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Impact of KRAS mutation subtypes on morphological heterogeneity and immune landscape in surgically treated lung adenocarcinoma

Torok, Klara ; Ferencz, Bence ; Boettiger, Kristiina ; Pozonec, Maria Dorothea ; Pipek, Orsolya ; Bogos, Julianna ; Lantos, Andras ; Hegedus, Zita ; Schelch, Karin and Radeczky, Peter , et al. (2025) In Translational Lung Cancer Research 14(6). p.1914-1928
Abstract

Background: Although Kirsten rat sarcoma virus (KRAS) mutations represent the most frequent oncogenic driver alterations in Caucasian lung adenocarcinoma (LADC) patients, their impact on immune phenotype and tumor morphology is largely unexplored. Here, we investigated the associations between KRAS mutation subtypes, immune landscape, and tumor heterogeneity in surgically treated LADC, with a particular focus on specific tumor growth patterns. Methods: This study included 87 surgically treated patients with histologically confirmed early-stage LADC. Three tumorous and one non-tumorous tissue microarray (TMA) cores were collected from each patient. KRAS genotyping was performed using polymerase chain reaction (PCR)-based assays. We... (More)

Background: Although Kirsten rat sarcoma virus (KRAS) mutations represent the most frequent oncogenic driver alterations in Caucasian lung adenocarcinoma (LADC) patients, their impact on immune phenotype and tumor morphology is largely unexplored. Here, we investigated the associations between KRAS mutation subtypes, immune landscape, and tumor heterogeneity in surgically treated LADC, with a particular focus on specific tumor growth patterns. Methods: This study included 87 surgically treated patients with histologically confirmed early-stage LADC. Three tumorous and one non-tumorous tissue microarray (TMA) cores were collected from each patient. KRAS genotyping was performed using polymerase chain reaction (PCR)-based assays. We assessed the immune landscape by evaluating the NLRP3 inflammasome, CD3, CD163, and PD-L1 expression. Results: The mutational landscape concerning the type of KRAS mutation was mostly homogenous across TMA cores, with KRASG12C being the most frequently detected alteration. Notably, in 19 cases, the dominant mutational subtype differed between the tumor punctures originating from the same tumor. Although KRASG12A mutation was not detected in LADC samples with a lepidic growth pattern and micropapillary LADCs lacked wild-type KRAS gene, no statistically significant association was found between the KRAS mutation subtype and LADC growth pattern. NLRP3 expression significantly correlated with CD3 and CD163 expressions (P<0.001), and elevated NLRP3 levels were characteristic of LADCs with solid growth pattern (P=0.001). Tumor samples with solid morphology expressed significantly higher levels of PD-L1 than acinar- or lepidic-pattern LADCs (P=0.007 and P=0.002, respectively). Conclusions: KRAS mutation subtypes may have a heterogeneous distribution across different tumor regions, contributing to cases with concomitant mutation subtypes that create significant diagnostic challenges. The growth pattern-specificity of NLRP3 and PD-L1 offers additional guidance for the future development of alternative immunotherapeutic approaches.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
immune response, inflammasome, Kirsten rat sarcoma virus subtypes (KRAS subtypes), lung adenocarcinoma, NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3)
in
Translational Lung Cancer Research
volume
14
issue
6
pages
15 pages
publisher
AME Publishing Company
external identifiers
  • pmid:40673097
  • scopus:105009109269
ISSN
2218-6751
DOI
10.21037/tlcr-2024-1092
language
English
LU publication?
yes
additional info
Publisher Copyright: © AME Publishing Company.
id
facac578-3c4e-4fe2-ab34-1018a5b49778
date added to LUP
2025-12-15 12:36:00
date last changed
2025-12-16 03:00:14
@article{facac578-3c4e-4fe2-ab34-1018a5b49778,
  abstract     = {{<p>Background: Although Kirsten rat sarcoma virus (KRAS) mutations represent the most frequent oncogenic driver alterations in Caucasian lung adenocarcinoma (LADC) patients, their impact on immune phenotype and tumor morphology is largely unexplored. Here, we investigated the associations between KRAS mutation subtypes, immune landscape, and tumor heterogeneity in surgically treated LADC, with a particular focus on specific tumor growth patterns. Methods: This study included 87 surgically treated patients with histologically confirmed early-stage LADC. Three tumorous and one non-tumorous tissue microarray (TMA) cores were collected from each patient. KRAS genotyping was performed using polymerase chain reaction (PCR)-based assays. We assessed the immune landscape by evaluating the NLRP3 inflammasome, CD3, CD163, and PD-L1 expression. Results: The mutational landscape concerning the type of KRAS mutation was mostly homogenous across TMA cores, with KRASG12C being the most frequently detected alteration. Notably, in 19 cases, the dominant mutational subtype differed between the tumor punctures originating from the same tumor. Although KRASG12A mutation was not detected in LADC samples with a lepidic growth pattern and micropapillary LADCs lacked wild-type KRAS gene, no statistically significant association was found between the KRAS mutation subtype and LADC growth pattern. NLRP3 expression significantly correlated with CD3 and CD163 expressions (P&lt;0.001), and elevated NLRP3 levels were characteristic of LADCs with solid growth pattern (P=0.001). Tumor samples with solid morphology expressed significantly higher levels of PD-L1 than acinar- or lepidic-pattern LADCs (P=0.007 and P=0.002, respectively). Conclusions: KRAS mutation subtypes may have a heterogeneous distribution across different tumor regions, contributing to cases with concomitant mutation subtypes that create significant diagnostic challenges. The growth pattern-specificity of NLRP3 and PD-L1 offers additional guidance for the future development of alternative immunotherapeutic approaches.</p>}},
  author       = {{Torok, Klara and Ferencz, Bence and Boettiger, Kristiina and Pozonec, Maria Dorothea and Pipek, Orsolya and Bogos, Julianna and Lantos, Andras and Hegedus, Zita and Schelch, Karin and Radeczky, Peter and Bogos, Krisztina and Teglas, Vivien and Megyesfalvi, Evelyn and Ferenczy, Anita and Renyi-Vamos, Ferenc and Aigner, Clemens and Megyesfalvi, Zsolt and Dome, Balazs and Fillinger, Janos}},
  issn         = {{2218-6751}},
  keywords     = {{immune response; inflammasome; Kirsten rat sarcoma virus subtypes (KRAS subtypes); lung adenocarcinoma; NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3)}},
  language     = {{eng}},
  month        = {{06}},
  number       = {{6}},
  pages        = {{1914--1928}},
  publisher    = {{AME Publishing Company}},
  series       = {{Translational Lung Cancer Research}},
  title        = {{Impact of KRAS mutation subtypes on morphological heterogeneity and immune landscape in surgically treated lung adenocarcinoma}},
  url          = {{http://dx.doi.org/10.21037/tlcr-2024-1092}},
  doi          = {{10.21037/tlcr-2024-1092}},
  volume       = {{14}},
  year         = {{2025}},
}