Search Results (242)

Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancers with adenocarcinoma being the most common subtype. Patients with stage IV NSCLC typically have poor prognosis. In these patients, identification of actionable genomic alterations allows for the selection of targeted therapy rather than chemotherapy or chemo-immunotherapy. EGFR mutations are a common oncogenic driver in NSCLC and are targetable by tyrosine kinase inhibitors (TKIs). However, most of the studies primarily focus on common mutations, which are exon 19 deletions (Ex19del) and exon 21 (L858R) point mutations, and there is inconsistent data on efficacy in the treatment of patients with uncommon EGFR mutations. Currently, the first-line treatment for patients with common EGFR mutations involves a third-generation TKI, typically osimertinib. This case describes a 66-year-old gentleman with two uncommon EGFR frameshift deletions (E701fs and L702fs). His tumor staging was denoted as cT3N2M1b, stage IVA. The patient demonstrated a radiological and biochemical response to osimertinib as part of the OCELOT clinical trial (supported by a grant from AstraZeneca), with evidence of tumor marker decline and radiographic improvement within two months of osimertinib treatment initiation. This response has been durable with continued radiological stability and biochemical improvement at 11 months and ongoing. This case will help guide management for patients with this uncommon EGFR mutations and contribute to the scarce literature of EGFR frameshift deletions in advanced NSCLC patients. Full article

Background: Non-small cell lung cancer (NSCLC), particularly in advanced stages, has poor prognosis. The main objective of the study is to evaluate real-world treatment outcomes in advanced NSCLC patients harboring an EGFR mutation and being treated with TKIs. Methods: The EGFR mutation status was ascertained by next-generation sequencing. The observational cohort study used prospectively maintained registry data. Patient data were collected at two high-volume institutions in Austria between November 2020 and February 2025. The prevalence of EGFR mutations was 11% (145 out of 1267 patients). Results: Among 53 patients (stage IIIB or higher) with an EGFR mutation, median overall survival (OS) and median progression-free survival (PFS) were 17.7 months (95% CI: 10.4–24.9) and 14.2 months (95% CI: 7.4–20.9), respectively. A total of 36 patients harbored common EGFR mutations (exon 19 deletion or L858R point mutation) and exhibited a significantly better OS than those with an uncommon EGFR genotype (p < 0.005). Patients with exon 19 deletion (n = 25) showed the longest mOS, followed by those with L858R mutation (32.5 vs. 17 months). In multivariable analysis, the EGFR common mutation subtype (HR = 3.71 95%CI: 1.23–11.2) was associated with better OS. Patients with common EGFR genotypes, especially exon 19 deletion obtained longer OS and PFS compared with those with uncommon mutations in exon 18–21. Conclusions: The results underscore the prognostic role of distinct EGFR genotypes and the urgency of determining the mutation status in non-small cell lung cancer patients to ensure the best treatment decision. The study also highlights the challenges regarding to EGFR uncommon mutations and the resulting need for further research to investigate alternative treatment options. Full article

Cognitive impairment is a frequent but heterogeneous consequence of SARS-CoV-2 infection, with objective cognitive deficits not always aligning with subjective cognitive complaints. Age, nutritional status, and stress-related biological pathways may contribute to this variability. The corticotropin-releasing hormone receptor 1 (CRHR1), a key regulator of stress and neuroendocrine responses, represents a biologically plausible candidate for post-infection cognitive vulnerability. In this pilot case–control study, we investigated associations between CRHR1 copy number variations (CNVs), prior viral exposures, and cognitive outcomes in adults following SARS-CoV-2 infection. Objective cognitive performance was assessed using the Montreal Cognitive Assessment (MoCA) and RBANS, alongside evaluation of subjective cognitive complaints and depressive symptoms. Analyses accounted for age and circulating levels of vitamins B12, B9, and vitamin D. CRHR1 CNVs affecting specific exons (Exon 1 [210 nucleotides] and Exon 11) were associated with objective cognitive impairment, whereas subjective cognitive complaints were more closely related to depressive symptoms than measurable cognitive deficits. Associations with age and certain viral seropositivities (HSV-1, HSV-2, and Hepatitis A) were also observed with objective cognitive outcomes; however, these findings should be interpreted cautiously given their exploratory nature. This study highlights CRHR1 CNVs as potential modifiers of objectively measured post-COVID-19 cognitive impairment and underscores the importance of distinguishing subjective cognitive complaints from objective cognitive dysfunction, providing a framework for future mechanistic and longitudinal studies. Full article

Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) is an RNA-binding protein known to play critical roles in metabolism, cell proliferation, and tumorigenesis. Although its involvement in muscle development has been documented in several species, the function of goose IGF2BP2 remains largely unexplored. In this study, we cloned and characterized the full-length cDNA and genomic DNA sequences of goose IGF2BP2. The cDNA is 2957 bp in length and contains a 1662 bp open reading frame encoding a 553-amino acid protein with five conserved RNA-binding domains. The genomic sequence spans 12,183 bp and consists of 12 exons and 11 introns. A total of 60 genetic variants were identified, including a deletion of a G base at position 2299 (g.2299delG) that results in a frameshift mutation. Expression analysis revealed high levels of IGF2BP2 mRNA in the liver, heart, and muscle tissues of female geese across embryonic (E25d), growing (A70d), and laying (L270d) stages, consistent with a potential role in muscle development (p < 0.05). Functionally, overexpression of IGF2BP2 in skeletal muscle satellite cells (SMSCs) was associated with significant changes in the expression of several genes linked to muscle development and signaling pathways, including upregulation of IGF1, EGFR, FGF19, BMP6, BMP2, ACVR1C and WNT5A and downregulation of MYBPC3, NODAL, HOXD13, TNXB, and ADD2 (Padj < 0.01). Furthermore, protein–protein interaction (PPI) network analysis of these genes suggests that IGF2BP2 may coordinate key genes, contributing to its potential role in skeletal muscle development in geese. Full article

Protein phosphatase 2Cs (PP2Cs) constitute a widespread family of signaling regulators in plants and play central roles in abscisic acid (ABA)-mediated stress signaling; however, the PP2C gene family has not yet been systematically identified and characterized in pea (Pisum sativum), a salt-sensitive legume crop. In this study, we identified 89 PsPP2C genes based on domain features and sequence homology. These genes are unevenly distributed across seven chromosomes and classified into ten subfamilies, providing a comparative framework for evaluating structural and regulatory diversification within the PsPP2C family. The encoded proteins vary substantially in length, physicochemical properties, and predicted subcellular localization, while most members contain the conserved PP2Cc catalytic domain. Intra- and interspecies homology analyses identified 19 duplicated gene pairs in pea and numerous orthologous relationships with several model plants; all reliable gene pairs exhibited Ka/Ks < 1, indicating pervasive purifying selection. PsPP2C genes also showed broad variation in exon number and intron phase, and their promoter regions contained diverse light-, hormone-, and stress-related cis-elements with heterogeneous positional patterns. Expression profiling across 11 tissues revealed pronounced tissue-specific differences, with generally higher transcript abundance in roots and seeds than in other tissues. Under salt treatment, approximately 20% of PsPP2C genes displayed concentration- or time-dependent transcriptional changes. Among them, PsPP2C67 and PsPP2C82—both belonging to the clade A PP2C subfamily—exhibited the most pronounced induction under high salinity and at early stress stages. Functional annotation indicated that these two genes are involved in ABA-related processes, including regulation of abscisic acid-activated signaling pathway, plant hormone signal transduction, and MAPK signaling pathway-plant. Collectively, this study provides a systematic characterization of the PsPP2C gene family, including its structural features, evolutionary patterns, and transcriptional responses to salt stress, thereby establishing a foundation for future functional investigations. Full article

The GLABROUS1 Enhancer Binding Protein (GeBP) family, plant-specific transcription factors with a non-classical Leu-zipper motif, plays crucial roles in plant development and stress responses. Although GeBP genes have been characterized in several Gramineae crops, including a preliminary genome-wide identification of 11 GeBP genes in common wheat (Triticum aestivum L.), a comprehensive and systematic analysis of the TaGeBP family remains lacking. In this study, 37 TaGeBP genes were identified in the wheat genome (cv. Chinese Spring), representing a substantially higher number than the 11 reported in the prior study. This discrepancy is likely attributable to the integration of updated genome assemblies, refined gene identification criteria, and comprehensive domain validation. Phylogenetic analysis classified these 37 TaGeBPs into four distinct groups, with members within the same subgroup sharing conserved exon–intron architectures and protein motif compositions. Promoter cis-acting element analysis revealed significant enrichment of motifs associated with abiotic stress responses and phytohormone signaling, implying potential involvement of TaGeBPs in mediating plant adaptive processes. Evolutionary analysis indicated that TaGeBP family expansion was primarily driven by allopolyploidization and segmental duplication, with purifying selection constraining their sequence divergence. Members within the same subgroup shared similar exon–intron structures and conserved protein motifs. Promoter analysis revealed that TaGeBP genes are enriched with cis-elements related to stress and phytohormone responses, suggesting their potential involvement in adaptive processes. Gene expansion in the TaGeBP family was mainly driven by allopolyploidization and segmental duplication, with evolution dominated by purifying selection. Tissue-specific expression profiling demonstrated that most TaGeBPs are preferentially expressed in roots and spikes, with varying expression patterns across different tissues. Under salt and drought stresses, qRT-PCR results indicated diverse response profiles among TaGeBPs. Furthermore, subcellular localization confirmed the nuclear presence of selected TaGeBPs, supporting their predicted role as transcription factors. These findings offer important insights for further functional characterization of TaGeBP genes, particularly regarding their roles in abiotic stress tolerance. Full article

Auxin response factors (ARFs) are crucial components of auxin signaling, playing a vital role in plant growth, development, hormone regulation, and stress responses. Salinity influences plant growth and development; however, Avicennia marina exhibits remarkable salt tolerance. This study analyzed Avicennia marina ARF genes (AmARFs) and their roles in responding to salt and indole-3-acetic acid (IAA) stress. The results indicated that across 5–15 days, endogenous IAA and abscisic acid (ABA) levels in A. marina leaves showed significant, time-dependent changes under salt and IAA treatments, with IAA fluctuating around 2.0–3.3 µg g⁻¹ FW and ABA rising sharply under combined high-salt + IAA conditions (AS25), reaching up to ~25 µg g⁻¹ FW (p < 0.05). This is the first genome-wide identification of 41 ARF genes in Avicennia marina with expression responses to combined salt and auxin treatments. We identified 41 AmARF genes spread across 23 chromosomes. These genes are divided into four groups according to their phylogenetic relationships. Their coding regions encode amino acids from 361 to 1264, and the number of exons varies from 2 to an unspecified upper limit of 25. Examining these gene promoters revealed various hormone- and stress-response elements, with each gene containing distinct response elements. Sixteen miRNAs can inhibit various ARF genes, while protein–protein interactions and 3D structures offered valuable insights into AmARF proteins. GO enrichment analysis revealed that all 41 AmARFs are involved in the auxin-activated signaling pathway and are also involved in cell division. According to the expression experiments, 11 randomly selected genes showed predominantly upregulation in response to salt and IAA stressors compared with controls. These findings extend our understanding of the functional roles of AmARFs in stress responses. The systematic annotation of AmARF family genes offers candidate genes for future functional validation, which may help elucidate the precise roles of AmARFs in stress responses. Full article

Background: Pathogenic variants in interphotoreceptor matrix proteoglycan 1 (IMPG1) have been associated with autosomal dominant and recessive retinitis pigmentosa (RP) and autosomal dominant adult vitelliform macular dystrophy (AVMD). Monoallelic pathogenic variants in IMPG2 have been linked to maculopathy and biallelic variants to RP with early onset macular atrophy. Herein we characterise the phenotypic and genotypic features of patients with IMPG1/IMPG2 retinopathy and report novel variants. Methods: Patients with IMPG1 and IMPG2 variants and compatible phenotypes were retrospectively identified. Clinical data were obtained from reviewing the medical records. Phenotypic data included visual acuity, imaging included ultra-widefield pseudo-colour, fundus autofluorescence, and optical coherence tomography (OCT). Genetic testing was performed using next generation sequencing (NGS). Variant pathogenicity was investigated using in silico analysis (SIFT, PolyPhen-2, mutation taster, SpliceAI). The evolutionary conservation of novel missense variants was also investigated. Results: A total of 13 unrelated patients were identified: 2 (1 male; 1 female) with IMPG1 retinopathy and 11 (7 male; 4 female) with IMPG2 retinopathy. Both IMPG1 retinopathy patients were monoallelic: one patient had adult vitelliform macular dystrophy (AVMD) with drusenoid changes while the other had pattern dystrophy (PD), and they presented to clinic at age 81 and 72 years, respectively. There were 5 monoallelic IMPG2 retinopathy patients with a maculopathy phenotype, of whom 1 had PD and 4 had AVMD. The mean age of symptom onset of this group was 54.2 ± 11.8 years, mean age at presentation was 54.8 ± 11.5 years, and mean BCVAs were 0.15 ± 0.12 logMAR OD and −0.01 ± 0.12 logMAR OS. Six biallelic IMPG2 patients had RP with maculopathy, where the mean age of onset symptom onset was 18.4 years, mean age at examination was 68.7 years, and mean BCVAs were 1.90 logMAR OD and 1.82 logMAR OS. Variants in IMPG1 included one missense and one exon deletion. A total of 11 different IMPG2 variants were identified (4 missense, 7 truncating). A splicing defect was predicted for the c.871C>A p.(Arg291Ser) missense IMPG2 variant. One IMPG1 and five IMPG2 variants were novel. Conclusions: This study describes the phenotypic spectrum of IMPG1/IMPG2 retinopathy and six novel variants are reported. The phenotypes of PD and AVMD in monoallelic IMPG2 patients may result from haploinsufficiency, supported by the presence of truncating variants in both monoallelic and biallelic cases. The identification of novel variants expands the known genetic landscape of IMPG1 and IMPG2 retinopathies. These findings contribute to diagnostic accuracy, informed patient counselling regarding inheritance pattern, and may help guide recruitment for future therapeutic interventions. Full article

Improving plant water use efficiency (WUE) and drought tolerance by modulating stomatal activity constitutes a promising strategy for mitigating the impacts of water scarcity. SnRK2, a key component of the abscisic acid (ABA) signaling pathway, plays a critical role in modulating stomatal behavior under abiotic stress. However, the functional role of SnRK2 in regulating stomatal movement to enhance WUE and drought tolerance in Populus euphratica remains to be characterized. In this study, 11 PeSnRK2 genes were identified in the P. euphratica genome, each comprising 9–14 exons and exhibiting an uneven distribution across seven chromosomes. Subcellular localization predictions indicated that these proteins are predominantly localized in the Cytoplasm and Cytoskeleton. Phylogenetic analysis grouped the PeSnRK2 genes into three distinct subfamilies, and conserved gene structures were observed within each clade. Analysis of cis-acting regulatory elements suggested that PeSnRK2 genes were involved in hormonal signaling and stress response pathways. Further transcriptomic data also indicated substantial alterations in PeSnRK2 expression due to polyethylene glycol (PEG) and abscisic acid (ABA) treatment. Finally, qRT-PCR and subcellular localization showed that PeSnRK2.6 is highly induced by ABA and functions in both nucleus and cytoplasm. This first characterization in a desert woody species bridged gaps in SnRK2 evolution and function. Full article

Introduction: The aim of the study was to analyse the results and potential complications of local treatment with HDR (high dose-rate) brachytherapy of liver metastases from colorectal cancer, depending on the targeted therapy used and considering RAS gene mutation and chemotherapy in individual treatment lines. Material and methods: The study included 142 patients with oligoprogressive liver metastases who underwent HDR brachytherapy without changing the line of treatment, based on a retrospective analysis of 270 patients treated between 2015 and 2022. The impact of RAS gene mutations, lines of chemotherapy depending on the treatment regimens used, PFS (progression free survival), OS (overall survival), LC (local control) and the degree of radiological response were analysed. The impact of these drugs on hepatotoxicity and the risk of haemorrhagic complications was also analysed. Results: The presence of mutations in KRAS/NRAS genes (exons 2, 3, 4) had a statistically significant impact on PFS in the first, third and fourth lines of treatment, and on OS and LC in the third and fourth lines of treatment. In the third and fourth lines of treatment, patients with a mutation in the RAS gene had a poorer radiological response to treatment regardless of the chemotherapy used. PFS, OS and LC differed depending on the line of treatment and amounted to 17.5, 11, 8.5, 6 and 4 months, 27, 19, 13, 11 and 11 months, and 27, 19, 11, 6 and 6 months, respectively. The greatest benefit in terms of PFS was achieved by patients treated with first-line chemotherapy combined with epidermal growth factor receptor (EGFR) inhibitors, in the absence of RAS gene mutations. In the third line, the greatest benefit was achieved by patients treated with trifluridine/tipiracil in the absence of RAS gene mutations. The greatest percentage reduction in the volume of treated lesions and the highest percentage of control were observed in the first three lines of treatment. The toxicity of the treatment was low; only in the third and fourth lines of treatment were differences in the decrease in albumin levels found depending on the type of treatment used. Conclusions: A mutation in the RAS genes worsens the prognosis, regardless of the line of treatment and the systemic treatment used. The greatest benefit from brachytherapy is seen in patients in the first three lines of treatment without RAS mutations, treated with anti-EGFR chemotherapy in the first line and trifluridine/tipiracil in the third line. Combining brachytherapy of liver metastases with systemic treatment is safe, regardless of the systemic treatment used. Full article

This study conducted a genome-wide identification and systematic evolutionary analysis of the banana WRKY gene family using bioinformatics, transcriptomics, and molecular biology approaches. A total of 153 WRKY genes were identified in the banana genome, with significant differences in the amino acid count, molecular weight, and other physicochemical properties of their encoded proteins. The subcellular localization of these proteins is primarily in the nucleus. These genes are unevenly distributed across 11 chromosomes, with the highest density on chromosome 7. WRKY gene family members exhibit diverse expression patterns during fruit development and ripening, and some can respond to multiple abiotic and biotic stresses. Systematic evolutionary analysis classified them into three major groups (I, II, and III), with Group II having the highest number of members, which are further divided into five subgroups. Conserved motif analysis revealed that Motif1, Motif2, and Motif4 are key structural elements in the family’s evolution, with some members having a WRKYGKK variant. The gene structure shows a wide range of exon numbers (1–22), and the promoter regions are rich in cis-elements related to light response, hormone signaling, and stress response, indicating their potential for integrating light signals, hormone networks, and multiple stress responses. Collinearity analysis identified 116 segmental duplication events, with Ka/Ks values all less than 1, indicating purifying selection. After ethylene treatment, 51 genes showed significant changes in expression, which can be categorized into four patterns: sustained upregulation, sustained downregulation, initial upregulation followed by downregulation, and delayed upregulation. Among these, MaWRKY10, MaWRKY88, and MaWRKY137 exhibited significant expression changes and may play key roles in fruit ripening. These findings significantly contribute to the theoretical framework regarding the evolution and function of the WRKY family in plants. Moreover, they offer valuable gene resources and regulatory strategies that enhance postharvest banana preservation and molecular breeding efforts. Full article

Background/Objectives: Liquid biopsy using cfDNA has emerged as a promising, minimally invasive alternative to traditional tissue biopsy for detecting cancer-associated mutations. However, the extremely low proportion of mutant DNA in cfDNA poses a major challenge for accurate detection, especially when using conventional sequencing methods. To address this limitation, we sought to develop a highly sensitive diagnostic strategy to selectively enrich rare mutant sequences and improve the detection of clinically important mutations in patients with NSCLC. Methods: We established a CRISPR/Cas12a-based diagnostic system designed to selectively cleave WT DNA, thereby increasing the relative abundance of mutant DNA in cfDNA samples. Following Cas12a-mediated WT cleavage, the remaining DNA was subjected to PCR amplification for mutation identification. The system was applied to plasma cfDNA from blood samples of 48 NSCLC patients to evaluate its ability to detect two major EGFR mutations: L858R and exon 19 deletion. Results: The CRISPR/Cas12a-based diagnostic system effectively identified low-frequency EGFR mutations in cfDNA. Specifically, all 7 L858R-positive samples and 6 out of 11 samples harboring exon 19 deletions—previously validated through tissue biopsy—were successfully detected. This demonstrated a high degree of concordance between our liquid biopsy approach and conventional diagnostic methods. Conclusions: Our findings highlight the potential of the CRISPR/Cas12a-based mutation enrichment system as a powerful tool for detecting rare oncogenic mutations in liquid biopsy samples. This technique enhances diagnostic sensitivity and could be broadly applicable for the non-invasive detection of various genetic alterations in cancer and other diseases. Full article

Background/Objectives: CDH1 gene is widely studied, as pathogenic variants are involved in diffuse gastric cancers and lobular breast cancers. CDH1 genotype contributes to the management of clinical practice recommendations for cancer prevention. We proposed a qualitative and quantitative description of CDH1 alternative splicing profile on lymphoblastoid cell lines (LCLs). The aim of this description was to allow a comprehensive interpretation of the effect of variants of uncertain significance (VUS) on CDH1 splicing. Methods: We studied, using RNAseq, the splicing profile of 22 LCLs (untreated and treated with puromycin) with no pathogenic variant on CDH1 and evaluated the effect on CDH1 splicing of four VUS. Results: We highlighted a total of eleven alternative splicing events including four junctions starting from intron 2, defining novel isoforms of CDH1. We also identified an isoform causing the skip of exon 11 and leading to a disruption of the reading frame with high levels of expression on negative CDH1 control LCLs, confirmed by ddPCR. Splicing RNAseq results for CDH1 VUS: c.1008+1G>A and c.1936+5G>A showed complex splicing patterns but allowed their classification as pathogenic. We studied CDH1 VUS exon 4 to exon 11 duplication with RNA analysis combined with Bionano optical genome mapping. Depending on alternative splicing of proximal and distal exons 11 within the duplication, we identified four distinct transcripts, leading to truncated proteins, classifying the duplication as pathogenic. Conclusions:CDH1 has a complex alternative splicing profile characterized by a dynamic splicing of intron 2 making CDH1 a good candidate for a study using long-read RNAseq. Full article

Background: The health and viability of captive elephants, which are central to off-site conservation efforts and health management in Thailand, is threatened by emerging infectious diseases. This is partly due to genetic differences in immune-related genes, especially in the major histocompatibility complex (MHC) and, among these, loci such as DQA play a crucial role in immune surveillance. Data pertaining to MHC polymorphisms in elephants are scarce, and thus this study investigated such polymorphisms and selection signatures in a partial fragment of exon 2 of the MHC Class II DQA gene. Methods: The approach we used targeted next-generation sequencing and diversity analyses of individuals from three captive elephant camps in Northern Thailand. Results: Eight alleles containing 11 SNPs were identified in the exon 2 fragment, encompassing both silent and missense mutations, some of which may influence immune function. Notably, the allele Elma-DQA*TH3, which is identical to Loaf-DQA*01 and Elma-DQA*01, previously reported as the most common alleles in Loxodonta and Elephas, was found at low frequencies. This shift may reflect local selective pressures that shape MHC allele distributions. Evidence of mixed selection (both positive and balancing) was detected in the partial fragment of DQA exon 2, suggesting a dynamic interplay between evolutionary forces. Positive selection likely reflects an adaptation to emerging or locally prevalent pathogens, whereas balancing selection maintains allelic diversity over time to enable a broad immunological response. Conclusions: Our findings reveal immunogenetic variations in captive Thai elephants, and provides insights into host–pathogen interactions that inform conservation and health strategies with the aim of improving disease resilience. Full article

Introduction: Epidermal growth factor receptor (EGFR) alterations exist in 15–50% of non-small cell lung cancer (NSCLC) diagnoses. Although effective therapeutics have been developed in the form of tyrosine kinase inhibitors (TKI), various mechanisms of resistance lead to treatment failure after exposure to EGFR TKI-based therapy. Of these, histologic transformation (HT) into small cell lung cancer (SCLC) represents approximately 14% of cases. Methods: Within a single institution, we retrospectively reviewed longitudinal data from both tissue and liquid biopsies of patients with histologic transformation after a diagnosis of EGFR-mutant NSCLC. We sought to further characterize the baseline and emergent genomic alterations after HT to SCLC in the context of TKI exposure, along with germline alterations that may contribute to lineage plasticity and outcomes. Results: Fifteen patients were included in our analysis. Of these, EGFR exon 19 deletions were the most frequent (n = 11, 73.3%), followed by L858R (n = 3, 20%) and L861Q (n = 1, 6.7%). The median time for transformation was 17 months (95%CI, 8.9–41.9 months). The median OS of our cohort was 51.6 months (95%CI, 26.3—NE) with a median OS post-transformation of 13.4 months. Recurrent genomic alterations included TP53, Rb1, PIK3CA, and BRAF. Germline testing revealed a pathogenic alteration in FBN1, with a recurrent variant of unknown significance (VUS) in PALLD. Conclusion: Post-transformation somatic mutation testing and germline testing at presentation revealed unique mutational profiles not previously reported in the setting of HT to SCLC. Further investigations are required to determine the optimal treatment and sequencing following HT. Full article