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Article

Comprehensive Genomic Profiling of Small-Cell Lung Cancer Reveals Frequent Potentially Targetable Alterations

by
Dániel Schmalz
1,
Zoltán Krabóth
2,
Veronika Czoma
2,
Péter Urbán
1,
Attila Gyenesei
1,
István Ruzsics
3,
Veronika Sárosi
3,
Árpád Boronkai
4,
Emőke Papp
4 and
Béla Kajtár
2,*
1
Center of Omics, János Szentágothai Research Center, University of Pécs, Ifjúság Street 20, 7624 Pécs, Hungary
2
Department of Pathology, Clinical Centre, University of Pécs, Szigeti Street 12, 7624 Pécs, Hungary
3
1st Department of Internal Medicine, Clinical Centre, University of Pécs, Ifjúság Street 13, 7624 Pécs, Hungary
4
Department of Oncotherapy, Clinical Centre, University of Pécs, Édesanyák Street 17, 7624 Pécs, Hungary
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2025, 26(23), 11512; https://doi.org/10.3390/ijms262311512
Submission received: 19 October 2025 / Revised: 23 November 2025 / Accepted: 25 November 2025 / Published: 27 November 2025
(This article belongs to the Special Issue Small Cell Lung Cancer Entering the Sphere of Personalized Treatment)
Browse Figure
Versions Notes

Abstract

Small-cell lung carcinoma (SCLC) remains one of the most aggressive lung cancers and continues to pose a major challenge for precision oncology. Despite its morphological uniformity, SCLC exhibits marked molecular heterogeneity with recurrent, potentially targetable genomic alterations. Comprehensive profiling is often hindered by limited tissue availability and the need for rapid therapeutic intervention. We performed genomic profiling of 55 primary and metastatic SCLC samples using a 324-gene hybrid-capture next-generation sequencing panel. Consistent with prior reports, nearly all tumors exhibited biallelic TP53 and RB1 inactivation. Recurrent alterations involved the PI3K/Akt/mTOR pathway (62%), chromatin regulators (42%), and NOTCH signaling genes (15%). PTEN mutations were enriched in brain metastases. Frequent copy-number gains affected SOX2, NKX2-1, MYC-family genes, and CCNE1. Two novel recurrent amplifications of potential clinical significance were identified: TYRO3 (33%) and SDHA (13%). TYRO3, a TAM family receptor tyrosine kinase, and SDHA, a mitochondrial enzyme involved in succinate metabolism, may contribute to tumor progression and represent emerging therapeutic vulnerabilities. These findings underscore the genomic diversity of SCLC and highlight the potential utility of broad next-generation sequencing in uncovering new molecular targets for precision therapy.

1. Introduction

Small-cell lung carcinoma (SCLC) is the most aggressive form of lung cancer, accounting for approximately 15% of cases. It occurs predominantly in heavy smokers and is characterized by neuroendocrine differentiation, rapid proliferation, and early metastatic spread [1]. Although initially responsive to chemotherapy, relapse is almost inevitable, resulting in limited long-term survival. SCLC is clinically categorized as limited or extended stage disease, the former being confined to a single thoracic radiation field. The five-year overall survival for extended stage SCLC remains below 6% [2]. The addition of immune checkpoint inhibitors to the standard platinum-based chemotherapy has modestly improved survival in extended stage cases, but only a minority of patients benefit, largely due to the profoundly immunosuppressive tumor microenvironment [3].
Molecular subtypes of SCLC have been delineated based on transcriptional profiles, each associated with distinct biological features. The most common is the ASCL1-defined SCLC-A subtype, representing 40–50% of cases and characterized by high neuroendocrine marker expression. The NEUROD1-driven subtype (SCLC-N) typically shows lower neuroendocrine marker expression, whereas the POU2F3-defined subset (SCLC-P) is largely without classical neuroendocrine markers. A fourth subtype was originally proposed to be defined by YAP1 expression (SCLC-Y); however, more recent studies suggest that the fourth lineage is better represented by an inflammation-associated state (SCLC-I) [4]. Despite their biological relevance, these classifications do not yield actionable targets or predictive biomarkers, limiting their clinical utility [3]. Genomic studies remain constrained by frequent necrosis and the scarcity of available tumor tissue. Although analysis of cell-free DNA and circulating tumor cells offers a promising alternative, its clinical applicability is still being defined [5].
Previous genomic studies have typically examined a relatively low number of patients with few investigating more than 50 SCLC cases, often enriched for limited-stage disease amenable to surgical resection [2,6,7,8,9,10,11]. A recent large-scale study analyzing 3600 SCLC tumor samples, primarily of European ancestry, provided valuable insights regarding incidence of genomic alterations and associations with clinical features [5]. There is, however, a wide variability in mutation frequencies across cohorts and methodologies.
The present study reports real-world comprehensive genomic profiling of 55 Hungarian limited and extended stage SCLC patients, including both primary tumors and metastases. Using a 324-gene hybrid-capture panel applicable to formalin-fixed paraffin-embedded and cytological specimens, we characterized the landscape of genetic alterations and evaluated their associations with clinicopathological features.

2. Results

2.1. Recurrent Small Genetic Variants

TP53 inactivation was detected in 54 of 55 samples (98%), appearing biallelic in all cases based on the presence of two independent mutations, homozygous deletion, or a single mutation with a variant allele frequency (VAF) indicative of loss of the wild-type allele. Twenty tumors harbored truncating TP53 mutations, including five splice-site and 15 frameshift variants, while 35 carried missense mutations (Figure 1, Supplementary Table S1).
RB1 inactivation was identified in 45 samples (82%). Homozygous deletions were detected in 4 cases, combined deletion and mutation in 1, and VAFs suggesting loss of wild-type RB1 in 40 cases. One sample harbored two distinct heterozygous RB1 mutations.
Alterations activating the PI3K/Akt/mTOR signaling pathway were present in 34 of 55 cases (62%). PTEN inactivation occurred in 22%, activating PIK3CA mutations in 5%, and inactivating TSC2 mutations in 4%. Amplifications of PRKCI, RICTOR, PIK3CA, PIK3CB, AKT1, or IRS2 were identified in an additional 34% of cases. Notably, all tumors lacking RB1 alterations showed genetic activation of the PI3K/Akt/mTOR pathway (p = 0.002, Supplementary Table S3).
Mutations affecting chromatin regulators—including histone methyltransferases, acetyltransferases, and genes modulating chromatin accessibility—were observed in 42% of cases. The most frequently altered genes were KMT2D (15%), CREBBP (7%), ARID1A (5%), and ATRX (5%), followed by EP300 and ASXL1 (two cases each). These alterations were mutually exclusive. Amplification of H3F3A, encoding the histone variant H3.3, was found in 13% of cases, often co-occurring with mutations in the above genes. TET2, encoding a DNA dioxygenase involved in epigenetic regulation, showed loss-of-function mutations in 5%.
Genes of the NOTCH signaling pathway were affected in 15% of cases (8/55), predominantly through loss-of-function mutations in NOTCH1 (7%), followed by FBXW7 inactivation (5%) and NOTCH2 mutation (one case). FBXW7 loss is expected to increase NOTCH1 activity, and that of other oncogenic targets (e.g., MYC, CCNE1), and may influence chromatin architecture through impaired degradation of multiple regulatory proteins.
Defects in homologous recombination repair (HRR) genes were identified in 10 of 55 cases (18%), involving ATR (two cases), and ATM, BRCA2, CDK12, NBN, FANCG, MLH1, RAD54L, and PARP2 (one case each). These alterations comprised truncating mutations or homozygous deletions and were significantly associated with PTEN loss (42% with mutation vs. 12% in PTEN-wild-type cases, p = 0.03).
The tumor mutation burden (TMB) was high across the cohort, with a mean of 12.7 mutations per megabase. Three samples could not be assessed with high confidence. Using a cutoff of 10 mutations/MB, 28 tumors exhibited high TMB, and 24 showed low TMB. All cases were microsatellite stable.

2.2. Recurrent Copy Number Changes

SOX2 amplification was detected in 27 of 55 tumors (49%) and was more frequent in metastases (64%) than in primary tumors (30%) (p = 0.01). It was also associated with high tumor mutation burden (TMB) (64% in high vs. 33% in low TMB cases; p = 0.025).
NKX2-1 amplification occurred in 24 of 55 tumors (44%), significantly enriched in metastases (81%) compared with primary tumors (19%) (p < 0.001). SOX2 and NKX2-1 were frequently coamplified (75% of NKX2-1- and 67% of SOX2-amplified cases showed amplification of the other gene, respectively; p < 0.001). Amplification of either gene correlated with the type of TP53 mutation: truncating TP53 variants predominated in SOX2/NKX2-1-amplified tumors (58% with vs. 19% without amplification; p = 0.003), whereas missense TP53 mutations were more common in non-amplified cases (81% vs. 42%; p = 0.003).
TYRO3, encoding a receptor tyrosine kinase, was amplified in 18 cases (33%). TYRO3 amplification correlated with mutations of chromatin regulators (57% with vs. 16% without amplification; p = 0.002) and was inversely associated with SOX2 or NKX2-1 amplification (11% with vs. 54% without SOX2 amplification; p < 0.001).
Amplifications of MYC (5%), MYCL (13%), and MYCN (5%) were recurrent but mutually exclusive. MYC-family amplifications were associated with SOX2 amplification (37% with vs. 11% without; p = 0.023) and were more frequent in tumors lacking TYRO3 amplification (6% with vs. 32% without TYRO3 amplification; p = 0.025).
Genetic alterations promoting cell cycle progression were identified in 13 of 55 cases (24%), including CCNE1 amplification (11%), CCND1 amplification (7%), CDK4 amplification (one case), and CDKN2A inactivation (one case).
SDHA amplification was detected in seven tumors (13%). TET2 or ASXL1 mutations were significantly associated with SDHA amplification (43% with vs. 4% without; p = 0.012).
Amplification of any gene located within the 3q chromosomal region was observed in 37 of 55 cases (67%), including KLHL6, SOX2, PRKCI, PIK3CA, PIK3CB, and TERC. KLHL6, PRKCI, and TERC were frequently coamplified, whereas SOX2 and PRKCI amplifications tended to be mutually exclusive: SOX2 amplification occurred in 25% of PRKCI-amplified tumors versus 56% of PRKCI-wild-type cases (p = 0.058; not reaching statistical significance).
Finally, six tumors (11%) showed amplification of BCL2, BCL2L1, or BCL2L2, consistent with enhanced apoptotic resistance and increased cell survival.

2.3. Genetic Alterations Recurrent in NSCLC

Genetic alterations more typically associated with non-small-cell lung carcinoma (NSCLC) were identified in seven cases. One patient—a never-smoker male—harbored an EGFR p.(L858R) activating mutation detected in a liver metastasis. He had been diagnosed with lung EGFR-mutated adenocarcinoma 28 months earlier. Following initial treatment with gefitinib, disease progression occurred after 14 months, at which time an EGFR p.(T790M) resistance mutation was identified by liquid biopsy. The patient was subsequently treated with osimertinib, achieving stable disease for 14 months, after which multiple liver metastases developed. Liver biopsy at that time revealed histologic transformation to SCLC. The transformed tumor retained the same EGFR p.(L858R), and RB1, TP53, and PIK3CA mutations as the original adenocarcinoma, while showing RICTOR amplification as a novel change.
In five additional cases, tumors carried KRAS or HRAS activating mutations or BRAF fusions, with no clinical evidence of a preceding NSCLC diagnosis. A further SCLC tumor exhibited a SMARCA4 loss-of-function mutation. Although histologic evaluation was limited by crush artifact, cytomorphologic and immunophenotypic features were consistent with SCLC, showing TTF1 expression and no consistent loss of SMARCA4 positivity by immunohistochemistry.

2.4. Correlation with Clinical Parameters

PTEN mutations and MYC-family amplifications (MYC, MYCL, or MYCN) were more frequent in brain metastases (43% and 38%, respectively) than in other sites (9% and 15%, respectively; p = 0.004 and p = 0.05, Table 1). Primary tumors more often harbored alterations in epigenetic regulators than metastatic samples (58% primary vs. 24% metastatic tumor; p = 0.012). TYRO3 amplification showed a similar pattern, being more frequent in primary tumors (65% primary vs. 3% metastatic tumor; p < 0.001). NKX2-1 and SOX2 amplifications were more common in metastases (p < 0.001 and p = 0.010).
Female patients exhibited a higher frequency of PTEN mutations (32% in females vs. 8% in males; p = 0.033) and missense TP53 mutations (81% vs. 42%; p = 0.003), whereas truncating TP53 mutations were less common in females (19% in females vs. 58% in males; p = 0.003, Table 2).
No genomic alterations showed significant correlation with overall survival, and tumors from patients with exceptionally long survival displayed alteration frequencies comparable to those of other cases (Supplementary Table S2).

3. Discussion

SCLC remains the most aggressive and lethal malignancy of the lung, with limited advances in targeted therapy and predictive biomarker development. Although immunotherapy has provided a modest survival benefit, only a minority of patients derive durable responses. Molecular subtyping of SCLC based on transcriptional profiles has recently been established, yet the clinical relevance of these categories remains incompletely understood [12]. Comprehensive genomic profiling of SCLC is therefore essential to identify actionable alterations and improve patient stratification; however, tumor heterogeneity and the limited availability of adequate tissue have hindered such efforts.
In this study, we demonstrated the feasibility of high-depth, DNA-based comprehensive genomic profiling using a targeted 324-gene panel, which enabled concurrent detection of single-nucleotide variants, copy number alterations, and tumor mutation burden (TMB), even from cytology-derived samples.
Consistent with previous reports, TP53 and RB1 were the most frequently altered genes, showing biallelic inactivation in 98% and 82% of cases, respectively—values at the upper end of published ranges (TP53: 80–97%, RB1: 60–80%) [2,5,6,7,8,9,10,11]. Interestingly, missense mutations were more common in female patients (Table 2). This difference between female and male patients has not been reported before and may reflect a sex-based disparity of TP53 gene expression and activity of gain-of-function mutations, as has been suggested previously related to tumorigenesis and cancer progression [13,14].
Alterations activating the PI3K/Akt/mTOR pathway were highly prevalent, affecting 62% of tumors. PTEN mutations occurred in 22% of cases and were strongly enriched in brain metastases (43% vs. 9% in other sites; p = 0.004), consistent with prior studies reporting a similar association [2,5,10]. This observation mirrors findings in NSCLC and other tumor types, where PTEN loss has been implicated in brain tropism [15,16] and aligns with the established role of PTEN in glioblastoma pathogenesis [17]. PIK3CA and TSC2 mutations were observed in 5% and 4% of cases, respectively, comparable to published frequencies (2–10%) [2,5,10,11]. In addition, amplifications of PRKCI, RICTOR, PIK3CA, PIK3CB, IRS2, or AKT1 were detected in 35% of cases, collectively indicating widespread pathway activation. RICTOR amplification occurred in 14% of cases, in line with previous reports, and it was suggested to be predictive of responsiveness to mTOR inhibition [18]. Although therapeutic blockade of PI3K/Akt/mTOR signaling remains a promising avenue, optimal patient selection and rational combination strategies are yet to be defined [19]. PRKCI amplification was detected in 22% of our cohort. PRKCI, encoding an atypical protein kinase C isoform, has been described as an oncogenic driver in ovarian and squamous lung carcinomas [20]. It contributes to tumorigenesis by disrupting cell polarity and suppressing autophagy and has been linked to poor prognosis in multiple cancer types [20]. The antirheumatic drug auranofin was recently shown to inhibit PRKCI and sensitize SCLC cells to sorafenib in vitro [21,22], highlighting a potential therapeutic avenue worth clinical exploration.
Amplifications of MYC, MYCL, and MYCN were found in 23% of cases, within the 6–25% range reported in the literature. MYC-family amplifications have been associated with increased sensitivity to aurora kinase inhibitors and poor prognosis, though no survival correlation was observed in our cohort [4,23,24].
Genetic alterations influencing epigenetic regulation are recurrent in SCLC. KMT2D (also known as MLL2) has been reported in 10–15% cases [5,6,7,10], CREBBP and EP300 mutations are also reported with 2–18% incidence [2,5,25]. These genes encode histone methyltransferase or acetyltransferase enzymes; their loss may alter chromatin accessibility, gene expression, and immune recognition [26]. ARID1A encodes a subunit of SWI/SNF chromatin remodeling complex that also contributes to the above-mentioned functions regarding chromatin maintenance. ARID1A mutations are also recurrent, occurring in 3–5% of cases. Alterations of chromatin remodeling have been reported to potentially contribute to immune evasion of cancer cells by downregulating MHC-I molecules and components of antigen presentation machinery [26]. It has been proposed that loss-of-function mutations of these genes may lead to reduced neuroendocrine identity and increased plasticity in SCLC, promoting survival and resistance to therapy [26]. ATRX encodes a chromatin remodeling protein that interacts with H3.3 histone proteins and is mutated in 2% of SCLC cases [5]. TET2 encodes a protein involved in DNA methylation affecting epigenetic regulation and is recurrently mutated in 1–2% of SCLC cases [5]. Our cohort showed mutations in the above-mentioned genes involved in epigenetic regulation in 42% of cases. Preclinical data suggest that patients harboring these alterations might benefit from BET, EZH2, or HDAC inhibitors, particularly in combination with immune checkpoint blockade [26].
Amplification of H3F3A, encoding histone variant H3.3, was observed in 13% of cases. H3F3A amplification or overexpression has been linked to enhanced migration and aggressive behavior in lung and esophageal cancers [27]. Activating mutations of H3F3A have been reported in gliomas and giant cell tumors of bone. Amplification has been described as recurrent in approximately 7.5% of esophageal carcinoma and was seen to be associated with shortened survival [28]. Similarly, SDHA amplification was detected in 13% of tumors and correlated with TET2 or ASXL1 mutations. SDHA encodes a mitochondrial enzyme; its amplification may alter cellular metabolism through changes in succinate and α-ketoglutarate levels, potentially influencing the activity of epigenetic regulators such as TET2 and ASXL1, and immune modulation within the tumor microenvironment. SDHA amplification has been described in ovarian and breast carcinomas, where it promotes metabolic reprogramming and sensitivity to agents such as shikonin [29,30]. Given preclinical reports that shikonin suppresses SCLC cell growth [31], SDHA amplification may represent a novel predictive biomarker warranting further investigation.
TYRO3 amplification was found in 33% of tumors, predominantly in primary sites. TYRO3, part of the TAM receptor tyrosine kinase family along with AXL and MERTK, regulates local anticoagulation, proliferation, migration, and immune evasion [32,33]. Overexpression of TYRO3 has been associated with resistance to immune checkpoint blockade via inhibition of ferroptosis [34]. Increased Dtk (a synonym of Tyro3) expression has been described in SCLC cell lines [35]. Although the TAM inhibitor sitravatinib failed to improve outcomes in unselected NSCLC patients when added to immunotherapy [36], TYRO3 amplification may identify a subset of SCLC patients who could benefit from TAM-targeted therapies [37].
Defects in homologous recombination repair (HRR) genes were observed in 18% of tumors, a frequency comparable to recent studies [38]. HRR-deficient tumors often exhibit sensitivity to platinum compounds and PARP inhibitors. In our cohort, HRR gene alterations were not associated with KMT2D mutation or high TMB as reported previously [38], but correlated with PTEN loss, suggesting a potential link between genomic instability and PI3K pathway deregulation. Studies have described germline pathogenic mutations of HRR genes like BRCA2, CHEK1 and RAD51D in SCLC patients [39] and have investigated the potential benefit of PARP inhibitors in SCLC therapy [40].
The most frequent alteration overall was SOX2 amplification (49%), which correlated with high TMB, NKX2-1 amplification, and metastatic localization. SOX2 plays a key role in neuroendocrine differentiation and pluripotency and is reported in 20–30% of SCLC cases [1]. Although NKX2-1 amplification is rarely described (2–3%), it is often expressed and is characteristic of the SCLC-A molecular subtype [41].
SCLC may arise from transformation of NSCLC, especially EGFR-mutated adenocarcinoma. In 13% of cases, we identified genomic alterations more characteristic of NSCLC, including EGFR, KRAS, and HRAS activating mutations, BRAF fusions, and SMARCA4 loss-of-function mutations. Except for a single case of histologically confirmed adenocarcinoma transformation, there was no clinical evidence of prior NSCLC. SMARCA4 mutations have been described in a small subset of SCLC but may also reflect SMARCA4-deficient undifferentiated carcinomas, a recently defined entity [5,42].
None of the genomic alterations identified in our study showed significant association with overall survival. Although amplification of 4q12 (including KIT, KDR, and PDGFRA) was recently linked to improved outcomes [5], no survival advantage was observed in our 4q12-amplified cases (5%), most likely attributable to the limited cohort size.
In summary, our comprehensive genomic analysis of 55 SCLC tumors revealed recurrent, potentially targetable alterations in the PI3K/Akt/mTOR, NOTCH, and chromatin remodeling pathways, and in genes involved in homologous recombination repair. Importantly, we report TYRO3 amplification for the first time in SCLC, detected in one-third of cases, suggesting a novel mechanism of tumor progression and a potential therapeutic vulnerability. It is important to note that published SCLC datasets—including the recent large real-world series by Sivakumar et al. [5]—exhibit substantial variability in mutation rates across genes and pathways. These differences may reflect heterogeneity in patient populations, sample types, sequencing platforms, and analytical pipelines rather than true biological divergence. Accordingly, our findings should be viewed as complementary to the larger datasets, while acknowledging that geographic or cohort-specific effects cannot be excluded. Validation in larger, multi-ethnic patient cohorts and functional studies is warranted to confirm the biological and clinical relevance of TYRO3 amplification in SCLC.

4. Materials and Methods

4.1. Patients and Samples

A total of 55 samples with adequate DNA of patients diagnosed with small-cell lung carcinoma (SCLC) at the Pathology Department of University of Pécs were included in this retrospective study. The mean age at diagnosis was 64 years (range, 43–87 years); 31 patients were female, and 24 were male (Table 3, Supplementary Table S4). All but one patient had a history of smoking.
Twenty-nine tumor samples were obtained from metastatic sites, most commonly from the central nervous system (n = 21), followed by the liver (n = 4), gastrointestinal tract (n = 2), lymph node (n = 1), and dermis (n = 1). The remaining 26 samples were derived from primary pulmonary tumors.
Cytological smears were available for 21 cases, while formalin-fixed, paraffin-embedded (FFPE) tissue blocks were used in 34. Tumor cellularity exceeded 20% in all specimens, with a mean tumor content of 75%.
Most patients received platinum-based chemotherapy. Ten patients underwent no systemic therapy or received palliative radiotherapy only, while treatment data were unavailable for 10 patients. The median follow-up duration was 8.5 months. Ten patients exhibited prolonged survival (>24 months), and survival data were not available for seven patients.

4.2. Comprehensive Genomic Profiling

Following pathological review and assessment of tumor purity, DNA was extracted using an automated purification system (Ion Torrent Genexus Purification System; FFPE DNA and RNA Purification Kit, Thermo Fisher Scientific, Waltham, MA, USA) according to the manufacturer’s instructions.
Comprehensive genomic profiling was performed using the AVENIO Tumor Tissue Comprehensive Genomic Profiling (CGP) Kit (Roche, Switzerland), a research-use-only, DNA-based hybrid-capture next-generation sequencing (NGS) assay targeting 324 cancer-associated genes (Supplementary Table S5). The panel enables detection of single-nucleotide variants (SNVs), insertions/deletions (indels), copy number variations (CNVs), and structural rearrangements, and estimation of tumor mutational burden (TMB) and microsatellite instability (MSI). The AVENIO CGP gene content and secondary analysis pipeline are aligned with the clinically validated FoundationOne CDx (F1CDx) FoundationOne (Cambridge, MA, USA) platform, which is FDA-approved as an in vitro diagnostic assay.
Sequencing was performed on an Illumina NextSeq 550 instrument (Illumina, San Diego, CA, USA) using eight indexed libraries per run. Primary and secondary data processing were conducted with the FoundationOne Analysis Platform, applying algorithms previously described by Milbury et al. [43]. Tertiary analysis was performed using Navify Mutation Profiler (version 2.4.1; Roche, Switzerland).
Variant calling thresholds were defined as ≥4% variant allele frequency (VAF) for SNVs/indels, ≥6 copies for amplifications, and ≥3 supporting reads for fusions. Oncogenic potential of small variants was further assessed using VarSeq (version 2.6.2; Golden Helix, USA) and refined by manual curation. Truncating variants in known oncogenes, missense variants with low predicted pathogenicity (REVEL score < 0.7), no functional data and low allele frequency in COSMIC (<15 counts), and fusions lacking critical functional domains of genes involved were classified as variants of uncertain significance (VUS) with minimal likelihood of oncogenicity and were excluded from downstream analyses.

4.3. Statistical Analysis

SPSS 30.0 software (SPSS Inc., Chicago, IL, USA) was used for statistical analysis. The significance of different incidence values was determined by the χ2 test or Fisher’s exact test, as appropriate. Associations with a p-value < 0.05 were considered statistically significant.

5. Conclusions

SCLC is an aggressive cancer type with a dismal prognosis and significant genetic heterogeneity. Genomic profiling may provide predictive information for novel targeted therapeutic approaches. Rapid comprehensive genomic profiling is possible in SCLC even when only cytological samples are available. Further clinical research may lead to the much-needed improvement of outcomes for patients with SCLC.

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/ijms262311512/s1.

Author Contributions

B.K., A.G. and E.P. made substantial contributions to the conception of the study. E.P., Á.B., I.R. and V.S. contributed and curated clinical data. V.C. and B.K. curated pathology data. Z.K. and P.U. performed laboratory procedures including DNA analysis, library preparation and sequencing. D.S. conducted bioinformatic analysis. D.S. and B.K. supervised and substantively revised the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This research was supported by F. Hoffmann-La Roche (financial support for AVENIO Tumor Tissue CGP testing and provision of reagents and software; PTE136209-3/2023).

Institutional Review Board Statement

The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Regional Clinical Research Ethics Committee of University of Pécs (Number: 9433-PTE2022, 8 November 2022). The tumor specimens were FFPE blocks left over from clinical histopathological evaluation.

Informed Consent Statement

Institutional Review Board approval of the study was obtained prior to study conduct and included a waiver of informed consent based on the retrospective, observational, noninterventional nature of the study according to regulations.

Data Availability Statement

The datasets generated and/or analyzed in the present study are available from the corresponding author upon reasonable request.

Acknowledgments

We thank Tara Love (Roche) for a courtesy review of the manuscript.

Conflicts of Interest

The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

References

  1. Rudin, C.M.; Durinck, S.; Stawiski, E.W.; Poirier, J.T.; Modrusan, Z.; Shames, D.S.; A Bergbower, E.; Guan, Y.; Shin, J.; Guillory, J.; et al. Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nat. Genet. 2012, 44, 1111–1116. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  2. George, J.; Lim, J.S.; Jang, S.J.; Cun, Y.; Ozretić, L.; Kong, G.; Leenders, F.; Lu, X.; Fernández-Cuesta, L.; Bosco, G.; et al. Comprehensive genomic profiles of small cell lung cancer. Nature 2015, 524, 47–53. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  3. Solta, A.; Ernhofer, B.; Boettiger, K.; Megyesfalvi, Z.; Heeke, S.; Hoda, M.A.; Lang, C.; Aigner, C.; Hirsch, F.R.; Schelch, K.; et al. Small cells—Big issues: Biological implications and preclinical advancements in small cell lung cancer. Mol. Cancer 2024, 23, 41. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  4. Megyesfalvi, Z.; Gay, C.M.; Popper, H.; Pirker, R.; Ostoros, G.; Heeke, S.; Lang, C.; Hoetzenecker, K.; Schwendenwein, A.; Boettiger, K.; et al. Clinical insights into small cell lung cancer: Tumor heterogeneity, diagnosis, therapy, and future directions. CA Cancer J. Clin. 2023, 73, 620–652. [Google Scholar] [CrossRef] [PubMed]
  5. Sivakumar, S.; Moore, J.A.; Montesion, M.; Sharaf, R.; Lin, D.I.; Colón, C.I.; Fleischmann, Z.; Ebot, E.M.; Newberg, J.Y.; Mills, J.M.; et al. Integrative Analysis of a Large Real-World Cohort of Small Cell Lung Cancer Identifies Distinct Genetic Subtypes and Insights into Histologic Transformation. Cancer Discov. 2023, 13, 1572–1591. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  6. Zhou, H.; Hu, Y.; Luo, R.; Zhao, Y.; Pan, H.; Ji, L.; Zhou, T.; Zhang, L.; Long, H.; Fu, J.; et al. Multi-region exome sequencing reveals the intratumoral heterogeneity of surgically resected small cell lung cancer. Nat. Commun. 2021, 12, 5431. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  7. Ross, J.S.; Wang, K.; Elkadi, O.R.; Tarasen, A.; Foulke, L.; E Sheehan, C.; A Otto, G.; Palmer, G.; Yelensky, R.; Lipson, D.; et al. Next-generation sequencing reveals frequent consistent genomic alterations in small cell undifferentiated lung cancer. J. Clin. Pathol. 2014, 67, 772–776. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  8. Zhang, J.; Zhang, L.; Luo, J.; Ge, T.; Fan, P.; Sun, L.; Hou, L.; Li, J.; Yu, H.; Wu, C.; et al. Comprehensive genomic profiling of combined small cell lung cancer. Transl. Lung Cancer Res. 2021, 10, 636–650. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  9. Wagner, A.H.; Devarakonda, S.; Skidmore, Z.L.; Krysiak, K.; Ramu, A.; Trani, L.; Kunisaki, J.; Masood, A.; Waqar, S.N.; Spies, N.C.; et al. Recurrent WNT pathway alterations are frequent in relapsed small cell lung cancer. Nat. Commun. 2018, 9, 3787. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  10. Oh, M.S.; Garon, E.B.; Lisberg, A.E.; Cummings, A.L.; Barrett, A.; Ashok, A.; Mauer, E.; Yilma, B.; Goldman, J.W. Brief Report: The Genomic Landscape of Small Cell Lung Cancer in Never-Smoking Patients. Clin. Lung Cancer 2025, 26, 434–439.e3. [Google Scholar] [CrossRef] [PubMed]
  11. Roper, N.; Velez, M.J.; Chiappori, A.; Kim, Y.S.; Wei, J.S.; Sindiri, S.; Takahashi, N.; Mulford, D.; Kumar, S.; Ylaya, K.; et al. Notch signaling and efficacy of PD-1/PD-L1 blockade in relapsed small cell lung cancer. Nat. Commun. 2021, 12, 3880. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  12. Horvath, L.; Lang, C.; Boettiger, K.; Aigner, C.; Dome, B.; Megyesfalvi, Z. Potential subtype-specific therapeutic approaches in small cell lung cancer. Curr. Opin. Oncol. 2024, 36, 51–56. [Google Scholar] [CrossRef] [PubMed]
  13. Cardano, M.; Buscemi, G.; Zannini, L. Sex Disparities in P53 Regulation and Functions: Novel Insights for Personalized Cancer Therapies. Cells 2025, 14, 363. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  14. Rockwell, N.C.; Yang, W.; Warrington, N.M.; Staller, M.V.; Griffith, M.; Griffith, O.L.; Gurnett, C.A.; Cohen, B.A.; Baldridge, D.; Rubin, J.B. Sex- and mutation-specific p53 gain-of-function activity in gliomagenesis. Cancer Res. Commun. 2021, 1, 148–163. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  15. Wang, H.; Ou, Q.; Li, D.; Qin, T.; Bao, H.; Hou, X.; Wang, K.; Wang, F.; Deng, Q.; Liang, J.; et al. Genes associated with increased brain metastasis risk in non-small cell lung cancer: Comprehensive genomic profiling of 61 resected brain metastases versus primary non-small cell lung cancer (Guangdong Association Study of Thoracic Oncology 1036). Cancer 2019, 125, 3535–3544. [Google Scholar] [CrossRef] [PubMed]
  16. Kang, Y.; Jin, Y.; Li, Q.; Yuan, X. Advances in Lung Cancer Driver Genes Associated with Brain Metastasis. Front. Oncol. 2021, 10, 606300. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  17. Hashemi, M.; Etemad, S.; Rezaei, S.; Ziaolhagh, S.; Rajabi, R.; Rahmanian, P.; Abdi, S.; Koohpar, Z.K.; Rafiei, R.; Raei, B.; et al. Progress in targeting PTEN/PI3K/Akt axis in glioblastoma therapy: Revisiting molecular interactions. Biomed. Pharmacother. 2023, 158, 114204. [Google Scholar] [CrossRef] [PubMed]
  18. Sakre, N.; Wildey, G.; Behtaj, M.; Kresak, A.; Yang, M.; Fu, P.; Dowlati, A. RICTOR amplification identifies a subgroup in small cell lung cancer and predicts response to drugs targeting mTOR. Oncotarget 2017, 8, 5992–6002. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  19. Krencz, I.; Sztankovics, D.; Danko, T.; Sebestyen, A.; Khoor, A. Progression and metastasis of small cell lung carcinoma: The role of the PI3K/Akt/mTOR pathway and metabolic alterations. Cancer Metastasis Rev. 2021, 40, 1141–1157. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  20. Liu, Y.; Justilien, V.; Fields, A.P.; Murray, N.R. Recurrent copy number gains drive PKCι expression and PKCι-dependent oncogenic signaling in human cancers. Adv. Biol. Regul. 2020, 78, 100754. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  21. Johnson, S.S.; Liu, D.; Ewald, J.T.; Robles-Planells, C.; Christensen, K.A.; Bayanbold, K.; Wels, B.R.; Solst, S.R.; O’Dorisio, M.S.; Allen, B.G.; et al. Auranofin Inhibition of Thioredoxin Reductase Sensitizes Lung Neuroendocrine Tumor Cells (NETs) and Small Cell Lung Cancer (SCLC) Cells to Sorafenib as well as Inhibiting SCLC Xenograft Growth. bioRxiv 2024. [Google Scholar] [CrossRef] [PubMed]
  22. Johnson, S.S.; Liu, D.; Ewald, J.T.; Robles-Planells, C.; Pulliam, C.; Christensen, K.A.; Bayanbold, K.; Wels, B.R.; Solst, S.R.; O’Dorisio, M.S.; et al. Auranofin inhibition of thioredoxin reductase sensitizes lung neuroendocrine tumor cells (NETs) and small cell lung cancer (SCLC) cells to sorafenib as well as inhibiting SCLC xenograft growth. Cancer Biol. Ther. 2024, 25, 2382524. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  23. Alves, R.d.C.S.; Meurer, R.T.; Roehe, A.V. MYC amplification is associated with poor survival in small cell lung cancer: A chromogenic in situ hybridization study. J. Cancer Res. Clin. Oncol. 2014, 140, 2021–2025. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  24. Mollaoglu, G.; Guthrie, M.R.; Böhm, S.; Brägelmann, J.; Can, I.; Ballieu, P.M.; Marx, A.; George, J.; Heinen, C.; Chalishazar, M.D.; et al. MYC Drives Progression of Small Cell Lung Cancer to a Variant Neuroendocrine Subtype with Vulnerability to Aurora Kinase Inhibition. Cancer Cell 2017, 31, 270–285. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  25. Peifer, M.; Fernández-Cuesta, L.; Sos, M.L.; George, J.; Seidel, D.; Kasper, L.H.; Plenker, D.; Leenders, F.; Sun, R.; Zander, T.; et al. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat. Genet. 2012, 44, 1104–1110. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  26. Kirk, N.A.; Kim, K.-B.; Park, K.-S. Effect of chromatin modifiers on the plasticity and immunogenicity of small-cell lung cancer. Exp. Mol. Med. 2022, 54, 2118–2127. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  27. Park, S.-M.; Choi, E.-Y.; Bae, M.; Kim, S.; Park, J.B.; Yoo, H.; Choi, J.K.; Kim, Y.-J.; Lee, S.-H.; Kim, I.-H. Histone variant H3F3A promotes lung cancer cell migration through intronic regulation. Nat. Commun. 2016, 7, 12914. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  28. Su, D.; Zhang, D.; Jin, J.; Ying, L.; Han, M.; Chen, K.; Li, B.; Wu, J.; Xie, Z.; Zhang, F.; et al. Identification of predictors of drug sensitivity using patient-derived models of esophageal squamous cell carcinoma. Nat. Commun. 2019, 10, 5076. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  29. Wang, L.; Cybula, M.; Rostworowska, M.; Wang, L.; Mucha, P.; Bulicz, M.; Bieniasz, M. Upregulation of Succinate Dehydrogenase (SDHA) Contributes to Enhanced Bioenergetics of Ovarian Cancer Cells and Higher Sensitivity to Anti-Metabolic Agent Shikonin. Cancers 2022, 14, 5097. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  30. Yong, L.; Fang, Y.; Jin, L.; Zhang, X.; Luis, M.A.; Lin, X.; Tang, S.; Cai, F. Unveiling the hidden role of SDHA in breast cancer proliferation: A novel therapeutic avenue. Cancer Cell Int. 2025, 25, 108. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  31. Qian, X.; Zhu, L.; Xu, M.; Liu, H.; Yu, X.; Shao, Q.; Qin, J. Shikonin suppresses small cell lung cancer growth via inducing ATF3-mediated ferroptosis to promote ROS accumulation. Chem. Biol. Interact. 2023, 382, 110588. [Google Scholar] [CrossRef] [PubMed]
  32. Park, M.; Kuen, D.-S.; Park, J.; Choi, M.; Kim, Y.; Roh, E.C.; Choi, Y.J.; Kim, Y.G.; Chung, Y.; Cho, S.Y.; et al. TYRO3 blockade enhances anti-PD-1 therapy response by modulating expression of CCN1 in tumor microenvironment. J. Immunother. Cancer 2023, 11, e006084. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  33. Ban, J.; Qian, J.; Zhang, C.; Li, J. Recent advances in TAM mechanisms in lung diseases. J. Transl. Med. 2025, 23, 479. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  34. Jiang, Z.; Lim, S.-O.; Yan, M.; Hsu, J.L.; Yao, J.; Wei, Y.; Chang, S.-S.; Yamaguchi, H.; Lee, H.-H.; Ke, B.; et al. TYRO3 induces anti–PD-1/PD-L1 therapy resistance by limiting innate immunity and tumoral ferroptosis. J. Clin. Investig. 2021, 131, e139434. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  35. Hamilton, G.; Rath, B.; Klameth, L.; Hochmair, M. Receptor tyrosine kinase expression of circulating tumor cells in small cell lung cancer. Oncoscience 2015, 2, 629–634. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  36. Borghaei, H.; de Marinis, F.; Dumoulin, D.; Reynolds, C.; Theelen, W.S.M.E.; Percent, I.; Gutierrez Calderon, V.; Johnson, M.L.; Madroszyk-Flandin, A.; Garon, E.B.; et al. SAPPHIRE: Phase III study of sitravatinib plus nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. Ann. Oncol. 2024, 35, 66–76. [Google Scholar] [CrossRef] [PubMed]
  37. Smart, S.K.; Vasileiadi, E.; Wang, X.; DeRyckere, D.; Graham, D.K. The Emerging Role of TYRO3 as a Therapeutic Target in Cancer. Cancers 2018, 10, 474. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  38. Wu, S.; Zhang, Y.; Zhang, Y.; Chen, L.; Ouyang, H.; Xu, X.; Du, Y.; Ti, X. Mutational landscape of homologous recombination-related genes in small-cell lung cancer. Cancer Med. 2023, 12, 4486–4495. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  39. Tlemsani, C.; Takahashi, N.; Pongor, L.; Rajapakse, V.N.; Tyagi, M.; Wen, X.; Fasaye, G.-A.; Schmidt, K.T.; Desai, P.; Kim, C.; et al. Whole-exome sequencing reveals germline-mutated small cell lung cancer subtype with favorable response to DNA repair-targeted therapies. Sci. Transl. Med. 2021, 13, eabc7488, Erratum in: Sci. Transl. Med. 2021, 13, eabm6064. https://doi.org/10.1126/scitranslmed.abm6064. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  40. Knelson, E.H.; Patel, S.A.; Sands, J.M. PARP Inhibitors in Small-Cell Lung Cancer: Rational Combinations to Improve Responses. Cancers 2021, 13, 727. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  41. Kong, R.; Patel, A.S.; Sato, T.; Jiang, F.; Yoo, S.; Bao, L.; Sinha, A.; Tian, Y.; Fridrikh, M.; Liu, S.; et al. Transcriptional Circuitry of NKX2-1 and SOX1 Defines an Unrecognized Lineage Subtype of Small-Cell Lung Cancer. Am. J. Respir. Crit. Care Med. 2022, 206, 1480–1494. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  42. Rekhtman, N. All That Is Small Is Not a Small-Cell Carcinoma: Thoracic SMARCA4-Deficient Undifferentiated Tumors Masquerading as SCLC. Clin. Cancer Res. 2024, 30, 1708–1711. [Google Scholar] [CrossRef] [PubMed]
  43. Milbury, C.A.; Creeden, J.; Yip, W.-K.; Smith, D.L.; Pattani, V.; Maxwell, K.; Sawchyn, B.; Gjoerup, O.; Meng, W.; Skoletsky, J.; et al. Clinical and analytical validation of FoundationOne®CDx, a comprehensive genomic profiling assay for solid tumors. PLoS ONE 2022, 17, e0264138. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
Ijms 26 11512 g001
Figure 1. Landscape of genomic alterations found in the cohort studied.
Figure 1. Landscape of genomic alterations found in the cohort studied.
Ijms 26 11512 g001
Table 1. Genomic alterations at primary and metastatic sites.
Table 1. Genomic alterations at primary and metastatic sites.
Genomic Alteration (N, %)Primary Tumors
(n = 26)		Metastatic Sites
(n = 29)		Significance
(p Value)
TP53 gene26 (100%)28 (97%)0.527
missense19 (73%)16 (55%)0.136
truncating8 (31%)12 (41%)0.297
RB1 gene19 (73%)26 (90%)0.107
PI3K/Akt/mTOR pathway17 (65%)17 (59%)0.407
PTEN *3 (12%)9 (31%)0.076
Chromatin regulators16 (62%)7 (24%)0.005
NOTCH pathway5 (19%)3 (10%)0.291
MYC-family *5 (19%)8 (28%)0.342
Cell cycle genes7 (27%)6 (21%)0.410
Homologous repair genes5 (19%)5 (17%)0.561
SOX28 (31%)19 (66%)0.010
NKX2-15 (19%)19 (65%)<0.001
TYRO317 (65%)1 (3%)<0.001
SDHA4 (15%)3 (10%)0.437
The table shows number and percentage of cases with genetic alterations involving genes or genetic pathways. * Metastatic sites in case of PTEN mutation and MYC-family amplification were exclusively the brain; PTEN mutation: 3/34 any site vs. 9/21 brain metastasis, p = 0.004; MYC-family amplification: 5/34 any site vs. 8/21 brain metastasis, p = 0.050).
Table 2. Genomic alterations and association with sex.
Table 2. Genomic alterations and association with sex.
Genomic AlterationTotal
(n = 55)		Female
(n = 31)		Male
(n = 24)		Significance
(p Value)
TP53 gene54 (98%)31 (100%)23 (96%)0.436
missense35 (64%)25 (81%)10 (42%)0.003
truncating20 (36%)6 (19%)14 (58%)0.003
RB145 (82%)25 (81%)20 (83%)0.542
PI3K/Akt/mTOR pathway34 (62%)20 (65%)14 (58%)0.424
PTEN12 (22%)10 (32%)2 (8%)0.033
Chromatin regulators23 (42%)15 (48%)8 (33%)0.199
NOTCH pathway8 (15%)6 (19%)2 (8%)0.225
MYC-family13 (24%)5 (16%)8 (33%)0.121
Cell cycle genes13 (24%)9 (29%)4 (17%)0.228
Homologous repair genes10 (18%)5 (16%)5 (21%)0.458
SOX227 (49%)12 (39%)15 (63%)0.069
NKX2-124 (44%)11 (36%)13 (54%)0.133
TYRO318 (33%)13 (42%)5 (21%)0.085
SDHA7 (13%)5 (16%)2 (16%)0.331
The table shows number and percentage of cases with genetic alterations involving genes or genetic pathways.
Table 3. Clinicopathologic characteristics of patients.
Table 3. Clinicopathologic characteristics of patients.
CharacteristicTotalFemaleMale
Number of patients5531 (56%)24 (44%)
Age, median (range)64 (43–87)65 (43–73)64 (53–87)
Stage at diagnosis
limited7 (13%)3 (10%)4 (17%)
extended48 (87%)28 (90%)20 (83%)
Survival, median8.58.09.0
>24 months10 (18%)6 (19%)4 (17%)
Site of biopsy
primary tumor26 (47%)15 (48%)11 (46%)
metastasis, brain21 (38%)12 (39%)9 (38%)
metastasis, liver4 (7%)3 (10%)1 (4%)
metastasis, other4 (7%)1 (3%)3 (13%)
Biopsy type
FFPE34 (62%)17 (55%)17 (71%)
cytology21 (38%)14 (45%)7 (29%)
Tumor purity (%)
median (range)81 (24–98)80 (24–98)84 (29–98)
The table shows number and percentage of cases with genetic alterations involving genes or genetic pathways.
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Schmalz, D.; Krabóth, Z.; Czoma, V.; Urbán, P.; Gyenesei, A.; Ruzsics, I.; Sárosi, V.; Boronkai, Á.; Papp, E.; Kajtár, B. Comprehensive Genomic Profiling of Small-Cell Lung Cancer Reveals Frequent Potentially Targetable Alterations. Int. J. Mol. Sci. 2025, 26, 11512. https://doi.org/10.3390/ijms262311512

AMA Style

Schmalz D, Krabóth Z, Czoma V, Urbán P, Gyenesei A, Ruzsics I, Sárosi V, Boronkai Á, Papp E, Kajtár B. Comprehensive Genomic Profiling of Small-Cell Lung Cancer Reveals Frequent Potentially Targetable Alterations. International Journal of Molecular Sciences. 2025; 26(23):11512. https://doi.org/10.3390/ijms262311512

Chicago/Turabian Style

Schmalz, Dániel, Zoltán Krabóth, Veronika Czoma, Péter Urbán, Attila Gyenesei, István Ruzsics, Veronika Sárosi, Árpád Boronkai, Emőke Papp, and Béla Kajtár. 2025. "Comprehensive Genomic Profiling of Small-Cell Lung Cancer Reveals Frequent Potentially Targetable Alterations" International Journal of Molecular Sciences 26, no. 23: 11512. https://doi.org/10.3390/ijms262311512

APA Style

Schmalz, D., Krabóth, Z., Czoma, V., Urbán, P., Gyenesei, A., Ruzsics, I., Sárosi, V., Boronkai, Á., Papp, E., & Kajtár, B. (2025). Comprehensive Genomic Profiling of Small-Cell Lung Cancer Reveals Frequent Potentially Targetable Alterations. International Journal of Molecular Sciences, 26(23), 11512. https://doi.org/10.3390/ijms262311512

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