Cancer of unknown primary site

Summary

Cancer of unknown primary site (MONDO:0858997) is a cancer with 2 cohort genes (1 CIViC-evidence somatic driver; 2 ClinVar predisposition records) and 15 clinical trials. Top therapeutic interventions include alectinib, capecitabine, and cobimetinib.

At a glance

• Classification: Cancer
• Cohort genes: 2
• ClinVar variants: 2
• Clinical trials: 15

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cancer of unknown primary site
Mondo ID	MONDO:0858997
Orphanet	631251
NCIT	C8566
UMLS	C0027667
MedGen	10298
GARD	0026640
Is cancer (heuristic)	yes

Data availability: 2 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › cancer or benign tumor › neoplastic disease or syndrome › neoplasm › cancer › cancer of unknown primary site

Related subtypes (32): respiratory system cancer, immune system cancer, musculoskeletal system cancer, integumentary system cancer, peritoneum cancer, cardiovascular cancer, reproductive system cancer, malignant giant cell tumor, digestive system cancer, lipomatous cancer, thoracic cancer, malignant glomus tumor, malignant mesenchymoma, carcinoma, sarcoma, blastoma, head and neck cancer, malignant mixed neoplasm, nervous system cancer, retroperitoneal cancer, malignant germ cell tumor, malignant mesothelioma, malignant urinary system neoplasm, childhood malignant neoplasm, anaplastic cancer, malignant spindle cell neoplasm, high grade malignant neoplasm, malignant endocrine neoplasm, malignant soft tissue neoplasm, secondary malignant neoplasm, refractory malignant neoplasm, malignant adenoma

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

2 retrieved; paginated sample, class counts are floors:

1 conflicting classifications of pathogenicity, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
469930	NM_000038.6(APC):c.3631_3632del (p.Met1211fs)	APC	Pathogenic	criteria provided, multiple submitters, no conflicts
183003	NM_005431.2(XRCC2):c.96del (p.Phe32fs)	XRCC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 8 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
APC	LoF	AML,ANSC,CHOL,COAD,COADREAD,CSCC,EGC,ESCA,ESCC,HCC,LUAD,MEL,MT,NETNOS,NSCLC,PRAD,PROSTATE,READ,STAD,STOMACH,UM,VULVA	CIViC #66

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
XRCC2	Orphanet:227535	Hereditary breast cancer
XRCC2	Orphanet:399805	Male infertility with azoospermia or oligozoospermia due to single gene mutation
XRCC2	Orphanet:84	Fanconi anemia
APC	Orphanet:220460	Attenuated familial adenomatous polyposis
APC	Orphanet:261584	5q22 microdeletion syndrome
APC	Orphanet:314022	Gastric adenocarcinoma and proximal polyposis of the stomach
APC	Orphanet:3258	Cenani-Lenz syndrome
APC	Orphanet:873	Desmoid tumor

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
XRCC2	HGNC:12829	ENSG00000196584	O43543	DNA repair protein XRCC2	clinvar
APC	HGNC:583	ENSG00000134982	P25054	Adenomatous polyposis coli protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
XRCC2	DNA repair protein XRCC2	Involved in the homologous recombination repair (HRR) pathway of double-stranded DNA, thought to repair chromosomal fragmentation, translocations and deletions.
APC	Adenomatous polyposis coli protein	Tumor suppressor.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
XRCC2	Other/Unknown	no		Rad51_C, RecA_ATP-bd, P-loop_NTPase
APC	Other/Unknown	no		Armadillo, APC_rpt, SAMP

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	1
lateral globus pallidus	1
tendon of biceps brachii	1
medial globus pallidus	1
substantia nigra pars compacta	1
substantia nigra pars reticulata	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
XRCC2	283	ubiquitous	marker	buccal mucosa cell, tendon of biceps brachii, lateral globus pallidus
APC	297	ubiquitous	marker	substantia nigra pars compacta, substantia nigra pars reticulata, medial globus pallidus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
APC	2,903
XRCC2	1,314

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
APC	P25054	31
XRCC2	O43543	16

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 40. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
APC truncation mutants are not K63 polyubiquitinated	1	5710.0×	0.007	APC
Signaling by AXIN mutants	1	519.1×	0.008	APC
Signaling by CTNNB1 phospho-site mutants	1	519.1×	0.008	APC
Signaling by APC mutants	1	519.1×	0.008	APC
Signaling by AMER1 mutants	1	519.1×	0.008	APC
APC truncation mutants have impaired AXIN binding	1	407.9×	0.008	APC
AXIN missense mutants destabilize the destruction complex	1	407.9×	0.008	APC
Truncations of AMER1 destabilize the destruction complex	1	407.9×	0.008	APC
Signaling by GSK3beta mutants	1	380.7×	0.008	APC
CTNNB1 S33 mutants aren’t phosphorylated	1	380.7×	0.008	APC
CTNNB1 S37 mutants aren’t phosphorylated	1	380.7×	0.008	APC
CTNNB1 S45 mutants aren’t phosphorylated	1	380.7×	0.008	APC
CTNNB1 T41 mutants aren’t phosphorylated	1	380.7×	0.008	APC
Beta-catenin phosphorylation cascade	1	335.9×	0.009	APC
Signaling by WNT in cancer	1	300.5×	0.009	APC
Apoptotic cleavage of cellular proteins	1	237.9×	0.009	APC
Apoptotic execution phase	1	237.9×	0.009	APC
Impaired BRCA2 binding to PALB2	1	228.4×	0.009	XRCC2
Defective homologous recombination repair (HRR) due to BRCA1 loss of function	1	211.5×	0.009	XRCC2
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function	1	211.5×	0.009	XRCC2
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function	1	211.5×	0.009	XRCC2
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)	1	196.9×	0.009	XRCC2
Homologous DNA Pairing and Strand Exchange	1	190.3×	0.009	XRCC2
Disassembly of the destruction complex and recruitment of AXIN to the membrane	1	178.4×	0.009	APC
Resolution of D-loop Structures through Holliday Junction Intermediates	1	150.3×	0.011	XRCC2
Ovarian tumor domain proteases	1	139.3×	0.011	APC
Presynaptic phase of homologous DNA pairing and strand exchange	1	135.9×	0.011	XRCC2
Deactivation of the beta-catenin transactivating complex	1	116.5×	0.012	APC
HDR through Homologous Recombination (HRR)	1	95.2×	0.014	XRCC2
Degradation of beta-catenin by the destruction complex	1	86.5×	0.015	APC

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of fibroblast apoptotic process	1	2808.7×	0.007	XRCC2
DNA strand invasion	1	2106.5×	0.007	XRCC2
regulation of microtubule-based movement	1	1404.3×	0.007	APC
negative regulation of cell cycle G1/S phase transition	1	1203.7×	0.007	APC
positive regulation of protein localization to centrosome	1	1203.7×	0.007	APC
negative regulation of cyclin-dependent protein serine/threonine kinase activity	1	1053.2×	0.007	APC
regulation of microtubule-based process	1	936.2×	0.007	APC
regulation of attachment of spindle microtubules to kinetochore	1	842.6×	0.007	APC
heart valve development	1	766.0×	0.007	APC
positive regulation of pseudopodium assembly	1	648.1×	0.007	APC
response to X-ray	1	443.5×	0.009	XRCC2
endocardial cushion morphogenesis	1	421.3×	0.009	APC
response to gamma radiation	1	290.6×	0.011	XRCC2
positive regulation of neurogenesis	1	290.6×	0.011	XRCC2
mitotic spindle assembly checkpoint signaling	1	280.9×	0.011	APC
cell fate specification	1	263.3×	0.011	APC
negative regulation of microtubule depolymerization	1	247.8×	0.011	APC
pattern specification process	1	234.1×	0.011	APC
somitogenesis	1	187.2×	0.012	XRCC2
negative regulation of G1/S transition of mitotic cell cycle	1	179.3×	0.012	APC
centrosome cycle	1	168.5×	0.012	XRCC2
bicellular tight junction assembly	1	165.2×	0.012	APC
mitotic cytokinesis	1	129.6×	0.015	APC
meiotic cell cycle	1	122.1×	0.015	XRCC2
insulin receptor signaling pathway	1	110.9×	0.016	APC
neurogenesis	1	104.0×	0.016	XRCC2
positive regulation of protein catabolic process	1	101.5×	0.016	APC
positive regulation of cold-induced thermogenesis	1	81.8×	0.020	APC
double-strand break repair via homologous recombination	1	78.0×	0.020	XRCC2
multicellular organism growth	1	68.5×	0.022	XRCC2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
XRCC2	0	0
APC	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
APC	24	Binding:24

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Drug repurposing candidates

0 approved/phased drugs hit cohort targets but don’t yet appear in disease-level clinical trials. Target-inhibition rationale is strongest for cancer driver genes; a bioactivity hit is a screening signal, not a treatment claim.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	XRCC2, APC

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
XRCC2	0	—
APC	24	—

Clinical trials & evidence

Clinical trials

Clinical trials: 15.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	7
PHASE2	5
PHASE1	2
PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03278600	PHASE3	COMPLETED	Tissue-of-origin Directing Therapy in Patients With Cancer of Unknown Primary
NCT01845337	PHASE2	COMPLETED	Study to Compare Cardiovascular Side Effects of Teysuno Versus Capecitabine
NCT03498521	PHASE2	COMPLETED	A Phase II Randomized Study Comparing the Efficacy and Safety of Targeted Therapy or Cancer Immunotherapy Versus Platinum-Based Chemotherapy in Patients With Cancer of Unknown Primary Site
NCT03752333	PHASE2	COMPLETED	Trial of Pembrolizumab in Cancer of Unknown Primary
NCT04131621	PHASE2	UNKNOWN	Nivolumab/Ipilimumab in Second Line CUP-syndrome
NCT05024968	PHASE2	COMPLETED	Sintilimab in Cancer of Unknown Primary
NCT04459273	PHASE1	ACTIVE_NOT_RECRUITING	Prospective Exploratory Study of FAPi PET/CT With Histopathology Validation in Patients With Various Cancers
NCT03053466	PHASE1	COMPLETED	APL-501 Study for Select Advanced or Relapsed/Recurrent Solid Tumors
NCT04504604	Not specified	RECRUITING	TCF-001 TRACK (Target Rare Cancer Knowledge) Study
NCT07366008	Not specified	NOT_YET_RECRUITING	The NorCUP Trial: Improving Prognosis and Personalized Treatment in Cancer of Unknown Primary (CUP)
NCT07372963	Not specified	NOT_YET_RECRUITING	18F-FAPI PET in Cancers of Unknown Primary Site
NCT04750109	Not specified	COMPLETED	Carcinoma of Unknown Primary (CUP): a Comparison Across Tissue and Liquid Biomarkers
NCT04952103	Not specified	UNKNOWN	Real World Study of Diagnosis and First-line Treatment Among Patients With Cancer of Unknown Primary in China
NCT05263700	Not specified	UNKNOWN	FAPI-CUP- Evaluating FAPI as a Novel Radiopharmaceutical for Cancer of Unknown Primary
NCT05841966	Not specified	COMPLETED	Surgeon-performed Intraoperative Transoral Ultrasound for Cancer of Unknown Primary

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ALECTINIB	4	1
CAPECITABINE	4	1
COBIMETINIB	4	1
ENTRECTINIB	4	1
IVOSIDENIB	4	1
PEMIGATINIB	4	1
VEMURAFENIB	4	1
VISMODEGIB	4	1
IPATASERTIB	3	1
APL-501	2	1
FAPI-46 GA-68	2	1
CHEMBL3415553	0	1
CHEMBL4209555	0	1
CHEMBL4538425	0	1
PLX-4720	0	1