Whole-Exome Sequencing Identifies Mutation Profile and Mutation Signature-Based Clustering Associated with Prognosis in Appendiceal Pseudomyxoma Peritonei.

Pseudomyxoma peritonei (PMP) is a rare malignant clinical syndrome with little known about the global mutation profile. In this study, whole-exome sequencing (WES) was performed in 49 appendiceal PMP to investigate mutation profiles and mutation signatures. A total of 4,020 somatic mutations were detected, with a median mutation number of 56 (1-402). Tumor mutation burden (TMB) was generally low (median 1.55 mutations/Mb, 0.12-11.26 mutations/Mb). Mutations were mainly enriched in the function of cancer-related axonogenesis, extracellular matrix-related processes, calcium signaling pathway, and cAMP signaling pathway. Mutations in FCGBP, RBFOX1, SPEG, RTK-RAS, PI3K-AKT, and focal adhesion pathways were associated with high-grade mucinous carcinoma peritonei. These findings revealed distinct mutation profile in appendiceal PMP. Ten mutation signatures were identified, dividing patients into mutation signature cluster (MSC) 1 (N = 28, 57.1%) and MSC 2 (N = 21, 42.9%) groups. MSC (P = 0.007) was one of the four independent factors associated with 3-year survival. TMB (P = 0.003) and microsatellite instability (P = 0.002) were independent factors associated with MSC 2 grouping. Taken together, our findings provided a broader view in the understanding of molecular pathologic mechanism in appendiceal PMP and may be critical to developing an individualized approach to appendiceal PMP treatment. IMPLICATIONS: This work describes exhaustive mutation profile of PMP based on WES data and derives ten mutation signatures, which divides patients into two clusters and serve as an independent prognostic factor associated with 3-year survival.

Survival benefit of combinatorial osimertinib rechallenge and entrectinib in an EGFR-mutant NSCLC patient with acquired LMNA-NTRK1 fusion following osimertinib resistance.

Acquired resistance to osimertinib is inevitable and heterogeneous despite its documented efficacy against EGFR-mutated non-small cell lung cancer (NSCLC). Subsequent therapeutic options assume the dominant form of the resistance mechanism; however, the more rare oncogenic driver, NTRK1 fusion, has also reportedly conferred osimertinib resistance. Nevertheless, clear-cut options when NSCLCs are driven by EGFR mutation and the subsequent NTRK fusion are lacking. This is a case of NSCLC wherein exon 19 deletion in EGFR (19del) and acquired LMNA-NTRK1 fusion were accompanied by the persistence of EGFR T790M. The patient underwent peritoneal metastasis after multiple targeted therapies: gefitinib, osimertinib, chemotherapy, and anlotinib plus docetaxel (in clinical trials). Osimertinib was subsequently re-administered with the NTRK fusion inhibitor entrectinib, resulting in remission of peritoneal metastases even after slow progression of pancreatic metastasis over the following 5 months. An extensive literature review to identify the efficacies of therapies for NTRK fusion as the means to acquired resistance to EGFR TKIs revealed that blocking both the EGFR mutation and the subsequent NTRK fusion can provide clinical benefits following EGFR TKIs resistance; however, the efficacy and safety of combination therapies must be further investigated. To precisely manage EGFR-mutated NSCLCs, it is also essential to identify the resistance mechanisms by repeating biopsies.

Targeted gene next-generation sequencing reveals genomic profile in a cohort of 46 Chinese patients with breast cancer.

BACKGROUND: The present study aimed to explore the genomic profile in a cohort of Chinese patients with breast cancer (BC), as well as provide potential strategies for clinic treatment in specific subset of BC patients. METHODS: Paired samples from 46 BC patients were subjected to DNA extraction and 537 gene targeted next-generation sequencing. RESULTS: In total, 742 somatic mutations were detected in these patients, which involved 303 genes. TP53 and PIK3CA were the most frequently mutated genes, with a mutation rate of 45.65% and 26.09%. C>T, T>C and C>A comprised the main single nucleotide base variation for this Chinese cohort. Triple negative breast cancer (TNBC) group had more TP53-mutated patients than the Non-TNBC group (p = 0.0229). In addition, the cohort was also divided into 'Young' and 'Old' groups based on the age of onset. Compared with the 'Young' group, the 'Old' group had more frameshift mutations (p = 0.0190), less missense mutations (p = 0.0269) and more HOXA11-mutated patients (p = 0.0197). Additionally, the HOXA11mt (HOXA11 gene mutated) group had more frameshift mutations than the HOXA11wt (HOXA11 gene without mutation) group (p < 0.0001). In KEGG (i.e. Kyoto Encyclopedia of Genes and Genomes) analysis, the HOXA11wt group had more gene mutations involved in the T cell receptor signaling pathway (p = 0.0197), Jak-STAT signaling pathway (p = 0.0380) and the HIF-1 signaling pathway (p = 0.0489) than the HOXA11mt group. In the present study, the heterogeneity of somatic mutations was revealed between different tumor subgroups, including TNBC/Non-TNBC, age of onset (Young/Old) and HOXA11 mutation (HOXA11mt /HOXA11wt ). CONCLUSIONS: The present study revealed the heterogeneity of gene mutation and clinical variables among BC subtypes and might provide guidance for developing a potential target for clinical treatment.