Ancient familial Mediterranean fever mutations in human pyrin and resistance to Yersinia pestis.

Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by homozygous or compound heterozygous gain-of-function mutations in MEFV, which encodes pyrin, an inflammasome protein. Heterozygous carrier frequencies for multiple MEFV mutations are high in several Mediterranean populations, suggesting that they confer selective advantage. Among 2,313 Turkish people, we found extended haplotype homozygosity flanking FMF-associated mutations, indicating evolutionarily recent positive selection of FMF-associated mutations. Two pathogenic pyrin variants independently arose >1,800 years ago. Mutant pyrin interacts less avidly with Yersinia pestis virulence factor YopM than with wild-type human pyrin, thereby attenuating YopM-induced interleukin (IL)-1ß suppression. Relative to healthy controls, leukocytes from patients with FMF harboring homozygous or compound heterozygous mutations and from asymptomatic heterozygous carriers released heightened IL-1ß specifically in response to Y. pestis. Y. pestis-infected MefvM680I/M680I FMF knock-in mice exhibited IL-1-dependent increased survival relative to wild-type knock-in mice. Thus, FMF mutations that were positively selected in Mediterranean populations confer heightened resistance to Y. pestis.

Genetic Mutation Analysis in Small Cell Lung Cancer by a Novel NGS-Based Targeted Resequencing Gene Panel and Relation with Clinical Features.

BACKGROUND: Small cell lung cancer (SCLC) is an aggressive and invasive malignancy that presents at advanced clinical stage with no more effective treatments. Development of a method for its early detection would be useful, also new therapeutic target need to be discovered; however, there is a lack of information about its oncogenic driver gene mutations. OBJECTIVES: We aim to identify the SCLC-related genomic variants that associate with clinical staging and serum protein biomarkers observed in other types of lung cancer. METHODS: We screened formalin-fixed paraffin-embedded (FFPE) biopsy tissues of 32 Chinese SCLC patients using the 303 oncogenic driver gene panel generated by Tiling PCR amplification sequencing (tPAS) and analyzed the patients' corresponding serum protein levels of CYFRA21-1 CEA, NSE, and SCCA. RESULTS: In total, we found 147 SCLC-related mutant genes, among these, three important genes (TP53, RB1, KMT2D) as well as five novel genes LRRK2, BRCA1, PTCH1, ARID2, and APC that altogether occurred in 90% of patients. Furthermore, increased mutations to 6 genes (WT1, NOTCH1, EPHA3, KDM6A, SETD2, ACVR1B) significantly associated with higher serum NSE levels (P = 0.0016) and higher clinical stages II + III compared to stage I (P = 0.06). CONCLUSIONS: Our panel is relatively reliable in detecting the oncogenic mutations of Chinese SCLC patients. Based on our findings, it may be possible to combine SCLC-related mutations and serum NSE for a simple detection of clinical staging.