Systemic AA amyloidosis caused by inflammatory hepatocellular adenoma

To the Editor: Amyloid A (AA) systemic amyloidosis is a complication of chronic inflammatory diseases that is caused by the deposition of insoluble aggregates of cleaved N-terminal fragments of serum amyloid A (SAA) protein in tissues and organs throughout the body. Under physiologic conditions, SAA protein is produced by hepatocytes during the acute inflammatory phase in response to various cytokines such as interleukin-6. SAA is also overexpressed by neoplastic hepatocytes in inflammatory hepatocellular adenomas, a specific molecular subtype of benign liver tumors

Life-threatening influenza pneumonitis in a child with inherited IRF9 deficiency

Life-threatening pulmonary influenza can be caused by inborn errors of type I and III IFN immunity. We report a 5-yr-old child with severe pulmonary influenza at 2 yr. She is homozygous for a loss-of-function IRF9 allele. Her cells activate gamma-activated factor (GAF) STAT1 homodimers but not IFN-stimulated gene factor 3 (ISGF3) trimers (STAT1/STAT2/IRF9) in response to IFN-α2b. The transcriptome induced by IFN-α2b in the patient's cells is much narrower than that of control cells; however, induction of a subset of IFN-stimulated gene transcripts remains detectable. In vitro, the patient's cells do not control three respiratory viruses, influenza A virus (IAV), parainfluenza virus (PIV), and respiratory syncytial virus (RSV). These phenotypes are rescued by wild-type IRF9, whereas silencing IRF9 expression in control cells increases viral replication. However, the child has controlled various common viruses in vivo, including respiratory viruses other than IAV. Our findings show that human IRF9- and ISGF3-dependent type I and III IFN responsive pathways are essential for controlling IAV

Targeted next-generation sequencing identifies clinically relevant somatic mutations in a large cohort of inflammatory breast cancer

Abstract Background Inflammatory breast cancer (IBC) is the most aggressive form of primary breast cancer. Using a custom-made breast cancer gene sequencing panel, we investigated somatic mutations in IBC to better understand the genomic differences compared with non-IBC and to consider new targeted therapy in IBC patients. Methods Targeted next-generation sequencing (NGS) of 91 candidate breast cancer-associated genes was performed on 156 fresh-frozen breast tumor tissues from IBC patients. Mutational profiles from 197 primary breast tumors from The Cancer Genome Atlas (TCGA) were used as non-IBC controls for comparison analysis. The mutational landscape of IBC was correlated with clinicopathological data and outcomes. Results After genotype calling and algorithmic annotations, we identified 392 deleterious variants in IBC and 320 variants in non-IBC cohorts, respectively. IBC tumors harbored more mutations than non-IBC (2.5 per sample vs. 1.6 per sample, p < 0.0001). Eighteen mutated genes were significantly different between the two cohorts, namely TP53, CDH1, NOTCH2, MYH9, BRCA2, ERBB4, POLE, FGFR3, ROS1, NOTCH4, LAMA2, EGFR, BRCA1, TP53BP1, ESR1, THBS1, CASP8, and NOTCH1. In IBC, the most frequently mutated genes were TP53 (43.0%), PIK3CA (29.5%), MYH9 (8.3%), NOTCH2 (8.3%), BRCA2 (7.7%), ERBB4 (7.1%), FGFR3 (6.4%), POLE (6.4%), LAMA2 (5.8%), ARID1A (5.1%), NOTCH4 (5.1%), and ROS1 (5.1%). After grouping 91 genes on 10 signaling pathways, we found that the DNA repair pathway for the triple-negative breast cancer (TNBC) subgroup, the RTK/RAS/MAPK and cell cycle pathways for the HR–/HER2+ subgroup, the DNA repair, RTK/RAS/MAPK, and NOTCH pathways for the HR+/HER2– subgroup, and the DNA repair, epigenome, and diverse pathways for the HR+/HER2+ subgroup were all significantly differently altered between IBC and non-IBC. PIK3CA mutation was independently associated with worse metastasis-free survival (MFS) in IBC since the median MFS for the PIK3CA mutant type was 26.0 months and for the PIK3CA wild type was 101.1 months (p = 0.002). This association was observed in TNBC (p = 0.04) and the HR–/HER2+ subgroups (p = 0.0003), but not in the HR+/HER2– subgroup of IBC. Conclusions Breast cancer-specific targeted NGS uncovered a high frequency of deleterious somatic mutations in IBC, some of which may be relevant for clinical management

Systemic AA Amyloidosis Caused by Inflammatory Hepatocellular Adenoma

International audienc

Additional file 3: of Targeted next-generation sequencing identifies clinically relevant somatic mutations in a large cohort of inflammatory breast cancer

Figure S1. Comparison of somatic mutation frequency between IBC and non-IBC in four subgroups. (a) The percentage of samples with somatic mutation in the TNBC subgroup; (b) the percentage of samples with somatic mutation in the HR–/HER2+ subgroup; (c) the percentage of samples with somatic mutation in the HR+/HER2– subgroup; (d) the percentage of samples with somatic mutation in the HR+/HER2+ subgroup. The gray bars indicate non-IBC, the black bars indicate IBC; *p < 0.05, **p < 0.01, ***p < 0.001. (PDF 52 kb

Additional file 6: of Targeted next-generation sequencing identifies clinically relevant somatic mutations in a large cohort of inflammatory breast cancer

Figure S4. MFS curves stratified by PIK3CA mutation in three subgroups of IBC patients. (a) Kaplan-Meier estimates of MFS according to PIK3CA mutations in patients of the HR– subgroup, (b) Kaplan-Meier estimates of MFS according to PIK3CA mutations in patients of the HER2+ subgroup, (c) Kaplan-Meier estimates of MFS according to PIK3CA mutations in patients of the HR+ subgroup. (PDF 42 kb

Additional file 2: of Targeted next-generation sequencing identifies clinically relevant somatic mutations in a large cohort of inflammatory breast cancer

Table S2. BreastCurie gene panel for targeted NGS. (PDF 411 kb

Additional file 4: of Targeted next-generation sequencing identifies clinically relevant somatic mutations in a large cohort of inflammatory breast cancer

Figure S2. Comparison of biological pathway between IBC and non-IBC in four subgroups. (a) The percentage of samples with alteration on 10 biological pathways in the TNBC subgroup; (b) the percentage of samples with alteration on 10 biological pathways in the HR–/HER2+ subgroup; (c) the percentage of samples with alteration on 10 biological pathways in the HR+/HER2– subgroup; (d) the percentage of samples with alteration on 10 biological pathways in the HR+/HER2+ subgroup. The gray bars indicate non-IBC, the black bars indicate IBC; *p < 0.05, **p < 0.01, ***p < 0.001. (PDF 41 kb

Additional file 1: of Targeted next-generation sequencing identifies clinically relevant somatic mutations in a large cohort of inflammatory breast cancer

Table S1. Pathological and clinical characteristics of non-IBC cohorts. (PDF 169 kb