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Machine learning for genetics-based classification and treatment response prediction in cancer of unknown primary


Cancer of unknown primary (CUP) is a type of cancer that cannot be traced back to its primary site and accounts for 3–5% of all cancers. Established targeted therapies are lacking for CUP, leading to generally poor outcomes. We developed OncoNPC, a machine-learning classifier trained on targeted next-generation sequencing (NGS) data from 36,445 tumors across 22 cancer types from three institutions. Oncology NGS-based primary cancer-type classifier (OncoNPC) achieved a weighted F1 score of 0.942 for high confidence predictions (\(\ge 0.9\)) on held-out tumor samples, which made up 65.2% of all the held-out samples. When applied to 971 CUP tumors collected at the Dana-Farber Cancer Institute, OncoNPC predicted primary cancer types with high confidence in 41.2% of the tumors. OncoNPC also identified CUP subgroups with significantly higher polygenic germline risk for the predicted cancer types and with significantly different survival outcomes. Notably, patients with CUP who received first palliative intent treatments concordant with their OncoNPC-predicted cancers had significantly better outcomes (hazard ratio (HR) = 0.348; 95% confidence interval (CI) = 0.210–0.570; P=\(2.32\times {10}^{-5}\)). Furthermore, OncoNPC enabled a 2.2-fold increase in patients with CUP who could have received genomically guided therapies. OncoNPC thus provides evidence of distinct CUP subgroups and offers the potential for clinical decision support for managing patients with CUP.

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Fig. 1: Overview of model development and analysis workflow.
Fig. 2: Cancer-type classification performance of OncoNPC.
Fig. 3: Application of OncoNPC to CUP tumors, germline PRS-based validation and interpretation of OncoNPC cancer-type predictions.
Fig. 4: OncoNPC-based risk stratification among patients with CUP and median survival comparison between CUP and CKP metastatic cases.
Fig. 5: Potential clinical decision support for patients with CUP based on OncoNPC predictions of their tumors.

Data availability

The multicenter NGS tumor panel sequencing data is available upon request at the AACR Project GENIE website: The fully trained OncoNPC model, processed somatic variants data from Profile DFCI and deidentified clinical data used in the treatment concordance analysis are available in

Code availability

We used the R (v4.0.2) and Python (v3.9.13) programming languages for OncoNPC feature processing (R deconstructSigs v1.8.0), OncoNPC model development and interpretation (Python xgboost v1.2.0, shap v0.41.0) and survival analysis (R survival v3.2.7, stats v4.0.2, Python lifelines v0.27.4, scipy v1.7.1). Please see for the preprocessing script, the fully trained OncoNPC model, a notebook demonstration on how to use OncoNPC and other reference materials.


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The participation of patients and the efforts of an institutional data collection system made this study possible, and we are grateful for their contributions. We would also like to express our appreciation to the DFCI Oncology Data Retrieval System (OncDRS) and AACR Project GENIE team for their role in aggregating, managing and delivering the data used in this project.

I.M. and A.G. were supported by R01 CA227237, R01 CA244569 and grants from The Louis B. Mayer Foundation, The Doris Duke Charitable Foundation, The Phi Beta Psi Sorority and The Emerson Collective. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Author information

Authors and Affiliations



I.M. and A.G. conceived and designed the study. I.M. curated the data, developed and evaluated the model and performed analyses. J.L. and L.S. performed clinical chart reviews. I.M. wrote the first manuscript. I.M., J.L. and G.S. revised the manuscript. All the authors took part in interpreting the findings and reviewing the manuscript.

Corresponding author

Correspondence to Alexander Gusev.

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The authors declare no conflicts of interest.

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Nature Medicine thanks Lincoln Stein, Linda Mileshkin and E. Cuppen for their contribution to the peer review of this work. Primary Handling Editor: Lorenzo Righetto, in collaboration with the Nature Medicine team.

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Extended data

Extended Data Fig. 1 OncoNPC classification performance: confusion matrix, and precision and recall.

Confusion matrices on the held-out test set (n = 7,289) for (a) 22 detailed cancer types and (b) 13 cancer groups (see Table 1). (c),(d) OncoNPC performance in precision and recall on the test set across (c) cancer types and (d) cancer groups at 4 different prediction confidences using \({p}_{\max }\) as a threshold. Each dot size is scaled by the proportion of tumor samples retained. In (d), we only considered cancer groups that have more than one cancer type. Overall F1 scores were weighted according to the number of confirmed cases across cancer types and cancer groups, respectively.

Extended Data Fig. 2 OncoNPC prediction performance and prediction confidence levels (that is, pmax) across different cohorts and centers.

(a), Center-specific OncoNPC performance (in F1) on the test CKP tumor samples (n = 7,289). The figure is a breakdown of Fig. 2c based on cancer center (DFCI: , MSK: , VICC: ). The performance was evaluated at 4 different prediction confidences (that is, minimum \({p}_{\max }\) thresholds). Each dot size is scaled by the proportion of tumor samples retained. See Supplementary Table 3 for the center-specific number of test CKP tumor samples broken down by cancer types and prediction confidence thresholds. (b), (c) Box plots of prediction confidence (\({p}_{\max }\)) across (b) DFCI CUP tumors, MSK CUP tumors, all DFCI CKP tumors (including those with cancer types not modeled in OncoNPC), DFCI held-out CKP tumors, and DFCI excluded CKP tumors (specifically those with cancer types not modeled in OncoNPC), and (c) DFCI held-out CKP tumors, MSK held-out CKP tumors, and VICC held-out CKP tumors. Note that DFCI excluded CKP tumors refers to the cohort of the rare CKP tumors whose cancer types were not considered during the development of OncoNPC. All cohorts in the analysis for (b) and (c) were not seen by OncoNPC during the model training.

Extended Data Fig. 3 Robustness of OncoNPC performance with respect to input genomics features.

The figure shows the breakdown of OncoNPC performance in F1 score by 22 cancer types across increasing prediction confidence. The cancer types on the y-axis are sorted in a decreasing order of the number of tumor samples. In order to investigate the impact of input genomics features on OncoNPC’s robustness, we performed a feature ablation study, where we chose the most important genes based on their aggregated SHAP values and gradually reduced them from all 846 features associated with those genes, as well as age and sex, to only the top 10% (that is, top 29 features). In each feature configuration, we re-trained the model with the same set of hyperparameters and evaluated its performance on the held-out CKP tumor samples (n = 7,289), which were utilized throughout this work. Supplementary Data 4 provides a list of input features that correspond to the selected genes in each configuration.

Extended Data Fig. 4 Explanation of OncoNPC prediction for a patient with CUP.

The patient is a 76-year-old male with a tumor biopsy from the liver. The pie chart on the left shows the top 10 important features across three different feature categories (that is, CNA events, somatic mutation and mutation signatures), and the scatter plot on the right shows their SHAP values and feature values. The size of each dot is scaled by corresponding absolute SHAP value. From the chart review, we found that the patient reported a 60-pack year smoking history, as well as having lived near a tar and chemical factory as a child. Despite the CUP diagnosis, OncoNPC confidently classified the primary site as NSCLC with posterior probability of 0.98. SBS4, a tobacco smoking-associated mutation signature, was significantly enriched in the patient’s tumor sample, which has, by far, the most impact on the prediction, followed by SBS24 mutation signature associated with known exposures to aflatoxin, and KRAS mutation.

Extended Data Fig. 5 Germline polygenic risk score (PRS) enrichment of CKP tumor samples and CUP tumor samples, broken down by 8 different cancer types.

(a), Colorectal adenocarcinoma (COADREAD), (b) diffuse glioma (DIFG), (c) invasive breast carcinoma (BRCA), (d) melanoma (MEL), (e) non-small cell lung cancer (NSCLC), (f) ovarian epithelial tumor (OVT), (g) prostate adenocarcinoma (PRAD) and (h) renal cell carcinoma (RCC). The magnitude of the enrichment is quantified by \(\hat{\varDelta }_{\mathrm{PRS}}\): the mean difference between the concordant (that is OncoNPC matching) cancer type PRS and mean of PRSs of discordant cancer types (see Methods). \(\hat{\varDelta }_{\mathrm{PRS}}\) is shown for CKPs in blue (for reference) and CUPs in green.

Extended Data Fig. 6 Exclusion criteria for downstream clinical analyses.

The boxes on the left show the number of the remaining patients in the cohort and relevant analyses, while the boxes on the right illustrate the exclusion criteria and the number of patients who were consequently removed.

Extended Data Fig. 7 Estimated survival curves for the concordant and discordant treatment groups among patients with CUP, broken down by OncoNPC predicted cancer types.

a, BRCA, (b) gastrointestinal (GI) group (CHOL, COADREAD, EGC and PAAD), (c) lung (NSCLC and PLMESO) and (d) other OncoNPC cancer types (BLCA, DIFG, GINET, HNSCC, MEL, OVT, PANET, PRAD, RCC and UCEC). In each figure, the concordant treatment group and discordant treatment group are shown in blue and red, respectively. To estimate each survival curve, we utilized inverse probability of treatment weighted (IPTW) Kaplan-Meier estimator while adjusting for patient covariates and left truncation until time of sequencing (see Methods). Statistical significance of the survival difference between the two groups was estimated by a weighted log-rank test.

Extended Data Fig. 8 Estimated survival curves for the concordant and discordant treatment groups among patients with CUP who received their initial treatments after the results of the OncoPanel sequencing were available to clinicians.

Similarly, we utilized inverse probability of treatment weighted (IPTW) Kaplan-Meier estimator for each survival curve while adjusting for patient covariates and left truncation until time of sequencing (see Methods). Statistical significance of the survival difference between the two groups was estimated by a weighted log-rank test. Refer to Supplementary Table 2 for demographic information on the cohort.

Extended Data Fig. 9 OncoNPC-guided actionable variants in patients with CUP.

(a), The number of CUP tumors with actionable targets, based on OncoKB (Methods), across actionable somatic variants (mutations, amplifications and fusions). Each bar corresponds to the total number of CUP tumors associated with each actionable target. The bars are color-coded by predicted cancer types. Note that each tumor may contain more than one actionable somatic variant. (b), Proportions of CUP tumor samples with actionable somatic variants (\({N}_{{action}}\)) to the total number of patients (\({N}_{{total}}\)) across OncoNPC predicted cancer types. Proportions for four different therapeutic levels based on OncoKB are shown in each bar: level 1—FDA-approved drugs, level 2—standard of care drugs, level 3—drugs supported by clinical evidence and level 4—drugs supported by biological evidence.

Extended Data Table 1 Demographic details of patients with CUP in the concordant and discordant treatment groups

Supplementary information

Supplementary Information

Supplementary Notes 1–13, Supplementary Figs. 1–10 and Supplementary Tables 1–3.

Reporting Summary

Supplementary Data 1

OncoNPC input feature genes targeted across different panel versions.

Supplementary Data 2

A full set of features utilized in OncoNPC.

Supplementary Data 3

Aggregated SHAP values for OncoNPC features.

Supplementary Data 4

Features utilized across different settings of the ablation study.

Supplementary Data 5

Patient information in the treatment concordance analysis cohort.

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Moon, I., LoPiccolo, J., Baca, S.C. et al. Machine learning for genetics-based classification and treatment response prediction in cancer of unknown primary. Nat Med 29, 2057–2067 (2023).

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