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. 2025 Nov 13;9(1):347.
doi: 10.1038/s41698-025-01126-x.

High clinical actionability of a pan-cancer tissue-based combined DNA and RNA next generation sequencing assay in a diverse Asian population

Jing Yi Lee  1   2 , Aya El Helali  3 , Donavan Jia Jie Tan  1 , Zi Yi Wan  4 , Donald Poon  5 , Jens Samol  6   7   8 , Tsz Him So  9 , Su Pin Choo  10 , Ravindran Kanesvaran  11 , Cheng-Vai Hui  12 , Joseph Siu-Kie Au  13 , Timothy Yip  4 , Ross A Soo  14 , Michelle Pek  4 , Ruifen Weng  15 , Bin Tean Teh  2 , Min-Han Tan  4 , Jonathan Poh  4 , Jason Yongsheng Chan  16   17
Affiliations

High clinical actionability of a pan-cancer tissue-based combined DNA and RNA next generation sequencing assay in a diverse Asian population

Jing Yi Lee et al. NPJ Precis Oncol. .

Abstract

Advancements in next-generation sequencing have facilitated tumour-agnostic approaches for cancer therapy. Here, we demonstrate the clinical utility of molecularly guided tumour-agnostic precision medicine in an Asian cohort, leveraging an Asian-centric DNA/RNA comprehensive genomic profiling (CGP) panel. A total of 1166 tissue samples encompassing 29 cancer types underwent real-world CGP testing. Actionable biomarkers were identified in 62.3% of samples, including 1291 (4.7%) somatic variants potentially targetable by regulatory-approved therapies. At least one tumour-agnostic biomarker, including high tumour mutation burden (TMB-high), microsatellite instability (MSI-high), NTRK/RET fusions, and BRAF V600E was identified in 98 samples across 26 cancer types (8.4%). ERBB2 amplification was identified in 42 samples (3.6%) and was most frequently detected in breast (15.0%), followed by endometrial (11.8%) and ovarian tumours (8.9%). Homologous recombination deficiency (HRD) was observed in 407 samples (34.9%). The high prevalence of actionable biomarkers underscores the significance of CGP in facilitating precision medicine in an Asian setting.

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Conflict of interest statement

Competing interests: M-H.T., Z.Y.W., T.Y., M.P. and J.P. are employees of and/or hold stock ownership in Lucence Diagnostics Pte Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Fig. 1
Fig. 1. Distribution of samples by cancer type in the study cohort.
A A total of 1166 cases were included, derived from patient cohorts from Singapore (SG, n = 777), Hong Kong (HK, n = 326), Taiwan (TW, n = 46) and other countries/territories (n = 17). B Ethnicity distribution of the study cohort. C A spectrum of 29 cancer types was included, consisting of subtypes beyond the original multigene panel design.
Fig. 2
Fig. 2. Landscape of genetic alterations across cancer types.
A 62.3% of samples harboured at least 1 alteration that were deemed broadly actionable. The most common actionable gene alterations were TP53, KRAS, EGFR and PIK3CA. B 4.7% of somatic variants were potentially targetable by regulatory-approved therapies. The likelihood of identifying at least one actionable mutation was highest in CNS tumours (83.6%), followed by lung cancer (81.2%), breast cancer (79.0%), and others.
Fig. 3
Fig. 3. Distribution of established tumour-agnostic biomarkers.
A At least 1 established tumour agnostic marker was detected in 19 out of the 29 cancer types, across 98 samples (8.4%), including in 30% of thyroid, 22.7% of melanoma, 16.8% of lung, 12% of unknown primary origin, 11.8% of endometrial tumours, and others. B Distribution of tumour-agnostic biomarkers except TMB-high across tumour types with at least 1 tumour-agnostic marker detected.
Fig. 4
Fig. 4. Tumour mutation burden (TMB) status.
A 77/1166 (6.6%) of samples were TMB-high, with a median TMB of 5.2 mutations/Mb. Tumours of the lung (15.4%), endometrium (11.8%) and oesophagus (11.1%) had the highest proportions of TMB-high tumours. B Range of TMB scores (mutations/Mb) in the top 10 cancer types with highest proportion of TMB-high cases are shown.
Fig. 5
Fig. 5. Microsatellite instability (MSI) status.
A 16/1166 (1.4%) of samples were MSI-high, with endometrial tumours (5.9%), gastric tumours (4.7%) and unknown primary tumours (4%) having highest proportions of MSI-high tumours. B TMB was significantly higher in MSI-high compared to MSS tumours (median TMB 23.0 vs 5.15, p = 3.303-11).
Fig. 6
Fig. 6. Homologous recombination deficiency (HRD) and ERBB2 amplification status.
A HRD was observed in 407 samples (34.9%) and were present in about half of the tumours of the breast (50%), colon (49.0%), lung (44.2%), ovary (42.2%) and gastric (39.5%). B Notably, HRD-positive tumours exhibited significantly higher TMB compared to HRD-negative tumours (median TMB 5.58 vs. 5.15, respectively, p = 0.000455). C ERBB2 amplification, a potential surrogate marker for HER2 overexpression, was identified in 42 samples (3.6%) and was most frequently detected in breast tumours (15%), followed by endometrial tumours (11.8%), ovarian tumours (8.9%), small intestinal tumours (8.3%), and others. Shown are cancers with ≥ 1 ERBB2-amplified case only. D ERBB2-amplified tumours exhibited significantly higher proportion of HRD-positive cases compared to ERBB2 non-amplified tumours (p = 0.023).
Fig. 7
Fig. 7. Summary of actionable biomarker landscape in the current study cohort.
A Established and emerging tumour agnostic biomarkers detected across all cancer types. B Proportion of clinically actionable biomarkers by ESCAT Tiers or otherwise. Inner circle: actionable and non-actionable. Outer circle: ESCAT tier proportions within each group.
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