Prognostic utility of six mutated genes for older patients with acute myeloid leukemia

Approximately 50% of older patients with acute myeloid leukemia (AML) do not obtain chromosomal abnormalities as an effective risk‐stratification, and present cytogenetically normal AML (CN‐AML). To develop a reliable prediction model for stratifying the risk of these elderly patients, we conducted a study with a discovery and validation design. As a result, we found the top 6 mutated genes in the discovery cohort of 26 case by the whole exome sequencing, and verified as recurrent mutations in the large cohort of 329 patients by Sanger sequencing. The top 6 genes were NPM1, FLT3‐ITD, DNMT3A, CEBPA double allele, IDH1 and IDH2 mutations, and the frequency of each gene in the combining cohort was 36.8%, 19.8%, 20.1%, 5.8%, 14.9% and 22.5%, respectively. In addition, clinical variables such as age, white blood cell counts, genes of IDH1 and DNMT3A mutations, European LeukemiaNet genotype (NPM1 mutations and lacking FLT3‐ITD or CEBPA double allele mutations) and treatment protocols were independent factors for predicting the probabilities of overall and event‐free survival. The prediction nomograms based on these significant factors showed accurate discrimination. In conclusion, we developed a reliable prediction model for stratifying the risk of elderly patients with CN‐AML.     

Genetic and clonal dissection of osteosarcoma progression and lung metastasis

Osteosarcoma is a primary malignant bone tumor that has a high potential to metastasize to lungs. Little is known about the mechanisms underlying the dissemination of OS cancer cells to lungs. We performed whole exome sequencing of 13 OS primary tumors, with matched lung metastases and normal tissues. Phylogenetic analyses revealed that lung metastatic tumors often harbor clones that are nonexistent or rare in the matched primary OS tumors. Spatially and temporally separated lung metastases were from parallel seeding events with a polyphyletic pattern. Loss of TP53 or RB1 is among the early events during OS tumorigenesis, while loss of PTEN is involved at the later stages associated with lung metastases. Finally, KEAP1 was identified as a novel biomarker for increased metastatic risk. Patients whose primary tumors harbored KEAP1 amplification have significantly poorer lung‐metastasis free survival. This finding was validated in two independent datasets. Further, in vitro experiments exhibited that KEAP1 depletion suppressed the invasion of OS cells. Our findings uncover the patterns of clonal evolution during OS progression and highlight KEAP1 as a novel candidate associated with the risk of lung metastasis in OS patients.     

<Emphasis Type="Italic">BIM</Emphasis> Deletion Polymorphism Confers Resistance to Osimertinib in <Emphasis Type="Italic">EGFR</Emphasis> T790M Lung Cancer: a Case Report and Literature Review

The third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib (AZD9291) has shown significant clinical efficacy against the EGFR T790M mutation in non-small cell lung cancer (NSCLC) patients. However, resistance inevitably occurs, and the mechanisms leading to treatment failure need to be further investigated. The B-cell lymphoma 2 (BCL-2)-like 11 (BIM) deletion polymorphism, which occurs at a frequency of 21% in East Asians but is absent in African and European populations, has been associated with resistance to first-generation EGFR TKIs, such as gefitinib and erlotinib; and is a poor prognostic factor for NSCLC patients with EGFR mutations. Nevertheless, the significance of this BIM deletion polymorphism in the resistance to osimertinib has not been reported. Here, we show for the first time that a NSCLC patient harboring the EGFR L858R/T790M mutations, as well as the BIM deletion polymorphism, exhibited poor clinical outcomes with osimertinib treatment. This result suggests that the BIM deletion polymorphism might have prognostic value for determining NSCLC patient outcomes following osimertinib treatment.     

Rapid subcutaneous progression after immunotherapy in pretreated patients with metastatic carcinoma: two case reports

There is heterogeneity in cancer patients’ responses to immune checkpoint inhibitors (ICIs), including hyperprogression, which is very rapid tumor progression following immunotherapy, and pseudoprogression, which is an initial increase followed by a decrease in tumor burden or in the number of tumor lesions. This heterogeneity complicates clinical decisions because either premature withdrawal of the treatment or prolonged ineffective treatment harms patients. We presented two patients treated with ICIs with heterogeneous responses. One patient had Merkel cell carcinoma in the right thigh, and the other had nasopharyngeal squamous carcinoma. The first patient was treated with sintilimab and the second with sintilimab combined with abraxane. In the first patient, subcutaneous lesions grew substantially after the first cycle of treatment with sintilimab. In the second patient, subcutaneous lesions grew gradually after the second cycle of treatment with sintilimab combined with abraxane. In both cases, biopsy examination confirmed that newly emerged lesions were metastases of the primary tumor. These two cases remind clinicians that when subcutaneous nodules appear after treatment with ICIs, pathological biopsy is needed to determine the nature—pseudoprogression or rapid progression—of the disease course.     

EGFR and ERBB2 Germline Mutations in Chinese Lung Cancer Patients and Their Roles in Genetic Susceptibility to Cancer

Introduction

Inherited genetic determinants of lung cancer risk remain relatively elusive. Germline mutations in EGFR and erb-b2 receptor tyrosine kinase 2 (ERBB2) have been previously reported in lung cancers that may be associated with genetic susceptibility to lung cancer.