Hamza Abderaouf, Gestraud Pierre, Karimi Maryam, Tran-Dien Alicia, Syx Laurène, Vacher Sophie, Peretti Quentin, Lacroix Ludovic, Attignon Valery, Soubeyran Isabelle, Jézéquel Pascal, Planchard David, Melaabi Samia, Dailey-Chwalibóg Trenton, Jimenez Marta, Michiels Stefan, Servant Nicolas, Le Tourneau Christophe, Girard Nicolas, André Fabrice, Besse Benjamin, Kamal Maud, Barlesi Fabrice, Bièche Ivan
Department of Genetics, Institut Curie, PSL Research University, Paris, France.
INSERM U1016, Paris Cité University, Faculty of Pharmaceutical and Biological Sciences, Paris, France.
Br J Cancer. 2025 Sep 11. doi: 10.1038/s41416-025-03183-2.
Identifying molecular alterations specific to advanced lung adenocarcinomas could provide insights into tumour progression and dissemination mechanisms.
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.
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.
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.
识别晚期肺腺癌特有的分子改变有助于深入了解肿瘤进展和扩散机制。
我们通过对45个癌症基因进行靶向测序以及比较基因组杂交阵列分析，对SAFIR02-Lung试验中晚期肺腺癌患者的肿瘤样本（来自局部病变或远处转移灶）进行分析，并将其与癌症基因组图谱中的早期肿瘤样本进行比较。
拷贝数改变频率的差异表明，LAMB3、TNN/KIAA0040/TNR、KRAS、DAB2、MYC、EPHA3和VIPR2参与肿瘤进展，而AREG、ZNF503、PAX8、MMP13、JAM3和MTURN参与转移扩散。相反，在致病性单核苷酸变异频率方面未发现有意义的差异，这强化了它们是肿瘤发生早期事件的观点。CDKN2A纯合缺失与早期肿瘤患者不良临床结局相关（总生存风险比2.17，95%置信区间：1.43 - 3.28，校正P值 = 0.01）。此外，我们发现KRAS突变等位基因特异性失衡，即突变等位基因的局灶性扩增，在转移性患者的局部或远处样本中比在早期病变中更常见（分别为8.4%、13%和2.8%）。这一观察结果在三个公共队列中得到了重复验证。具有KRAS突变等位基因特异性失衡的肿瘤与关键癌症基因如CDKN2A、TP53、STK11和NKX2-1的改变呈现出特定的共现和相互排斥模式，且通常具有肿瘤类型依赖性。
晚期肺腺癌肿瘤表现出更高的拷贝数改变负担，具有与肿瘤进展和转移相关的独特改变。CDKN2A纯合缺失预示早期疾病预后不良，而KRAS突变等位基因特异性失衡在晚期肿瘤中更为富集。
