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Genetics and Genomics

Molecular analysis of lung adenocarcinomas from the SAFIR02-Lung cohort reveals new metastasis-associated copy-number alterations including frequent mutant-specific KRAS-allelic imbalance and identifies CDKN2A homozygous deletions as an independent biomarker of poor prognosis

British Journal of Cancer (2025)Cite this article

Subjects

Abstracts

Background

Identifying molecular alterations specific to advanced lung adenocarcinomas could provide insights into tumour progression and dissemination mechanisms.

Method

We analysed tumour samples, either from locoregional lesions or distant metastases, from patients with advanced lung adenocarcinoma from the SAFIR02-Lung trial by targeted sequencing of 45 cancer genes and comparative genomic hybridisation array and compared them to early tumours samples from The Cancer Genome Atlas.

Results

Differences in copy-number alterations frequencies suggest the involvement in tumour progression of LAMB3, TNN/KIAA0040/TNR, KRAS, DAB2, MYC, EPHA3 and VIPR2, and in metastatic dissemination of AREG, ZNF503, PAX8, MMP13, JAM3, and MTURN. Conversely, no meaningful difference was found in pathogenic single-nucleotide variant frequencies, reinforcing the notion that they are early events in tumorigenesis. CDKN2A homozygous deletion was linked to poor clinical outcome in patients with early tumours (overall survival hazard ratio 2.17, 95% CI: 1.43–3.28, corrected p-value = 0.01). Furthermore, we found that KRAS mutant allele specific imbalance, i.e. focal amplification of the mutant allele, is more prevalent in locoregional or distant samples of metastatic patients than in early lesions (8.4%, 13% and 2.8% respectively). This observation was replicated in three public cohorts. Tumours with KRAS mutant allele specific imbalance show specific patterns of co-occurrence and mutual exclusion with alterations in key cancer genes like CDKN2A, TP53, STK11 and NKX2-1, often in a tumour type dependent manner.

Conclusion

Advanced LUAD tumours exhibit higher copy-number alteration burden, with distinct alterations associated with tumour progression and metastasis. CDKN2A homozygous deletions predict poor prognosis in early disease, while KRAS mutant allele-specific imbalance is enriched in advanced tumours.

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Fig. 1: SAFIR02-Lung tumours show increased chromosomal instability.
Fig. 2: Patterns of copy-number alterations frequency variations across LUAD types.
Fig. 3: CDKN2A homozygous deletion are linked to poor survival outcomes in LUAD.
Fig. 4: KRAS mutant-allele amplifications are enriched in metastatic KRAS-mutated tumours.
Fig. 5: Among KRAS-mutated tumours, co-occurring pathogenic variants frequencies differ by KRAS-amplification status.

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Data availability

Chromosomal microarray raw data are available on the Sequence Read Archive under the accession number SUB15395068.

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Author information

Author notes

  1. These authors contributed equally: Abderaouf Hamza, Pierre Gestraud, Maryam Karimi.

  2. These authors jointly supervised this work: Maud Kamal, Ivan Bièche.

Authors and Affiliations

  1. Department of Genetics, Institut Curie, PSL Research University, Paris, France

    Abderaouf Hamza, Sophie Vacher, Quentin Peretti, Samia Melaabi & Ivan Bièche

  2. INSERM U1016, Paris Cité University, Faculty of Pharmaceutical and Biological Sciences, Paris, France

    Abderaouf Hamza & Ivan Bièche

  3. Computational Oncology, PSL Research University, Mines Paris Tech, INSERM U91331, Paris, France

    Pierre Gestraud, Laurène Syx & Nicolas Servant

  4. Service de Biostatistique et d’Épidémiologie, Gustave Roussy, Université Paris-Saclay, Villejuif, France

    Maryam Karimi & Stefan Michiels

  5. Oncostat U1018, Inserm, Université Paris-Saclay, Équipe Labellisée Ligue Contre le Cancer, Villejuif, France

    Maryam Karimi & Stefan Michiels

  6. Bioinformatics Platform, Gustave Roussy, Villejuif, France

    Alicia Tran-Dien

  7. Department of Medical Biology and Pathology, Gustave Roussy, Villejuif, France

    Ludovic Lacroix

  8. Cancer Genomic Platform, Centre Léon Bérard, Lyon, France

    Valery Attignon

  9. Department of Biopathology, Institut Bergonié, Bordeaux, France

    Isabelle Soubeyran

  10. Omics and Data Science Unit, Institut de Cancérologie de l’Ouest (ICO), Angers-Nantes, France

    Pascal Jézéquel

  11. Department of Medical Oncology, Gustave Roussy, Villejuif, France

    David Planchard, Fabrice André, Benjamin Besse, Maud Kamal & Fabrice Barlesi

  12. Department of Food Technology, Safety and Health, Faculty of Bioscience Engineering, Ghent University, Ghent, Belgium

    Trenton Dailey-Chwalibóg

  13. Agence de Formation de Recherche et d’Expertise en Santé pour l’Afrique (AFRICSanté), Bobo-Dioulsso, Burkina Faso

    Trenton Dailey-Chwalibóg

  14. R&D Unicancer, Paris, France

    Marta Jimenez

  15. Department of Drug Development and Innovation (D3i), Institut Curie, Paris, France

    Christophe Le Tourneau

  16. Thorax Institute Curie Montsouris, Department of Medical Oncology, Institut Curie, Paris, France

    Nicolas Girard

  17. Gustave Roussy Cancer Campus, PRISM-PRecISion Medicine Center in Oncology, Villejuif, France

    Fabrice André & Maud Kamal

  18. Paris Saclay University, Kremlin-Bicêtre, France

    David Planchard, Fabrice André, Maud Kamal & Fabrice Barlesi

Authors
  1. Abderaouf Hamza
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  2. Pierre Gestraud
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  3. Maryam Karimi
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  4. Alicia Tran-Dien
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  7. Quentin Peretti
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  8. Ludovic Lacroix
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  9. Valery Attignon
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  10. Isabelle Soubeyran
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  11. Pascal Jézéquel
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  12. David Planchard
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  24. Ivan Bièche
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Contributions

Benjamin Besse, Maud Kamal, Fabrice Barlesi and Ivan Bièche conceived the study and participated in its design. Benjamin Besse, Ivan Bièche and Marta Jimenez acquired the financial support for the project. David Planchard, Marta Jimenez, Christophe Le Tourneau, Nicolas Girard, Benjamin Besse and Fabrice Barlesi provided patient samples and gathered and curated clinical data. Ludovic Lacroix, Valery Attignon, Isabelle Soubeyran, Pascal JézéquelIvan Bièche provided laboratory reagents and instrumentation. Sophie Vacher performed sequencing experiments. Abderaouf Hamza, Alicia Tran-Dien, Laurène Syx and Pierre Gestraud performed and Nicolas Servant performed the bioinformatic analysis. Maryam Karimi, Stefan Michiels, and Trenton Dailey-Chwalibóg performed statistical analyses. Abderaouf Hamza, Samia Melaabi, Quentin Peretti, Isabelle Soubeyran, Ludovic Lacroix and Valeri Attignon analysed the data, created the visualisations and wrote the original drafts. Ivan Bièche reviewed the original drafts. All authors reviewed and approved the final manuscript.

Corresponding author

Correspondence to Ivan Bièche.

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Competing interests

F Barlesi reports personal fees from AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer-Ingelheim, Eli Lilly Oncology, F Hoffmann-La Roche Ltd, Novartis, Merck, Mirati, MSD, Pierre Fabre, Pfizer, Seattle Genetics and Takeda; grants from Abbvie, ACEA, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer-Ingelheim, Eisai, Eli Lilly Oncology, F Hoffmann-La Roche Ltd., Genentech, Ipsen, Ignyta, Innate Pharma, Loxo, Novartis, Medimmune, Merck, MSD, Pierre Fabre, Pfizer, Sanofi-Aventis, and Takeda; and nonfinancial support from AstraZeneca, BMS, Merck, Pierre Fabre, and F Hoffmann-La Roche outside the submitted work. S. Michiels reports personal fees from Amaris, Roche, Sensorion, Biophytis, Servier, and Yuhan outside the submitted work. A Madroszyk reports personal fees and nonfinancial support from AstraZeneca and Roche, and nonfinancial support from Lilly outside the submitted work. I Soubeyran reports grants and nonfinancial support from AstraZeneca; grants from Takeda and ThermoFisher; and personal fees from GSK, Lilly, and Servier outside the submitted work. M. Jimenez reports grants and nonfinancial support from AstraZeneca and grants from Fondation ARC during the conduct of the study. B. Besse reports grants from 4D Pharma, AbbVie, Amgen, Aptitude Health, AstraZeneca, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Celgene, Cergentis, Chugai pharmaceutical, Cristal Therapeutics, Daiichi-Sankyo, Eli Lilly, EISAI, Genzyme Corporation, GSK, Inivata, IPSEN, Janssen, Onxeo, OSE immunotherapeutics, Pfizer, Roche-Genentech, Sanofi, Takeda, Tolero Pharmaceuticals, and Turning Point Therapeutics during the conduct of the study. No disclosures were reported by the other authors.

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Hamza, A., Gestraud, P., Karimi, M. et al. Molecular analysis of lung adenocarcinomas from the SAFIR02-Lung cohort reveals new metastasis-associated copy-number alterations including frequent mutant-specific KRAS-allelic imbalance and identifies CDKN2A homozygous deletions as an independent biomarker of poor prognosis. Br J Cancer (2025). https://doi.org/10.1038/s41416-025-03183-2

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