Rectal cancer

Summary

Rectal cancer (MONDO:0006519) is a cancer (an umbrella term covering 6 Mondo subtypes) with 12 cohort genes (46 GWAS associations across 13 studies; 4 CIViC-evidence somatic drivers) and 1,331 clinical trials. Molecularly, MSI High confers sensitivity to Dostarlimab in Rectum Cancer (CIViC Level B); 2 further subtype–drug associations are mapped below. Top therapeutic interventions include leucovorin, irinotecan, and tipiracil.

At a glance

• Classification: Cancer
• Umbrella term: 6 Mondo subtypes
• Cohort genes: 12
• GWAS associations: 46
• Clinical trials: 1,331
• Precision-medicine evidence (CIViC): 3 subtype–drug associations

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	rectal cancer
Mondo ID	MONDO:0006519
EFO	EFO:1000657
DOID	DOID:1993
ICD-10-CM	C20
ICD-11	1113099195
NCIT	C7418
SNOMED CT	363351006
UMLS	C0949022
MedGen	181763
Anatomy (UBERON)	UBERON:0001052
Is cancer (heuristic)	yes

Also known as: cancer of rectum · carcinoma of rectum · carcinoma of the rectum · malignant neoplasm of rectum · malignant neoplasm of the rectum · malignant rectal neoplasm · malignant rectal tumor · malignant rectal tumour · malignant rectum neoplasm · malignant rectum tumour · malignant tumor of rectum · malignant tumor of the rectum · malignant tumour of rectum · malignant tumour of the rectum · rectal cancer · rectum cancer

Data availability: 46 GWAS associations (13 studies).

Disease family

An umbrella term covering 6 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › digestive system disorder › intestinal disorder › large intestine disorder › rectal disorder › rectal neoplasm › rectal cancer

Related subtypes (3): anus neoplasm, benign neoplasm of rectum, epithelial neoplasm of rectum

Subtypes (6): anus cancer, rectum lymphoma, rectum malignant melanoma, rectum sarcoma, rectosigmoid junction cancer, rectal carcinoma

Genetics & variants

GWAS landscape

46 GWAS associations across 13 studies. Top hits map to 33 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs6983267	5e-10	PCAT1, CASC8, POU5F1B, CCAT2	G	1.22
rs28611105	5e-09	PYGL, ABHD12B	G	1.11
rs58658771	1e-08	SCG5 - GREM1	A	1.24
rs3087967	3e-08	POU2AF2	T	1.2
rs145503185	4e-08	LINC03142 - SUMO2P2	C	1.81
rs4939827	5e-08	SMAD7	T	1.19
rs1570271	1e-07	PPIAP39 - HABP2	?	3.66
rs17604996	1e-07	MEGF10	G	1.45
rs17057166	2e-07	LINC01847	?	5.56
rs2027077	2e-07	LAMC1	G	1.18
rs4868304	3e-07	LINC01942	?	2.91
rs146801533	4e-07	SCP2D1-AS1 - SLC24A3	G	1.82
rs141553824	5e-07	BRD7	C	45.8
rs6854845	6e-07	BTC - HSPE1P23	?	3.31
rs73171906	6e-07	CNTNAP2	T	2.2
rs17026425	7e-07	IQCM	?	5.06
rs34829185	7e-07	DLC1 - SGCZ	A	1.27
rs12612141	7e-07	PLCL1 - RNU7-147P	G	1.17
rs16892766	8e-07	LINC00536 - EIF3H	C	1.29
rs78144988	8e-07	LINC01709	C	54.9
rs72909399	8e-07	Y_RNA - RNU4-12P	T	74.7
rs72716373	1e-06	SCOC	C	1.73
rs13403794	1e-06	YWHAQ - RNU4-73P	C	65.5
rs354856	1e-06	LRP1B	C	17.4
rs116443146	1e-06	IL15 - INPP4B	G	40.3
rs157411	2e-06	LINC02997 - RNU6-1232P	?	2.89
rs7004484	2e-06	EFR3A	?	2.79
rs2302274	2e-06	CDX1	G	1.07
rs9773025	2e-06	XKR5	G	0.5
rs79619562	2e-06	DYRK1A	C	2.7

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST012204	Huyghe JR	2021	16,212	64,159	Genetic architectures of proximal and distal colorectal cancer are partly distinct.
GCST90011810	Rashkin SR	2020	2,091	410,350	Pan-cancer study detects genetic risk variants and shared genetic basis in two large cohorts.
GCST90079583	Backman JD	2021	1,884	385,913	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90083569	Backman JD	2021	1,884	385,913	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90079083	Backman JD	2021	1,566	72,664	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90083069	Backman JD	2021	1,566	72,664	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90043857	Jiang L	2021	1,473	454,875	A generalized linear mixed model association tool for biobank-scale data.
GCST90246024	Walters RG	2023	447	75,488	Genotyping and population characteristics of the China Kadoorie Biobank.
GCST004169	Wang H	2017	443	4,703	Novel colon cancer susceptibility variants identified from a genome-wide association study in African Americans.
GCST90041896	Jiang L	2021	326	455,950	A generalized linear mixed model association tool for biobank-scale data.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	3
Tier 3: regulatory	2
Tier 4: intronic/intergenic	40

MAF distribution

Bucket	Variants
common (>=0.05)	33
low_freq (0.01-0.05)	12
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intron_variant	30
intergenic_variant	9
3_prime_UTR_variant	2
regulatory_region_variant	2
non_coding_transcript_exon_variant	1
5_prime_UTR_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs6983267	8	127401060	G>T	0.05	non_coding_transcript_exon_variant	PCAT1, CASC8, POU5F1B, CCAT2	5e-10	Tier 4: intronic/intergenic
rs28611105	14	50892940	T>A,G	0.215	intron_variant	PYGL, ABHD12B	5e-09	Tier 4: intronic/intergenic
rs58658771	15	32709533	T>A,C,G	0.05	intergenic_variant	SCG5 - GREM1	1e-08	Tier 4: intronic/intergenic
rs3087967	11	111286111	T>A,C,G	0.05	3_prime_UTR_variant	POU2AF2	3e-08	Tier 2: splice/UTR
rs145503185	9	23455766	T>C	0.013	intergenic_variant	LINC03142 - SUMO2P2	4e-08	Tier 4: intronic/intergenic
rs4939827	18	48927093	T>A,C	0.05	intron_variant	SMAD7	5e-08	Tier 4: intronic/intergenic
rs1570271	10	113528742	A>C,G,T	0.05	intron_variant	PPIAP39 - HABP2	1e-07	Tier 4: intronic/intergenic
rs17604996	5	127427395	A>G,T	0.039	intron_variant	MEGF10	1e-07	Tier 4: intronic/intergenic
rs17057166	5	159821007	C>T	0.05	intron_variant	LINC01847	2e-07	Tier 4: intronic/intergenic
rs2027077	1	183104318	G>A,C,T	0.05	intron_variant	LAMC1	2e-07	Tier 4: intronic/intergenic
rs4868304	5	173704454	C>T	0.05	intron_variant	LINC01942	3e-07	Tier 4: intronic/intergenic
rs146801533	20	19186027	T>C,G	0.01	intergenic_variant	SCP2D1-AS1 - SLC24A3	4e-07	Tier 4: intronic/intergenic
rs141553824	16	50346475	T>C	0.017	intron_variant	BRD7	5e-07	Tier 4: intronic/intergenic
rs6854845	4	74821455	G>T	0.05	intergenic_variant	BTC - HSPE1P23	6e-07	Tier 4: intronic/intergenic
rs73171906	7	148289437	C>T	0.23	intron_variant	CNTNAP2	6e-07	Tier 4: intronic/intergenic
rs17026425	4	149751362	G>A	0.05	intron_variant	IQCM	7e-07	Tier 4: intronic/intergenic
rs34829185	8	13706716	C>A,G,T	0.094	intron_variant	DLC1 - SGCZ	7e-07	Tier 4: intronic/intergenic
rs12612141	2	199006308	G>A	0.328	intron_variant	PLCL1 - RNU7-147P	7e-07	Tier 4: intronic/intergenic
rs16892766	8	116618444	A>C	0.05	regulatory_region_variant	LINC00536 - EIF3H	8e-07	Tier 3: regulatory
rs78144988	1	101733832	T>C,G	0.013	intron_variant	LINC01709	8e-07	Tier 4: intronic/intergenic
rs72909399	6	85871327	G>T	0.014	intergenic_variant	Y_RNA - RNU4-12P	8e-07	Tier 4: intronic/intergenic
rs72716373	4	140385611	T>C	0.012	3_prime_UTR_variant	SCOC	1e-06	Tier 2: splice/UTR
rs13403794	2	9644931	T>A,C	0.012	intron_variant	YWHAQ - RNU4-73P	1e-06	Tier 4: intronic/intergenic
rs354856	2	141676101	T>A,C	0.027	intron_variant	LRP1B	1e-06	Tier 4: intronic/intergenic
rs116443146	4	141778240	A>G,T	0.013	intron_variant	IL15 - INPP4B	1e-06	Tier 4: intronic/intergenic
rs157411	5	67999079	G>A,T	0.05	regulatory_region_variant	LINC02997 - RNU6-1232P	2e-06	Tier 3: regulatory
rs7004484	8	131922291	A>C,T	0.05	intron_variant	EFR3A	2e-06	Tier 4: intronic/intergenic
rs2302274	5	150166863	A>C,G,T	0.478	5_prime_UTR_variant	CDX1	2e-06	Tier 2: splice/UTR
rs9773025	8	6816936	A>C,G,T	0.414	intron_variant	XKR5	2e-06	Tier 4: intronic/intergenic
rs79619562	21	37370120	T>C	0.1	intron_variant	DYRK1A	2e-06	Tier 4: intronic/intergenic

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 33 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
KRAS	Act	ALL,AML,ANSC,BLADDER,BLCA,BRCA,CEAD,CESC,CHOL,CLLSLL,COAD,COADREAD,DLBCLNOS,EGC,ESCA,ESCC,HCC,LUAD,LUSC,MEL,MGCT,MT,NSCLC,OVT,PAAD,PANCREAS,PAST,PCM,PRAD,PRCC,READ,STAD,STOMACH,UCEC,UCS,WDTC	CIViC #30
MTHFR			CIViC #3672
PIK3CA	Act	ACYC,ANGS,ANSC,BCC,BLADDER,BLCA,BRCA,CCRCC,CEAD,CESC,CHOL,COAD,COADREAD,EPM,ESCA,ESCC,GB,GBM,HCC,HGGNOS,HNSC,LGGNOS,LIPO,LMS,LUAD,LUSC,MBL,MGCT,NPC,NSCLC,OVT,PAAD,PAST,PLMESO,PRAD,PRCC,PROSTATE,RCC,SACA,SKCM,SOFT_TISSUE,STAD,UCEC,UCS,UTUC,VULVA,WDTC	CIViC #37
NIN	LoF	COADREAD,PLMESO,STAD

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KRAS	Orphanet:1333	Familial pancreatic carcinoma
KRAS	Orphanet:1340	Cardiofaciocutaneous syndrome
KRAS	Orphanet:144	Lynch syndrome
KRAS	Orphanet:146	Differentiated thyroid carcinoma
KRAS	Orphanet:2396	Encephalocraniocutaneous lipomatosis
KRAS	Orphanet:251615	Pilomyxoid astrocytoma
KRAS	Orphanet:2612	Linear nevus sebaceus syndrome
KRAS	Orphanet:268114	RAS-associated autoimmune leukoproliferative disease
KRAS	Orphanet:3339	Oculoectodermal syndrome
KRAS	Orphanet:648	Noonan syndrome
KRAS	Orphanet:86834	Juvenile myelomonocytic leukemia
MTHFR	Orphanet:395	Homocystinuria due to methylene tetrahydrofolate reductase deficiency
MTHFR	Orphanet:563609	Isolated anencephaly
MTHFR	Orphanet:563612	Isolated exencephaly
PIK3CA	Orphanet:140944	CLOVES syndrome
PIK3CA	Orphanet:144	Lynch syndrome
PIK3CA	Orphanet:168984	CLAPO syndrome
PIK3CA	Orphanet:201	Cowden syndrome
PIK3CA	Orphanet:210159	Adult hepatocellular carcinoma
PIK3CA	Orphanet:221061	Familial cerebral cavernous malformation
PIK3CA	Orphanet:2495	Meningioma
PIK3CA	Orphanet:276280	Hemihyperplasia-multiple lipomatosis syndrome
PIK3CA	Orphanet:295239	Macrodactyly of fingers, unilateral
PIK3CA	Orphanet:295243	Macrodactyly of toes, unilateral
PIK3CA	Orphanet:314662	Segmental progressive overgrowth syndrome with fibroadipose hyperplasia
PIK3CA	Orphanet:60040	Megalencephaly-capillary malformation-polymicrogyria syndrome
PIK3CA	Orphanet:714737	Diffuse capillary malformation with overgrowth
PIK3CA	Orphanet:90308	Capillary-lymphatic-venous malformation with segmental distribution
PIK3CA	Orphanet:99802	Hemimegalencephaly
SP6	Orphanet:100031	Hypoplastic amelogenesis imperfecta
NIN	Orphanet:319675	Microcephalic primordial dwarfism, Dauber type
NIN	Orphanet:808	Seckel syndrome
PYGL	Orphanet:369	Glycogen storage disease due to liver glycogen phosphorylase deficiency

Cohort genes → proteins

12 cohort genes, 11 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	9
civic_only	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KRAS	HGNC:6407	ENSG00000133703	P01116	GTPase KRas	civic_evidence
MTHFR	HGNC:7436	ENSG00000177000	P42898	Methylenetetrahydrofolate reductase (NADPH)	civic_evidence
PIK3CA	HGNC:8975	ENSG00000121879	P42336	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform	civic_evidence
SP6	HGNC:14530	ENSG00000189120	Q3SY56	Transcription factor Sp6	gwas
NIN	HGNC:14906	ENSG00000100503	Q8N4C6	Ninein	gwas
CDX1	HGNC:1805	ENSG00000113722	P47902	Homeobox protein CDX-1	gwas
ABHD12B	HGNC:19837	ENSG00000131969	Q7Z5M8	Protein ABHD12B	gwas
SLC22A23	HGNC:21106	ENSG00000137266	A1A5C7	Solute carrier family 22 member 23	gwas
ANO1	HGNC:21625	ENSG00000131620	Q5XXA6	Anoctamin-1	gwas
EFR3A	HGNC:28970	ENSG00000132294	Q14156	Protein EFR3 homolog A	gwas
LINC00513	HGNC:43566	ENSG00000233559		long intergenic non-protein coding RNA 513	gwas
PYGL	HGNC:9725	ENSG00000100504	P06737	Glycogen phosphorylase, liver form	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KRAS	GTPase KRas	Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.
MTHFR	Methylenetetrahydrofolate reductase (NADPH)	Catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a cosubstrate for homocysteine remethylation to methionine.
PIK3CA	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform	Phosphoinositide-3-kinase (PI3K) phosphorylates phosphatidylinositol (PI) and its phosphorylated derivatives at position 3 of the inositol ring to produce 3-phosphoinositides.
SP6	Transcription factor Sp6	Promotes cell proliferation.
NIN	Ninein	Centrosomal protein required in the positioning and anchorage of the microtubule minus-end in epithelial cells.
CDX1	Homeobox protein CDX-1	Plays a role in transcriptional regulation.
ANO1	Anoctamin-1	Calcium-activated chloride channel (CaCC).
EFR3A	Protein EFR3 homolog A	Component of a complex required to localize phosphatidylinositol 4-kinase (PI4K) to the plasma membrane.
PYGL	Glycogen phosphorylase, liver form	Allosteric enzyme that catalyzes the rate-limiting step in glycogen catabolism, the phosphorolytic cleavage of glycogen to produce glucose-1-phosphate, and plays a central role in maintaining cellular and organismal glucose homeostasis.

Protein-family classification

Druggable: 5 · Difficult: 2 · Unknown: 5 · Druggable fraction: 0.42

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
Transporter	1	6.5×	0.360
Enzyme (other)	3	3.0×	0.360
Kinase	1	2.3×	0.545
Transcription factor	2	1.4×	0.545
Other/Unknown	5	0.8×	0.899

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KRAS	Enzyme (other)	yes	3.6.5.2	Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type
MTHFR	Enzyme (other)	yes	1.5.1.20	Mehydrof_redctse-like, Fadh2_euk, FAD-linked_oxidoreductase-like
PIK3CA	Kinase	yes	2.7.1.137	PI3K_Ras-bd_dom, PI3/4_kinase_cat_dom, PI3K_accessory_dom
SP6	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf
NIN	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair
CDX1	Transcription factor	no		HTH_motif, HD, Caudal_activation_dom
ABHD12B	Other/Unknown	no		ABHD17C-like, AB_hydrolase_fold
SLC22A23	Transporter	yes		MFS_sugar_transport-like, Sugar_transporter_CS, MFS_dom
ANO1	Other/Unknown	no		Anoctamin, Anoct_dimer, Anoctamin_TM
EFR3A	Other/Unknown	no		ARM-type_fold, EFR3-like_ARM, EFR3_Homologs
LINC00513	Other/Unknown	no
PYGL	Enzyme (other)	yes	2.4.1.1	Glyco_trans_35, Glycg_phsphrylas, Pyridoxal_P_attach_site

Expression context

Cohort genes with no expression data: 0.

11 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)	12
unknown	0

Top tissues across cohort

Tissue	Cohort genes
corpus epididymis	2
sural nerve	2
upper arm skin	2
ileal mucosa	2
nipple	1
pylorus	1
trigeminal ganglion	1
apex of heart	1
adrenal tissue	1
calcaneal tendon	1
tendon	1
lower esophagus mucosa	1
placenta	1
buccal mucosa cell	1
cardiac muscle of right atrium	1
oviduct epithelium	1
mucosa of transverse colon	1
rectum	1
skin of abdomen	1
skin of leg	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KRAS	298	ubiquitous	marker	trigeminal ganglion, pylorus, nipple
MTHFR	254	ubiquitous	marker	corpus epididymis, sural nerve, apex of heart
PIK3CA	284	ubiquitous	marker	calcaneal tendon, adrenal tissue, tendon
SP6	140	broad	yes	lower esophagus mucosa, upper arm skin, placenta
NIN	253	ubiquitous	marker	oviduct epithelium, buccal mucosa cell, cardiac muscle of right atrium
CDX1	124	tissue_specific	marker	mucosa of transverse colon, rectum, ileal mucosa
ABHD12B	182	tissue_specific	marker	upper arm skin, skin of leg, skin of abdomen
SLC22A23	247	ubiquitous	marker	pancreatic ductal cell, ileal mucosa, ganglionic eminence
ANO1	214	broad	marker	caput epididymis, seminal vesicle, corpus epididymis
EFR3A	299	ubiquitous	marker	choroid plexus epithelium, endothelial cell, pons
LINC00513	158	broad	marker	sural nerve, bone marrow cell, colonic epithelium
PYGL	255	ubiquitous	marker	blood, monocyte, mononuclear cell

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KRAS	14,509
PIK3CA	5,157
MTHFR	3,492
PYGL	2,733
NIN	2,525
CDX1	1,498
EFR3A	1,377
ANO1	1,344
SP6	1,080
SLC22A23	918

Intra-cohort edges

A	B	Sources
KRAS	PIK3CA	string_interaction

Structural data

PDB: 6 · AlphaFold-only: 5 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KRAS	P01116	511
PIK3CA	P42336	135
PYGL	P06737	19
MTHFR	P42898	4
CDX1	P47902	2
EFR3A	Q14156	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ABHD12B	Q7Z5M8	87.88
ANO1	Q5XXA6	77.20
SLC22A23	A1A5C7	73.39
NIN	Q8N4C6	64.47
SP6	Q3SY56	52.79

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 127. Enrichment computed across 12 evidence-associated genes (5 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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Signaling by FGFR4 in disease	2	380.7×	4e-04	KRAS, PIK3CA
Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants	2	351.4×	4e-04	KRAS, PIK3CA
Signaling by PDGFRA extracellular domain mutants	2	351.4×	4e-04	KRAS, PIK3CA
Signaling by FLT3 ITD and TKD mutants	2	304.5×	4e-04	KRAS, PIK3CA
Constitutive Signaling by EGFRvIII	2	285.5×	4e-04	KRAS, PIK3CA
Signaling by ERBB2 ECD mutants	2	268.7×	4e-04	KRAS, PIK3CA
Tie2 Signaling	2	240.4×	4e-04	KRAS, PIK3CA
Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants	2	228.4×	4e-04	KRAS, PIK3CA
Signaling by FLT3 fusion proteins	2	228.4×	4e-04	KRAS, PIK3CA
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	2	207.6×	4e-04	KRAS, PIK3CA
Signaling by FGFR3 in disease	2	198.6×	4e-04	KRAS, PIK3CA
Signaling by ERBB2 KD Mutants	2	169.2×	6e-04	KRAS, PIK3CA
Downstream signal transduction	2	152.3×	6e-04	KRAS, PIK3CA
DAP12 signaling	2	147.3×	6e-04	KRAS, PIK3CA
FLT3 Signaling	2	138.4×	6e-04	KRAS, PIK3CA
Signaling by CSF1 (M-CSF) in myeloid cells	2	138.4×	6e-04	KRAS, PIK3CA
Signaling by FGFR1 in disease	2	117.1×	8e-04	KRAS, PIK3CA
Signaling by FGFR2 in disease	2	106.2×	1e-03	KRAS, PIK3CA
Signaling by SCF-KIT	2	99.3×	0.001	KRAS, PIK3CA
Signaling by RAS GAP mutants	1	761.3×	0.008	KRAS
Signaling by RAS GTPase mutants	1	761.3×	0.008	KRAS
Activation of RAS in B cells	1	456.8×	0.013	KRAS
MET activates PI3K/AKT signaling	1	380.7×	0.013	PIK3CA
Activated NTRK3 signals through PI3K	1	380.7×	0.013	PIK3CA
RAF/MAP kinase cascade	2	24.4×	0.013	KRAS, PIK3CA
RAS signaling downstream of NF1 loss-of-function variants	1	326.3×	0.013	KRAS
Activated NTRK2 signals through PI3K	1	326.3×	0.013	PIK3CA
Estrogen-stimulated signaling through PRKCZ	1	326.3×	0.013	KRAS
Signaling by LTK in cancer	1	326.3×	0.013	PIK3CA
SOS-mediated signalling	1	285.5×	0.015	KRAS

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 11 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
response to muscle inactivity	1	1532.0×	0.020	PIK3CA
response to mineralocorticoid	1	1532.0×	0.020	KRAS
response to butyrate	1	1532.0×	0.020	PIK3CA
response to vitamin B2	1	766.0×	0.020	MTHFR
centrosome-templated microtubule nucleation	1	766.0×	0.020	NIN
forebrain astrocyte development	1	510.7×	0.020	KRAS
response to L-leucine	1	510.7×	0.020	PIK3CA
S-adenosylmethionine metabolic process	1	510.7×	0.020	MTHFR
cellular response to hydrostatic pressure	1	510.7×	0.020	PIK3CA
glial cell projection elongation	1	510.7×	0.020	ANO1
phosphatidylserine catabolic process	1	383.0×	0.020	ABHD12B
response to isolation stress	1	383.0×	0.020	KRAS
obsolete methionine biosynthetic process	1	306.4×	0.020	MTHFR
regulation of odontogenesis	1	306.4×	0.020	SP6
L-methionine metabolic process	1	255.3×	0.020	MTHFR
response to gravity	1	255.3×	0.020	KRAS
regulation of somitogenesis	1	255.3×	0.020	CDX1
negative regulation of actin filament depolymerization	1	255.3×	0.020	PIK3CA
regulation of cellular respiration	1	255.3×	0.020	PIK3CA
iodide transport	1	218.9×	0.020	ANO1
corpus callosum morphogenesis	1	218.9×	0.020	NIN
corticospinal tract morphogenesis	1	218.9×	0.020	NIN
response to folic acid	1	218.9×	0.020	MTHFR
monoacylglycerol catabolic process	1	218.9×	0.020	ABHD12B
regulation of actin filament organization	1	218.9×	0.020	PIK3CA
autosome genomic imprinting	1	218.9×	0.020	PIK3CA
negative regulation of fibroblast apoptotic process	1	218.9×	0.020	PIK3CA
phosphatidylinositol phosphate biosynthetic process	2	87.5×	0.020	EFR3A, PIK3CA
liver development	2	40.3×	0.020	KRAS, PIK3CA
negative regulation of neuron apoptotic process	2	20.2×	0.020	KRAS, PIK3CA

Therapeutics

Drugs indicated for this disease

0 approved, 21 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Bevacizumab	Phase 3 (in late-stage trials)
Capecitabine	Phase 3 (in late-stage trials)
Celecoxib	Phase 3 (in late-stage trials)
Cetuximab	Phase 3 (in late-stage trials)
Eniluracil	Phase 3 (in late-stage trials)
Envafolimab	Phase 3 (in late-stage trials)
Fluorouracil	Phase 3 (in late-stage trials)
Gentamicin	Phase 3 (in late-stage trials)
Interferon Alfa	Phase 3 (in late-stage trials)
Irinotecan	Phase 3 (in late-stage trials)
Lactobacillus Acidophilus	Phase 3 (in late-stage trials)
Ornidazole	Phase 3 (in late-stage trials)
Oxaliplatin	Phase 3 (in late-stage trials)
Rifaximin	Phase 3 (in late-stage trials)
Sennosides	Phase 3 (in late-stage trials)
Sildenafil	Phase 3 (in late-stage trials)
Tegafur	Phase 3 (in late-stage trials)
Tislelizumab	Phase 3 (in late-stage trials)
Uracil	Phase 3 (in late-stage trials)
Vatalanib	Phase 3 (in late-stage trials)
Vitamin E	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Adebrelimab, Aflibercept, Amifostine, Ascorbic Acid, Aspirin, Atezolizumab, Avelumab, Azacitidine, Bleomycin, Cabozantinib, Cadonilimab, Calcium, Camrelizumab, Catequentinib, Cholecalciferol, Clobetasol Propionate, Dasatinib Anhydrous, Dexamethasone, Dostarlimab, Durvalumab, Entinostat, Folic Acid, Fruquintinib, Ganetespib, Gemcitabine, Gimeracil, Ipilimumab, Irinotecan Sucrosofate, Lansoprazole, Levoleucovorin, Linifanib, Metformin, Metronidazole, Neomycin, Nimotuzumab, Nivolumab, Onabotulinumtoxina, Oteracil, Panitumumab, Pegfilgrastim, Pembrolizumab, Pemetrexed, Penpulimab, Raltitrexed, Ramucirumab, Regorafenib, Rosuvastatin, Saracatinib, Savolitinib, Simvastatin, Sintilimab, Sodium Chloride, Tecemotide, Temozolomide, Thymalfasin, Tipiracil, Tiragolumab, Toripalimab, Trifluridine, Vorinostat, Zimberelimab.

Drug target analysis

Approved (phase 4): 3 · Phase ≥3: 4 · Phased (≥1): 4 · Undrugged: 8

Druggability breadth: 4 of 12 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
KRAS	VEMURAFENIB
PIK3CA	IDELALISIB
ANO1	NITAZOXANIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PIK3CA	67	4
KRAS	11	4
PYGL	3	3
ANO1	2	4
MTHFR	0	0
SP6	0	0
NIN	0	0
CDX1	0	0
ABHD12B	0	0
SLC22A23	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VEMURAFENIB	4	KRAS
DABRAFENIB	4	KRAS
LONAFARNIB	4	KRAS
SOTORASIB	4	KRAS
ADAGRASIB	4	KRAS
IDELALISIB	4	PIK3CA
ALPELISIB	4	PIK3CA
DUVELISIB	4	PIK3CA
COPANLISIB	4	PIK3CA
FEDRATINIB	4	PIK3CA
ROMIDEPSIN	4	PIK3CA
COPANLISIB HYDROCHLORIDE	4	PIK3CA
LENIOLISIB	4	PIK3CA
BELINOSTAT	4	PIK3CA
INAVOLISIB	4	PIK3CA
SUNITINIB	4	PIK3CA
DASATINIB	4	PIK3CA
CRIZOTINIB	4	PIK3CA
MIDOSTAURIN	4	PIK3CA
NITAZOXANIDE	4	ANO1
NICLOSAMIDE	4	ANO1
OPNURASIB	3	KRAS
DACTOLISIB	3	PIK3CA
BUPARLISIB	3	PIK3CA
RESVERATROL	3	PIK3CA
IPATASERTIB	3	PIK3CA
TASELISIB	3	PIK3CA
EPIGALOCATECHIN GALLATE	3	PIK3CA
GEDATOLISIB	3	PIK3CA
LESTAURTINIB	3	PIK3CA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 4.

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

Symbol	Assays	Type breakdown
PIK3CA	2,034	Binding:2009, ADMET:19, Toxicity:4, Functional:2
KRAS	861	Binding:829, Functional:32
PYGL	58	Binding:58
ANO1	32	Binding:32

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
KRAS	3.6.5.2	small monomeric GTPase
MTHFR	1.5.1.20, 1.5.1.53	methylenetetrahydrofolate reductase [NAD(P)H], methylenetetrahydrofolate reductase (NADPH)
PIK3CA	2.7.1.137, 2.7.1.153, 2.7.11.1	phosphatidylinositol 3-kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase, non-specific serine/threonine protein kinase
PYGL	2.4.1.1	glycogen phosphorylase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
KRAS	861
PIK3CA	2,034

Pharmacogenomics

Cohort genes with a PharmGKB record: 11; with CPIC/DPWG dosing guidelines: 0.

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

Drug repurposing candidates

29 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.

Compound	Max phase	Cohort target (bioactivity)
VEMURAFENIB	4	KRAS
DABRAFENIB	4	KRAS
LONAFARNIB	4	KRAS
SOTORASIB	4	KRAS
ADAGRASIB	4	KRAS
IDELALISIB	4	PIK3CA
DUVELISIB	4	PIK3CA
COPANLISIB	4	PIK3CA
FEDRATINIB	4	PIK3CA
ROMIDEPSIN	4	PIK3CA
COPANLISIB HYDROCHLORIDE	4	PIK3CA
LENIOLISIB	4	PIK3CA
BELINOSTAT	4	PIK3CA
INAVOLISIB	4	PIK3CA
SUNITINIB	4	PIK3CA
DASATINIB	4	PIK3CA
CRIZOTINIB	4	PIK3CA
MIDOSTAURIN	4	PIK3CA
NITAZOXANIDE	4	ANO1
NICLOSAMIDE	4	ANO1
OPNURASIB	3	KRAS
DACTOLISIB	3	PIK3CA
BUPARLISIB	3	PIK3CA
RESVERATROL	3	PIK3CA
IPATASERTIB	3	PIK3CA
TASELISIB	3	PIK3CA
EPIGALOCATECHIN GALLATE	3	PIK3CA
GEDATOLISIB	3	PIK3CA
LESTAURTINIB	3	PIK3CA

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	KRAS, PIK3CA, ANO1
B	Phased (≥1) drug, not yet approved	1	PYGL
C	Druggable family + PDB, no drug	1	MTHFR
D	Druggable family + AlphaFold only, no drug	1	SLC22A23
E	Difficult family or no structure, no drug	6	SP6, NIN, CDX1, ABHD12B, EFR3A, LINC00513

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MTHFR	0	—
SP6	0	—
NIN	0	—
CDX1	0	—
ABHD12B	0	—
SLC22A23	0	—
EFR3A	0	—
LINC00513	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1,331.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	476
PHASE2	328
PHASE1	100
PHASE3	96
PHASE1/PHASE2	66
PHASE2/PHASE3	18
PHASE4	8
EARLY_PHASE1	8

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05148767	PHASE4	RECRUITING	UGT1A1-Based Irinotecan Therapy for Locally Advanced Rectal Cancer
NCT07209787	PHASE4	RECRUITING	SIS-Reinforced vs. Conventional Anastomosis for Mid-to-Low Rectal Cancer: A Multicenter RCT on Anastomotic Leak
NCT07483060	PHASE4	NOT_YET_RECRUITING	Next Generation STAR-TREC (NG-ST) - Organ Preservation in Early Rectal Cancer
NCT01421940	PHASE4	COMPLETED	The Efficacy of Penile Rehabilitation Using Udenafil After Total Mesorectal Excision of Rectal Cancer
NCT01579721	PHASE4	COMPLETED	Prospective Randomized Study of SILS Versus CLS for Rectal Cancer
NCT02958566	PHASE4	UNKNOWN	Multimodal Narcotic Limited Perioperative Pain Control With Colorectal Surgery
NCT04747951	PHASE4	UNKNOWN	Total Neoadjuvant Therapy in Rectal Cancer Treatment
NCT05406765	PHASE4	COMPLETED	Enhanced Recovery After Laparoscopic Colorectal Surgery
NCT01558921	PHASE3	ACTIVE_NOT_RECRUITING	Rectal Cancer And Pre-operative Induction Therapy Followed by Dedicated Operation. The RAPIDO Trial
NCT02843191	PHASE3	ACTIVE_NOT_RECRUITING	Consolidation Chemotherapy for Locally Advanced Mid or Low Rectal Cancer After Neoadjuvant Concurrent Chemoradiotherapy
NCT03051464	PHASE2/PHASE3	RECRUITING	No Surgery Trial / Two Dose-escalation Strategies
NCT03671252	PHASE3	RECRUITING	Prospectively Randomized Control Clinical Trial of FOLFOXIRI Preoperative Chemotherapy Alone on Rectal Cancer in Local Advance Comparing to Oral Capecitabine Combined With Long-term Radiation
NCT03875781	PHASE3	RECRUITING	Non Inferiority Study of Preoperative Chemotherapy Without Pelvic Irradiation for Rectal Cancer
NCT03879109	PHASE3	ACTIVE_NOT_RECRUITING	Chemotherapy Followed by Pelvic Reirradiation Versus Chemotherapy Alone as Pre-operative Treatment for Locally Recurrent Rectal Cancer
NCT03975049	PHASE3	NOT_YET_RECRUITING	Triplet Combination or Doublet Regimen Versus Chemoradiation as Neoadjuvant Therapy for Locally Advanced Rectal Cancer
NCT04087421	PHASE3	RECRUITING	Comparison of Transanal Irrigation and Glycerol Suppositories in Treatment of Low Anterior Resection Syndrome
NCT04095299	PHASE3	RECRUITING	Standard Dose Versus High Dose of Radiotherapy in Rectal Preservation With Chemo-radiotherapy in Rectal Cancer Patients
NCT04215731	PHASE3	RECRUITING	Neoadjuvant mFOLFOXIRI Plus Bevacizumab in Patients With High-Risk Locally Advanced Rectal Cancer
NCT04246684	PHASE3	ACTIVE_NOT_RECRUITING	Short RT Versus RCT,Followed by Chemo.and Organ Preservation for Interm and High-risk Rectal Cancer Patients
NCT04288999	PHASE3	RECRUITING	Surgery Plus Chemo Versus Chemoradiotherapy Followed by Surgery Plus Chemo for Locally Recurrent Rectal Cancer
NCT04389086	PHASE3	RECRUITING	Induction Chemotherapy for Locally Recurrent Rectal Cancer
NCT04495088	PHASE3	RECRUITING	Preoperative FOLFOX Versus Postoperative Risk-adapted Chemotherapy in Patients With Locally Advanced Rectal Cancer
NCT04922853	PHASE3	ACTIVE_NOT_RECRUITING	Comparison of the Pathological Effect Between 2 and 4 Cycles Neoadjuvant CAPOX for Low/Intermediate Risk II/III Rectal Cancer
NCT04928807	PHASE3	ACTIVE_NOT_RECRUITING	Short-Course Radiotherapy Followed by Neoadjuvant Chemotherapy and Camrelizumab in Locally Advanced Rectal Cancer (UNION)
NCT05201430	PHASE3	RECRUITING	Neoadjuvant FOLFOXIRI Versus CapeOX Chemotherapy for Local Advanced Rectal Cancer
NCT05646511	PHASE3	RECRUITING	TNT of SCRT+CAPOX vs SCRT+CAPOXIRI for Locally Advanced Rectal Cancer
NCT05752136	PHASE3	RECRUITING	Preoperative Short-course Radiation Followed by Envafolimab Plus CAPEOX for MSS Locally Advanced Rectal Adenocarcinoma
NCT05939687	PHASE3	RECRUITING	Prophylactic Mesh Placement During Stoma Closure After Low Anterior Resection
NCT05984485	PHASE3	RECRUITING	The Efficacy of Primary Total Mesorectal Excision (TME) Surgery Versus Neoadjuvant Chemotherapy Combined With TME Surgery in Low-risk Locally Advanced Rectal Cancer
NCT06097416	PHASE3	NOT_YET_RECRUITING	Neoadjuvant Chemoradiotherapy Versus Total Neoadjuvant Therapy in the Treatment of T3 Rectal Cancer
NCT06123156	PHASE3	RECRUITING	Interest of Early Erectile Rehabilitation With Sildenafil After Radiotherapy and Proctectomy for Rectal Cancer
NCT06205485	PHASE3	RECRUITING	Neoadjuvant Chemotherapy, Excision And Observation vs Chemoradiotherapy For Rectal Cancer
NCT06229041	PHASE3	RECRUITING	Total Neoadjuvant Treatment ±Immunotherapy for High Risk Locally Advanced Rectal Cancer (TNTi)
NCT06443671	PHASE2/PHASE3	NOT_YET_RECRUITING	Neoadjuvant Fruquintinib Plus Tislelizumab Combined With mCapeOX Versus CapeOX for Mid-high pMMR/MSS Locally Advanced Rectal Cancer
NCT06450574	PHASE3	NOT_YET_RECRUITING	Preoperative Chemoradiotherapy and Transanal Endoscopic Microsurgery Versus Ttransanal Endoscopic Microsurgery in T1 N0, M0 Rectal Cancer (TAUTEM-T1 Study)
NCT06507371	PHASE3	RECRUITING	Node-sparing Short-Course Radiation Combined With CAPOX and Tislelizumab for MSS Rectal Cancer
NCT06758830	PHASE2/PHASE3	RECRUITING	Total Neoadjuvant Therapy and Organ Preservation Versus Surgery for Rectal Cancer.
NCT06832917	PHASE3	NOT_YET_RECRUITING	Short-course Radiation (SCRT) Followed by 6 Cycles of Cadonilimab Plus MFOLFOX6 As Neoadjuvant Therapy for Patients with Locally Advanced Rectal Cancer (LARC): a Multicenter, Two-arm Parallel, Open-label, Randomised Phase III Trial (NeoCaCRT-III)
NCT06850090	PHASE3	RECRUITING	Neoadjuvant Radiotherapy for Rectal Adenocarcinoma With Capecitabine Versus TAS-102 (Neo-REACT): A Multi-center, Randomized, Phase III Trial
NCT06936774	PHASE3	RECRUITING	Improving Functional Outcomes and Quality of Life in Patients With Rectal Cancer After Surgery With Intensified Follow-up & Surveillance

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
LEUCOVORIN	4	14
IRINOTECAN	4	11
TIPIRACIL	4	9
TRIFLURIDINE	4	8
OXALIPLATIN	4	7
FRUQUINTINIB	4	6
PANITUMUMAB	4	6
ALDESLEUKIN	4	5
BEVACIZUMAB	4	4
FLOXURIDINE	4	4
INDOCYANINE GREEN ACID FORM	4	4
KETOROLAC	4	3
ORPHENADRINE	4	3
RALTITREXED	4	3
AMIFOSTINE	4	2
CAPECITABINE	4	2
ENCORAFENIB	4	2
ERLOTINIB HYDROCHLORIDE	4	2
FLUDEOXYGLUCOSE F 18	4	2
FLUOROURACIL	4	2
PEGFILGRASTIM	4	2
REGORAFENIB	4	2
SELUMETINIB	4	2
TUCATINIB	4	2
VORINOSTAT	4	2
ABEMACICLIB	4	1
ALPELISIB	4	1
ATORVASTATIN CALCIUM	4	1
AVELUMAB	4	1
BRODALUMAB	4	1

Precision-medicine subtype map (CIViC)

Drug × molecular subtype: 3 predictive associations from 3 curated evidence items; also 4 prognostic.

Molecular subtype	Therapy	Effect	Level	CIViC
MSI High	Dostarlimab	Sensitivity/Response	CIViC B	EID12368
MTHFR A222V	Fluorouracil	Sensitivity/Response	CIViC B	EID1757
NOTCH3 Overexpression	Tarextumab	Sensitivity/Response	CIViC D	EID7002