Pathology, research and practice · 2025
CDKN2A alternations in non-small cell lung cancer: An evaluation using next-generation sequencing.
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Feng Xu, Chang Heng, Xu Yuyin, Yu Chengli, Yao Qianlan, Jia Liqin, Zhu Xiaoli, Zhou Xiaoyan, Bai Qianming
Аннотация
BACKGROUND: Next-generation sequencing (NGS) is widely used for assessing CDKN2A status in cancers due to its high throughput and efficiency. However, discrepancies between NGS and fluorescence in situ hybridization (FISH)-the gold standard for detecting copy number variations (CNVs)-are occasionally observed. This study aimed to evaluate the accuracy of NGS in detecting CDKN2A deletions by comparing it with FISH.
METHODS: A total of 1118 non-small cell lung cancer (NSCLC) patients who underwent NGS at Fudan University Shanghai Cancer Center (FUSCC) were retrospectively analyzed. Among them, 56 patients were identified with CDKN2A copy number deletions by NGS, and 51 cases with sufficient tissue were further validated by FISH.
RESULTS: FISH confirmed CDKN2A deletion in 88.2 % (45/51) of cases identified by NGS. Among these, 93.3 % (42/45) showed homozygous deletions and 6.7 % (3/45) showed heterozygous deletions. The remaining 11.8 % (6/51) had normal CDKN2A copy number by FISH, with CDKN2A/CEP9 ratios ranging from 0.71 to 1.09. These discordant cases had intermediate CN values by NGS (average: 1.02), unstable CNV baselines, and in most cases (>30 %) evidence of haploidy, which may have contributed to misclassification.
CONCLUSIONS: While NGS demonstrates high concordance with FISH in detecting CDKN2A deletions, false positives may occur, particularly in samples with intermediate CN values, low tumor purity, or unstable CNV baselines. These factors should be carefully evaluated when interpreting NGS-based CDKN2A CNV results in clinical practice.
METHODS: A total of 1118 non-small cell lung cancer (NSCLC) patients who underwent NGS at Fudan University Shanghai Cancer Center (FUSCC) were retrospectively analyzed. Among them, 56 patients were identified with CDKN2A copy number deletions by NGS, and 51 cases with sufficient tissue were further validated by FISH.
RESULTS: FISH confirmed CDKN2A deletion in 88.2 % (45/51) of cases identified by NGS. Among these, 93.3 % (42/45) showed homozygous deletions and 6.7 % (3/45) showed heterozygous deletions. The remaining 11.8 % (6/51) had normal CDKN2A copy number by FISH, with CDKN2A/CEP9 ratios ranging from 0.71 to 1.09. These discordant cases had intermediate CN values by NGS (average: 1.02), unstable CNV baselines, and in most cases (>30 %) evidence of haploidy, which may have contributed to misclassification.
CONCLUSIONS: While NGS demonstrates high concordance with FISH in detecting CDKN2A deletions, false positives may occur, particularly in samples with intermediate CN values, low tumor purity, or unstable CNV baselines. These factors should be carefully evaluated when interpreting NGS-based CDKN2A CNV results in clinical practice.