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Shallow whole-genome sequencing of plasma cell-free DNA accurately differentiates small from non-small cell lung carcinoma

(2020) GENOME MEDICINE. 12(1).
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Abstract
Background Accurate lung cancer classification is crucial to guide therapeutic decisions. However, histological subtyping by pathologists requires tumor tissue-a necessity that is often intrinsically associated with procedural difficulties. The analysis of circulating tumor DNA present in minimal-invasive blood samples, referred to as liquid biopsies, could therefore emerge as an attractive alternative. Methods Concerning adenocarcinoma, squamous cell carcinoma, and small cell carcinoma, our proof of concept study investigates the potential of liquid biopsy-derived copy number alterations, derived from single-end shallow whole-genome sequencing (coverage 0.1-0.5x), across 51 advanced stage lung cancer patients. Results Genomic abnormality testing reveals anomalies in 86.3% of the liquid biopsies (16/20 for adenocarcinoma, 13/16 for squamous cell, and 15/15 for small cell carcinoma). We demonstrate that copy number profiles from formalin-fixed paraffin-embedded tumor biopsies are well represented by their liquid equivalent. This is especially valid within the small cell carcinoma group, where paired profiles have an average Pearson correlation of 0.86 (95% CI 0.79-0.93). A predictive model trained with public data, derived from 843 tissue biopsies, shows that liquid biopsies exhibit multiple deviations that reflect histological classification. Most notably, distinguishing small from non-small cell lung cancer is characterized by an area under the curve of 0.98 during receiver operating characteristic analysis. Additionally, we investigated how deeper paired-end sequencing, which will eventually become feasible for routine diagnosis, empowers tumor read enrichment by insert size filtering: for all of the 29 resequenced liquid biopsies, the tumor fraction could be increased in silico, thereby "rescuing" three out of five cases with previously undetectable alterations. Conclusions Copy number profiling of cell-free DNA enables histological classification. Since shallow whole-genome sequencing is inexpensive and often fully operational at routine molecular laboratories, this finding has current diagnostic potential, especially for patients with lesions that are difficult to reach.
Keywords
Genetics(clinical), Molecular Medicine, Genetics, Molecular Biology, Lung cancer, Liquid biopsy, Cell-free DNA, Shallow whole-genome sequencing, Copy number alterations, Histological classification, LIQUID BIOPSY, CANCER

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MLA
Raman, Lennart, et al. “Shallow Whole-Genome Sequencing of Plasma Cell-Free DNA Accurately Differentiates Small from Non-Small Cell Lung Carcinoma.” GENOME MEDICINE, vol. 12, no. 1, 2020, doi:10.1186/s13073-020-00735-4.
APA
Raman, L., Van Der Linden, M., Van der Eecken, K., Vermaelen, K., Demedts, I., Surmont, V., … Van Dorpe, J. (2020). Shallow whole-genome sequencing of plasma cell-free DNA accurately differentiates small from non-small cell lung carcinoma. GENOME MEDICINE, 12(1). https://doi.org/10.1186/s13073-020-00735-4
Chicago author-date
Raman, Lennart, Malaïka Van Der Linden, Kim Van der Eecken, Karim Vermaelen, Ingel Demedts, Veerle Surmont, Ulrike Himpe, et al. 2020. “Shallow Whole-Genome Sequencing of Plasma Cell-Free DNA Accurately Differentiates Small from Non-Small Cell Lung Carcinoma.” GENOME MEDICINE 12 (1). https://doi.org/10.1186/s13073-020-00735-4.
Chicago author-date (all authors)
Raman, Lennart, Malaïka Van Der Linden, Kim Van der Eecken, Karim Vermaelen, Ingel Demedts, Veerle Surmont, Ulrike Himpe, Franceska Dedeurwaerdere, Liesbeth Ferdinande, Yolande Lievens, Kathleen Claes, Björn Menten, and Jo Van Dorpe. 2020. “Shallow Whole-Genome Sequencing of Plasma Cell-Free DNA Accurately Differentiates Small from Non-Small Cell Lung Carcinoma.” GENOME MEDICINE 12 (1). doi:10.1186/s13073-020-00735-4.
Vancouver
1.
Raman L, Van Der Linden M, Van der Eecken K, Vermaelen K, Demedts I, Surmont V, et al. Shallow whole-genome sequencing of plasma cell-free DNA accurately differentiates small from non-small cell lung carcinoma. GENOME MEDICINE. 2020;12(1).
IEEE
[1]
L. Raman et al., “Shallow whole-genome sequencing of plasma cell-free DNA accurately differentiates small from non-small cell lung carcinoma,” GENOME MEDICINE, vol. 12, no. 1, 2020.
@article{8659548,
  abstract     = {Background Accurate lung cancer classification is crucial to guide therapeutic decisions. However, histological subtyping by pathologists requires tumor tissue-a necessity that is often intrinsically associated with procedural difficulties. The analysis of circulating tumor DNA present in minimal-invasive blood samples, referred to as liquid biopsies, could therefore emerge as an attractive alternative. Methods Concerning adenocarcinoma, squamous cell carcinoma, and small cell carcinoma, our proof of concept study investigates the potential of liquid biopsy-derived copy number alterations, derived from single-end shallow whole-genome sequencing (coverage 0.1-0.5x), across 51 advanced stage lung cancer patients. Results Genomic abnormality testing reveals anomalies in 86.3% of the liquid biopsies (16/20 for adenocarcinoma, 13/16 for squamous cell, and 15/15 for small cell carcinoma). We demonstrate that copy number profiles from formalin-fixed paraffin-embedded tumor biopsies are well represented by their liquid equivalent. This is especially valid within the small cell carcinoma group, where paired profiles have an average Pearson correlation of 0.86 (95% CI 0.79-0.93). A predictive model trained with public data, derived from 843 tissue biopsies, shows that liquid biopsies exhibit multiple deviations that reflect histological classification. Most notably, distinguishing small from non-small cell lung cancer is characterized by an area under the curve of 0.98 during receiver operating characteristic analysis. Additionally, we investigated how deeper paired-end sequencing, which will eventually become feasible for routine diagnosis, empowers tumor read enrichment by insert size filtering: for all of the 29 resequenced liquid biopsies, the tumor fraction could be increased in silico, thereby "rescuing" three out of five cases with previously undetectable alterations. Conclusions Copy number profiling of cell-free DNA enables histological classification. Since shallow whole-genome sequencing is inexpensive and often fully operational at routine molecular laboratories, this finding has current diagnostic potential, especially for patients with lesions that are difficult to reach.},
  articleno    = {35},
  author       = {Raman, Lennart and Van Der Linden, Malaïka and Van der Eecken, Kim and Vermaelen, Karim and Demedts, Ingel and Surmont, Veerle and Himpe, Ulrike and Dedeurwaerdere, Franceska and Ferdinande, Liesbeth and Lievens, Yolande and Claes, Kathleen and Menten, Björn and Van Dorpe, Jo},
  issn         = {1756-994X},
  journal      = {GENOME MEDICINE},
  keywords     = {Genetics(clinical),Molecular Medicine,Genetics,Molecular Biology,Lung cancer,Liquid biopsy,Cell-free DNA,Shallow whole-genome sequencing,Copy number alterations,Histological classification,LIQUID BIOPSY,CANCER},
  language     = {eng},
  number       = {1},
  pages        = {12},
  title        = {Shallow whole-genome sequencing of plasma cell-free DNA accurately differentiates small from non-small cell lung carcinoma},
  url          = {http://dx.doi.org/10.1186/s13073-020-00735-4},
  volume       = {12},
  year         = {2020},
}

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