A 28-year-old woman experienced gross hematuria after the administration of the second dose of an messenger ribonucleic acid (mRNA) vaccine (BNT162b2). She was diagnosed with Immunogloblin A nephropathy (IgAN) by a renal biopsy two weeks after vaccination, which revealed a mild increase in mesangial cells and a matrix with co-depositions of galactose-deficient IgA1 and C3 in the mesangial region. The gross hematuria and proteinuria gradually improved without any medication, suggesting that immune activation by the mRNA vaccine may not elicit continuous disease progression of IgAN. Thus, further studies investigating the relationship between mRNA vaccines against COVID-19 and the progression of IgAN should be conducted.
Abstract There are multiple transcription start sites (TSSs) in agreement with multiple transcript variants encoding different isoforms of NKX2‐1/TTF‐1 (thyroid transcription factor 1); however, the clinicopathological significance of each transcript isoform of NKX2‐1/TTF‐1 in lung adenocarcinoma (LAD) is unknown. Herein, TSS‐level expression of NKX2‐1/TTF‐1 isoforms was evaluated in 71 LADs using bioinformatic analysis of cap analysis of gene expression (CAGE)‐sequencing data, which provides genome‐wide expression levels of the 5′‐untranslated regions and the TSSs of different isoforms. Results of CAGE were further validated in 664 LADs using in situ hybridisation. Fourteen of 17 TSSs in NKX2‐1/TTF‐1 (80% of known TSSs in FANTOM5, an atlas of mammalian promoters) were identified in LADs, including TSSs 1–13 and 15; four isoforms of NKX2‐1/TTF‐1 transcripts ( NKX2‐1_001 , NKX2‐1_002 , NKX2‐1_004 , and NKX2‐1_005 ) were expressed in LADs, although NKX2‐1_005 did not contain a homeodomain. Among those, six TSSs regulated NKX2‐1_004 and NKX2‐1_005 , both of which contain exon 1. LADs with low expression of isoforms from TSS region 11 regulating exon 1 were significantly associated with poor prognosis in the CAGE data set. In the validation set, 62 tumours (9.3%) showed no expression of NKX2‐1/TTF‐1 exon 1; such tumours were significantly associated with older age, EGFR wild‐type tumours, and poor prognosis. In contrast, 94 tumours, including 22 of 30 pulmonary invasive mucinous adenocarcinomas (IMAs) exhibited exon 1 expression without immunohistochemical TTF‐1 protein expression. Furthermore, IMAs commonly exhibited higher exon 1 expression relative to that of exon 4/5, which contained a homeodomain in comparison with EGFR‐ mutated LADs. These transcriptome and clinicopathological results reveal that LAD use at least 80% of NKX2‐1 TSSs and expression of the NKX2‐1/TTF‐1 transcript isoform without exon 1 ( NKX2‐1_004 and NKX2‐1_005 ) defines a distinct subset of LAD characterised by aggressive behaviour in elder patients. Moreover, usage of alternative TSSs regions regulating NKX2‐1_005 may occur in subsets of LADs.
A distinct subset of lung adenocarcinomas (LADs), arising from a series of peripheral lung cells defined as the terminal respiratory unit (TRU), is characterised by thyroid transcription factor 1 (TTF-1) expression. The clinical relevance of transcription factors (TFs) other than TTF-1 remains unknown in LAD and was explored in the present study.Seventy-one LAD samples were subjected to high-throughput transcriptome screening of LAD using cap analysis gene expression (CAGE) sequencing data; CAGE provides genome-wide expression levels of the transcription start sites (TSSs). In total, 1083 invasive LAD samples were subjected to immunohistochemical examination for paired box 9 (PAX9) and TTF-1 expression levels. PAX9 is an endoderm development-associated TF that most strongly and inversely correlates with the expression of TTF-1 TSS subsets. Immunohistochemically, PAX9 expression was restricted to the nuclei of ciliated epithelial and basal cells in the bronchi and bronchioles and the nuclei of epithelial cells of the bronchial glands; moreover, PAX9 expression was observed in 304 LADs (28%). PAX9-positive LADs were significantly associated with heavy smoking, non-lepidic subtype, EGFR wild-type tumours and PD-L1 expression (all P < 0.0001). All these characteristics were opposite to those of TRU-type LADs with TTF-1 expression. PAX9 expression was an independent prognostic factor for decreased overall survival (P = 0.022).Our results revealed that PAX9 expression defines an aggressive subset of LADs preferentially occurring in smokers that may arise from bronchial or bronchiolar cells.
Abstract RAC1 at 7p22.1 encodes a RAC family small GTPase that regulates actin cytoskeleton organization and intracellular signaling pathways. Pathogenic RAC1 variants result in developmental delay and multiple anomalies. Here, exome sequencing identified a rare de novo RAC1 variant [NM_018890.4:c.118T > C p.(Tyr40His)] in a male patient. Fetal ultrasonography indicated the patient to have multiple anomalies, including persistent left superior vena cava, total anomalous pulmonary venous return, esophageal atresia, scoliosis, and right-hand polydactyly. After birth, craniofacial dysmorphism and esophagobronchial fistula were confirmed and VACTERL association was suspected. One day after birth, the patient died of respiratory failure caused by tracheal aplasia type III. The molecular mechanisms of pathogenic RAC1 variants remain largely unclear; therefore, we biochemically examined the pathophysiological significance of RAC1-p.Tyr40His by focusing on the best characterized downstream effector of RAC1, PAK1, which activates Hedgehog signaling. RAC1-p.Tyr40His interacted minimally with PAK1, and did not enable PAK1 activation. Variants in the RAC1 Switch II region consistently activate downstream signals, whereas the p.Tyr40His variant at the RAC1-PAK1 binding site and adjacent to the Switch I region may deactivate the signals. It is important to accumulate data from individuals with different RAC1 variants to gain a full understanding of their varied clinical presentations.
Subtypes of small cell lung carcinoma (SCLC) are defined by the expression of ASCL1, NEUROD1, and POU2F3 markers. The aim of our study was to explore the extent to which the intratumoral heterogeneity of ASCL1, NEUROD1, and POU2F3 may lead to discrepancies in expression of these markers in surgical samples and their matched tissue microarray (TMA) and lymph node (LN) metastatic sites. METHODS AND RESULTS: The cohort included 77 patients with SCLC. Immunohistochemical examinations were performed on whole slides of the primary tumour, paired TMAs, and metastatic LN sites. Samples with H-scores >50 were considered positive. Based on the ASCL1, NEUROD1, and POU2F3 staining pattern, we grouped the tumours as follows: ASCL1-dominant (SCLC-A), NEUROD1-dominant (SCLC-N), ASCL1/NEUROD1 double-negative with POU2F3 expression (SCLC-P), and negative for all three markers (SCLC-I). In whole slides, 40 SCLC-A (52%), 20 SCLC-N (26%), 15 SCLC-P (20%), and two SCLC-I (3%) tumours were identified. Comparisons of TMAs or LN metastatic sites and corresponding surgical specimens showed that positivity for ASCL1, NEUROD1, and POU2F3 in TMAs (all P < 0.0001) or LN metastatic sites (ASCL1, P = 0.0047; NEUROD1, P = 0.0069; POU2F3, P < 0.0001) correlated significantly with that of corresponding surgical specimens. CONCLUSION: The positivity for these markers in TMAs and LN metastatic sites was significantly correlated with that of corresponding surgical specimens, indicating that biopsy specimens could be used to identify molecular subtypes of SCLC in patients.
Lymphangioleiomyomatosis (LAM) is a tuberous sclerosis complex (TSC)-associated tumor, characterized by the expression of neural crest lineages including neuronal markers. Neural crest cells can differentiate into multiple cell types that contribute to tissues associated with TSC-related tumors, and TSC-related tumors could be specifically associated with distinct neural crest subtypes. This study aimed to clarify the clinicopathological effects of expression of neuronal markers in LAM. Lung tissues from 40 patients with LAM (of whom 13, 1, and 26 had undergone lung transplantation, lobectomy, and partial lung resection, respectively) were immunohistochemically analyzed. All patients were women, and their median age was 36 years (range: 24-62 y). All patients who underwent lung transplantation or lobectomy were classified as LAM histologic score (LHS)-3, whereas those who underwent partial lung resection were classified as LHS-1. LAM cells expressed peripherin (65%), and neuron-specific βIII-tubulin (43%). A comparison of the early (LHS-1) and advanced (LHS-3) stages of LAM revealed that neuron-specific βIII-tubulin was significantly expressed in the early stage of LAM ( P = 0.0009). Neuron-specific βIII-tubulin-positive LAM was associated with younger age ( P < 0.0001), the coexistence of renal angiomyolipoma ( P = 0.027), and the absence of retroperitoneal LAM ( P = 0.045). Furthermore, based on the expression levels of immunohistochemical markers in LAM, 2 distinct clusters with different expression levels of neuronal markers were observed. Approximately 40% to 60% of patients with LAM expressed neuron-specific βIII-tubulin and peripherin. Neuronal expression may be associated with disease severity.
