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Tissue of origin prediction for cancer of unknown primary using a targeted methylation sequencing panel.


ABSTRACT:

Rationale

Cancer of unknown primary (CUP) is a group of rare malignancies with poor prognosis and unidentifiable tissue-of-origin. Distinct DNA methylation patterns in different tissues and cancer types enable the identification of the tissue of origin in CUP patients, which could help risk assessment and guide site-directed therapy.

Methods

Using genome-wide DNA methylation profile datasets from The Cancer Genome Atlas (TCGA) and machine learning methods, we developed a 200-CpG methylation feature classifier for CUP tissue of origin prediction (MFCUP). MFCUP was further validated with public-available methylation array data of 2977 specimens and targeted methylation sequencing of 78 Formalin-fixed paraffin-embedded (FFPE) samples from a single center.

Results

MFCUP achieved an accuracy of 97.2% in a validation cohort (n = 5923) representing 25 cancer types. When applied to an Infinium 450 K array dataset (n = 1052) and an Infinium EPIC (850 K) array dataset (n = 1925), MFCUP achieved an overall accuracy of 93.4% and 84.8%, respectively. Based on MFCUP, we established a targeted bisulfite sequencing panel and validated it with FFPE sections from 78 patients of 20 cancer types. This methylation sequencing panel correctly identified tissue of origin in 88.5% (69/78) of samples. We also found that the methylation levels of specific CpGs can distinguish one cancer type from others, indicating their potential as biomarkers for cancer diagnosis and screening.

Conclusion

Our methylation-based cancer classifier and targeted methylation sequencing panel can predict tissue of origin in diverse cancer types with high accuracy.

SUBMITTER: Sun M 

PROVIDER: S-EPMC10854167 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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Publications

Tissue of origin prediction for cancer of unknown primary using a targeted methylation sequencing panel.

Sun Miaomiao M   Xu Bo B   Chen Chao C   Zhu Youjie Y   Li Xiaomo X   Chen Kuisheng K  

Clinical epigenetics 20240209 1


<h4>Rationale</h4>Cancer of unknown primary (CUP) is a group of rare malignancies with poor prognosis and unidentifiable tissue-of-origin. Distinct DNA methylation patterns in different tissues and cancer types enable the identification of the tissue of origin in CUP patients, which could help risk assessment and guide site-directed therapy.<h4>Methods</h4>Using genome-wide DNA methylation profile datasets from The Cancer Genome Atlas (TCGA) and machine learning methods, we developed a 200-CpG m  ...[more]

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