A pilot prospective study of plasma cell-free DNA whole-genome sequencing identified chromosome 7p copy number gains as a specific biomarker for early lung cancer detection.

Hong-Jie Yu,Hai-Tao Ma,Jia Tang,Xun Lu,Xiao-Jun Yu

doi:10.4149/neo_2021_201106n1189

Hong-Jie Yu, Hai-Tao Ma + Show 3 more

Open Access

https://doi.org/10.4149/neo_2021_201106n1189

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Abstract

Chromosome 7 plays an important role in lung tumorigenesis. Chromosome 7 copy number changes might be an early event of lung cancer tumorigenesis. Here we investigate whether chromosome 7p copy number gain is a detectable genetic event with plasma cell-free DNA for early lung cancer detection. Eighteen surgical eligible lung cancer patients and eighteen non-cancer controls were recruited. Peripheral blood was collected before surgery. Cell-free DNA was profiled with low coverage whole-genome sequencing. Chromosome 7 copy number gains were defined as chr7 normalized coverage ≥1.0005 and p-value <0.05. Plasma cell-free DNA chr7 copy gains were then compared to pathological examinations on surgical tissues. 83.3% of patients were confirmed as malignancy post-operation, 12 patients with adenocarcinoma, and 3 with squamous-carcinoma. The other 16.7% were benign lesions. Cell-free DNA was successfully extracted from pre-surgical plasma samples, with a concentration range from 0.18 to 0.49 ng/µl. Chromosome 7 short arm copy gains were found in 66.7% (10/15) patients, including 66.7% (4/6) T1aN0M0 and 50.0% (1/2) Tis patients, otherwise, chr7p gain was found in 0% (0/3) benign lesions. The specificity was further examined in 18 volunteers who undergoing routine body examinations. Meanwhile, positive carcinoembryonic antigen (CEA) and cytokeratin-19-fragment (CYFRA21-1) were only found in 1/18 (5.7%) and 4/18 (22.2%), respectively. Taking together, Ultrasensitive- Chromosomal Aneuploidy Detector (UCAD) chr7p or UCAD chr7p and tumor biomarker positivity can predict 12/15 (80%, 95% CI: 49.0-94.3%) early lung cancers. Further analyses showed that chr7p copy number gains tend to be enriched in normal EGFR/KRAS patients (Fisher's test, p-value = 0.077). Chromosome 7p copy gain is a useful peripheral blood tumor biomarker from lung cancer detection.

Highlights

Lung cancer is the leading cause of cancer-related death worldwide
There are improvements in lung cancer diagnosis and treatment in recent years, the 5-year survival rate is still less than 20% of all lung cancer patients [1]
In addition to somatic point mutations, chromosomal copy number changes were detected in breast cancer [4], hepatocellular carcinoma [5], and lung cancer [6]

Summary

Introduction

Lung cancer is the leading cause of cancer-related death worldwide. there are improvements in lung cancer diagnosis and treatment in recent years, the 5-year survival rate is still less than 20% of all lung cancer patients [1]. In addition to somatic point mutations, chromosomal copy number changes were detected in breast cancer [4], hepatocellular carcinoma [5], and lung cancer [6]. We investigate whether chromosome 7 aneuploidy can be detected in early lung cancer. Chromosome 7 amplifications were frequently reported in lung cancer tissue profiling studies. Chromosome 7 aneuploidy could be found in both malignant tissues and in pre-cancerous lesions, but not healthy tissues, which support chromosome 7 copy number changes might be an early event of lung cancer tumorigenesis [7,8,9].

Results

Conclusion