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Background: Risk stratifications for endometrial carcinoma (EC) depend on histopathology and molecular pathology. Histopathological risk stratification lacks reproducibility, neglects heterogeneity and contributes little to surgical procedures. Existing molecular stratification is useless in patients with specific pathological or molecular characteristics and cannot guide postoperative adjuvant radiotherapies. Chromosomal instability (CIN), the numerical and structural alterations of chromosomes resulting from ongoing errors of chromosome segregation, is an intrinsic biological mechanism for the evolution of different prognostic factors of histopathology and molecular pathology and may be applicable to the risk stratification of EC. Results: By analyzing CIN25 and CIN70, two reliable gene expression signatures for CIN, we found that EC with unfavorable prognostic factors of histopathology or molecular pathology had serious CIN. However, the POLE mutant, as a favorable prognostic factor, had elevated CIN signatures, and the CTNNB1 mutant, as an unfavorable prognostic factor, had decreased CIN signatures. Only if these two mutations were excluded were CIN signatures strongly prognostic for outcomes in different adjuvant radiotherapy subgroups. Integrating pathology, CIN signatures and POLE/CTNNB1 mutation stratified stageIendometrioid EC into four groups with improved risk prognostication and treatment recommendations. Conclusions: We revealed the possibility of integrating histopathology and molecular pathology by CIN for risk stratification in early-stage EC. Our integrated risk model deserves further improvement and validation. [ABSTRACT FROM AUTHOR]

Background: Pulmonary sarcomatoid carcinoma (SC) consists of both carcinomatous and sarcomatous tumors with high degree of malignancy, rapid progression, and poor prognosis. However, little is known regarding how pulmonary SC develops and progresses.Case Presentation: A 66-year-old male was initially diagnosed with stage IIIa lung cancer containing both adenocarcinoma (ADC) and SC. Adjuvant chemotherapy was administrated post-surgery, however, recurrence with SC only soon followed. Mutation profiling of the patient's microdissected ADC and SC components of the primary lesion and recurrent tumor was performed by targeted next-generation sequencing (NGS) of 416 cancer-relevant genes. Our data showed that primary SC/ADC and the recurrent SC shared multiple gene mutations including EGFR, NF1, TP53, CDKN2B, and SMARCA4, while both primary and recurrent SCs had a unique TP53 exon 4 splicing mutation frequently observed in sarcoma. Interestingly, a novel PHF20-NTRK1 fusion was acquired in the recurrent SC, which may be a potential driver for SC recurrence.Conclusions: The molecular genetic characteristics of tumor tissues at different stages reveals a linear tumor evolution model in this case, and support that the primary SC derived from the original lung ADC during the evolution of the tumor. We also identified a novel PHF20-NTRK1 fusion, which may contribute to the disease recurrence, and that can be potentially targeted with NTRK1 inhibitors for treatment. [ABSTRACT FROM AUTHOR]

Background: Esophageal sarcomatoid carcinoma (ESC) is a rare disease with a mixture of both carcinomatous and sarcomatous components in the tumor. Its genetic background and mechanisms of oncogenesis remain largely unknown.Methods: Here we performed targeted next generation sequencing (NGS) on a pan-cancer gene panel in 15 ESC tumors to explore their genetic alterations, and aimed to identify clinically actionable mutations for future treatment instructions.Results: TP53 alterations were identified in all patients. Alterations in receptor tyrosine kinases (RTK) were identified in 10 out of 15 patients. Members of downstream RAS and PI3-kinase pathways are also mutated in 10 patients, and PIK3CA is the top mutated gene in these pathways. In addition, we identified mutations on histone modification genes in 5 patients, including histone acetyltransferase gene EP300 and its homologue CREBBP, lysine methyltransferase genes KMT2A and KMT2B, and lysine demethylase gene KDM5A. Finally, mismatch repair (MMR) genes and proofreading gene POLE all together were mutated in one third of the ESC patients.Conclusions: This is the first study to unravel the mutational profile of ESC tumors. Our findings could match 9 patients to the targeted therapies currently available in clinical practice or in active clinical trials, suggesting the potential utility of targeted therapies for this rare disease in the future. [ABSTRACT FROM AUTHOR]