysis showed high expression of PHKA1, FZD2, NLGN4, IGF1R, and ANK3 in the pediatric and young adult versus older adult cases. GISTs that occur in children are a separate clinicopathologic and molecular subset with predilection for girls, multifocal gastric tumors, and wild-type KIT/PDGFRA genotype. In contrast, GISTs in young adults are a more heterogeneous group, including cases that resemble either the pediatric or the older adult-type tumors. The distinct gene expression profile suggests avenues for investigation of pathogenesis and potential therapeutic strategies.     

A rare FGF5 candidate variant (rs112475347) for predisposition to nonsquamous,nonsmall-cell lung cancer

A unique approach with rare resources was used to identify candidate variants predisposing to familial nonsquamous nonsmall-cell lung cancers (NSNSCLC). We analyzed sequence data from NSNSCLC-affected cousin pairs belonging to high-risk lung cancer pedigrees identified in a genealogy of Utah linked to statewide cancer records to identify rare, shared candidate predisposition variants. Variants were tested for association with lung cancer risk in UK Biobank. Evidence for linkage with lung cancer was also reviewed in families from the Genetic Epidemiology of Lung Cancer Consortium. Protein prediction modeling compared the mutation with reference. We sequenced NSNSCLC-affected cousin pairs from eight high-risk lung cancer pedigrees and identified 66 rare candidate variants shared in the cousin pairs. One variant in the FGF5 gene also showed significant association with lung cancer in UKBiobank. This variant was observed in 3/163 additional sampled Utah lung cancer cases, 2 of whom were related in another independent pedigree. Modeling of the predicted protein predicted a second binding site for SO₄ that may indicate binding differences. This unique study identified multiple candidate predisposition variants for NSNSCLC, including a rare variant in FGF5 that was significantly associated with lung cancer risk and that segregated with lung cancer in the two pedigrees in which it was observed. FGF5 is an oncogenic factor in several human cancers, and the mutation found here (W81C) changes the binding ability of heparan sulfate to FGF5, which might lead to its deregulation. These results support FGF5 as a potential NSNSCLC predisposition gene and present additional candidate predisposition variants.     

Factors Influencing Surgical and Adjuvant Therapy in Stage I Breast Cancer: A SEER 18 Database Analysis

Background

Randomized trials have shown no survival difference for patients with stage I breast cancer treated with mastectomy versus breast-conserving surgery (BCS) with radiotherapy (RT). RT is recommended after BCS in order to decrease local recurrence and mortality. We sought to evaluate the treatment trends in patients with stage I breast cancer.

Methods

We used the Surveillance, Epidemiology, and End Results (SEER) database to identify 194,860 women with stage I breast cancer diagnosed from 1988 to 2007. We evaluated factors that were associated surgical treatment and the utilization of RT after BCS.

Results

There was a progressive decline in the proportion of patients with stage I breast cancer who were treated with mastectomy from 1998 to 2007. Significant predictors for being treated with mastectomy included single/divorced women (p = 0.007), white race (p < 0.001), estrogen receptor negativity (p < 0.001), earlier year of diagnosis (p < 0.001), smaller tumor size (p < 0.001), and region (p < 0.001). Twenty percent of the BCS cohort did not receive RT, and this proportion did not change over time. Significant predictors for not receiving RT included small tumor size (p < 0.001), African American race (p < 0.001), increasing age (p < 0.001), single/divorced women (p < 0.001), estrogen receptor negativity (p < 0.001), and region (p < 0.001). The survival for patients treated with BCS and RT was significantly higher than for those who did not receive RT (p < 0.001).

Conclusions

The use of BCS for the treatment of stage I breast cancer increased over time. A constant proportion of patients did not receive RT after BCS. Omission of RT in BCS is associated with an increase in mortality.     

Potential Microbial Consortium for Plant Growth Promotion of Sunflower (Helianthus annuus L.)

Proceedings of the National Academy of Sciences, India Section B: Biological Sciences - Bioinoculants are formulations of beneficial microorganisms used to promote plant growth. Their mode of...     

Carbon dot mediated G quadruplex nano-network formation for enhanced DNAzyme activity and easy catalyst reclamation

The significant application potential of the DNAzyme activity of G-quadruplex (G4)–hemin complexes has prompted considerable research efforts to amplify their peroxidase mimicking activity to match that of their enzymatic counterparts. However, concurrent improvements in the catalytic cycle and catalyst recovery remain elusive. Herein, we report the creation of a network array of G-quadruplex (G4)–hemin complexes crosslinked by carbon quantum dots (CDs) that not only significantly improves the G-quadruplex–hemin DNAzyme activity, stability, and catalytic cycle, but also points towards easy catalyst regeneration via a semi-heterogeneous catalysis approach. 5′-phosphate terminated G-rich single-stranded DNA molecules proficient in generating intermolecular and intramolecular G-quadruplexes were covalently conjugated to anthrarufin derived CDs through phosphoramidite chemistry. The network array was achieved through K⁺ mediated intermolecular G-quadruplex formation that readily complexes with hemin to give the catalytic core. The presence of CDs in close vicinity ensures a favorable microenvironment that helps in amplifying the DNAzyme activity in both the intermolecular CD–G-quadruplex network assembly and the intramolecular CD–G quadruplex conjugate, while the former is necessary for easy catalyst regeneration. The CD photophysics enable the monitoring of the DNAzyme recovery and reaction progress.

Enhanced DNAzyme activity of G-quadruplex–hemin complex in carbon dot crosslinked nanonetwork with access to easy catalyst regeneration.     

Spleens of myelofibrosis patients contain malignant hematopoietic stem cells

Cancer stem cell behavior is thought to be largely determined by intrinsic properties and by regulatory signals provided by the microenvironment. Myelofibrosis (MF) is characterized by hematopoiesis occurring not only in the marrow but also in extramedullary sites such as the spleen. In order to study the effects of these different microenvironments on primitive malignant hematopoietic cells, we phenotypically and functionally characterized splenic and peripheral blood (PB) MF CD34⁺ cells from patients with MF. MF spleens contained greater numbers of malignant primitive HPCs than PB. Transplantation of PB MF CD34⁺ cells into immunodeficient (NOD/SCID/IL2Rγ^null) mice resulted in a limited degree of donor cell chimerism and a differentiation program skewed toward myeloid lineages. By contrast, transplanted splenic MF CD34⁺ cells achieved a higher level of chimerism and generated both myeloid and lymphoid cells that contained molecular or cytogenetic abnormalities indicating their malignant nature. Only splenic MF CD34⁺ cells were able to sustain hematopoiesis for prolonged periods (9 months) and were able to engraft secondary recipients. These data document the existence of MF stem cells (MF-SCs) that reside in the spleens of MF patients and demonstrate that these MF-SCs retain a differentiation program identical to that of normal hematopoietic stem cells.