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Ref Type Journal Article
PMID (22810696)
Authors Cancer Genome Atlas Network
Title Comprehensive molecular characterization of human colon and rectal cancer.
Journal Vol Issue Date Pages Journal Short Title
Nature 487 7407 2012 Jul 18 330-7 Nature
URL
Abstract Text To characterize somatic alterations in colorectal carcinoma, we conducted a genome-scale analysis of 276 samples, analysing exome sequence, DNA copy number, promoter methylation and messenger RNA and microRNA expression. A subset of these samples (97) underwent low-depth-of-coverage whole-genome sequencing. In total, 16% of colorectal carcinomas were found to be hypermutated: three-quarters of these had the expected high microsatellite instability, usually with hypermethylation and MLH1 silencing, and one-quarter had somatic mismatch-repair gene and polymerase ε (POLE) mutations. Excluding the hypermutated cancers, colon and rectum cancers were found to have considerably similar patterns of genomic alteration. Twenty-four genes were significantly mutated, and in addition to the expected APC, TP53, SMAD4, PIK3CA and KRAS mutations, we found frequent mutations in ARID1A, SOX9 and FAM123B. Recurrent copy-number alterations include potentially drug-targetable amplifications of ERBB2 and newly discovered amplification of IGF2. Recurrent chromosomal translocations include the fusion of NAV2 and WNT pathway member TCF7L1. Integrative analyses suggest new markers for aggressive colorectal carcinoma and an important role for MYC-directed transcriptional activation and repression.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
ARID1A D2157N missense unknown ARID1A D2157N lies within the GR binding domain of the Arid1a protein (PMID: 23208470). D2157N has been identified in sequencing studies (PMID: 22810696), but has not been biochemically characterized and therefore, its effect on Arid1a protein function is unknown (PubMed, Aug 2024).
ARID1A R1223C missense unknown ARID1A R1223C does not lie within any known functional domains of the Arid1a protein (UniProt.org). R1223C has been identified in sequencing studies (PMID: 22810696, PMID: 28292439, PMID: 30675285), but has not been biochemically characterized and therefore, its effect on Arid1a protein function is unknown (PubMed, Oct 2024).
ATM F2140V missense unknown ATM F2140V lies within the FAT domain of the Atm protein (UniProt.org). F2140V has been identified in sequencing studies (PMID: 22810696), but has not been biochemically characterized and therefore, its effect on Atm protein function is unknown (PubMed, Oct 2024).
ATM L1408I missense unknown ATM L1408I does not lie within any known functional domains of the Atm protein (UniProt.org). L1408I has been identified in sequencing studies (PMID: 29107334, PMID: 22810696), but has not been biochemically characterized and therefore, its effect on Atm protein function is unknown (PubMed, Oct 2024).
ATM L2077I missense unknown ATM L2077I lies within the FAT domain of the Atm protein (UniProt.org). L2077I has been identified in sequencing studies (PMID: 22810696, PMID: 34954471), but has not been biochemically characterized and therefore, its effect on Atm protein function is unknown (PubMed, Oct 2024).
ATM P2353T missense unknown ATM P2353T lies within the FAT domain of the Atm protein (UniProt.org). P2353T has been identified in sequencing studies (PMID: 22810696), but has not been biochemically characterized and therefore, its effect on Atm protein function is unknown (PubMed, Oct 2024).
ATM R2598Q missense unknown ATM R2598Q does not lie within any known functional domains of the Atm protein (UniProt.org). R2598Q has been identified in sequencing studies (PMID: 22810696), but has not been biochemically characterized and therefore, its effect on Atm protein function is unknown (PubMed, Oct 2024).
ATR R177Q missense unknown ATR R177Q does not lie within any known functional domains of the Atr protein (UniProt.org). R177Q has been identified in sequencing studies (PMID: 22810696), but has not been biochemically characterized and therefore, its effect on Atr protein function is unknown (PubMed, Aug 2024).
CD274 R260C missense unknown CD274 R260C lies within the cytoplasmic domain of the Cd274 protein (UniProt.org). R260C has been identified in sequencing studies (PMID: 22810696, PMID: 35039462, PMID: 34130989), but has not been biochemically characterized and therefore, its effect on Cd274 protein function is unknown (PubMed, Jan 2025).
CDK12 D502Y missense unknown CDK12 D502Y does not lie within any known functional domains of the Cdk12 protein (UniProt.org). D502Y has been identified in sequencing studies (PMID: 23303603, PMID: 22810696), but has not been biochemically characterized and therefore, its effect on Cdk12 protein function is unknown (PubMed, Oct 2024).
CSF3R R190H missense unknown CSF3R R190H lies within fibronectin type-III domain 1 of the Csf3r protein (UniProt.org). R190H has been identified in sequencing studies (PMID: 22810696), but has not been biochemically characterized and therefore, its effect on Csf3r protein function is unknown (PubMed, Aug 2024).
CSF3R R269C missense unknown CSF3R R269C lies within fibronectin type-III domain 2 of the Csf3r protein (UniProt.org). R269C has been identified in sequencing studies (PMID: 22810696), but has not been biochemically characterized and therefore, its effect on Csf3r protein function is unknown (PubMed, Aug 2024).
CTNNB1 D162E missense unknown CTNNB1 D162E lies within ARM repeat 1 of the Ctnnb1 protein (UniProt.org). D162E has been identified in sequencing studies (PMID: 22810696), but has not been biochemically characterized and therefore, its effect on Ctnnb1 protein function is unknown (PubMed, Sep 2024).
CTNNB1 R515Q missense unknown CTNNB1 R515Q lies within ARM repeat 9 of the Ctnnb1 protein (UniProt.org). R515Q has been identified in sequencing studies (PMID: 22810696), but has not been biochemically characterized and therefore, its effect on Ctnnb1 protein function is unknown (PubMed, Sep 2024).
FBXW7 D520N missense unknown FBXW7 D520N lies within WD repeat 4 of the Fbxw7 protein (UniProt.org). D520N has been identified in sequencing studies (PMID: 22810696, PMID: 24121792, PMID: 34074070), but has not been biochemically characterized and therefore, its effect on Fbxw7 protein function is unknown (PubMed, Aug 2024).
FBXW7 G437R missense unknown FBXW7 G437R lies within WD repeat 2 of the Fbxw7 protein (UniProt.org). G437R has been identified in sequencing studies (PMID: 34975100, PMID: 22810696), but has not been biochemically characterized and therefore, its effect on Fbxw7 protein function is unknown (PubMed, Oct 2024).
FBXW7 R14Q missense unknown FBXW7 R14Q does not lie within any known functional domains of the Fbxw7 protein (UniProt.org). R14Q has been identified in sequencing studies (PMID: 22810696, PMID: 27149842), but has not been biochemically characterized and therefore, its effect on Fbxw7 protein function is unknown (PubMed, Oct 2024).
FBXW7 R179H missense unknown FBXW7 R179H does not lie within any known functional domains of the Fbxw7 protein (UniProt.org). R179H has been identified in sequencing studies (PMID: 22810696), but has not been biochemically characterized and therefore, its effect on Fbxw7 protein function is unknown (PubMed, Oct 2024).
FGFR1 G610D missense unknown FGFR1 G610D lies within the protein kinase domain of the Fgfr1 protein (UniProt.org). G610D has been identified in the scientific literature (PMID: 36462464, PMID: 22810696), but has not been biochemically characterized and therefore, its effect on Fgfr1 protein function is unknown (PubMed, Apr 2024).
FGFR1 S430F missense unknown FGFR1 S430F lies within the cytoplasmic domain of the Fgfr1 protein (UniProt.org). S430F has been identified in sequencing studies (PMID: 22810696), but has not been biochemically characterized and therefore, its effect on Fgfr1 protein function is unknown (PubMed, Oct 2024).
FGFR2 D336N missense unknown FGFR2 D336N lies within Ig-like C2-type domain 3 of the Fgfr2 protein (UniProt.org). D336N has been identified in sequencing studies (PMID: 22810696, PMID: 26373574), but has not been biochemically characterized and therefore, its effect on Fgfr2 protein function is unknown (PubMed, Nov 2024).
FGFR2 L551I missense unknown FGFR2 L551I lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). L551I has been identified in sequencing studies (PMID: 22810696, PMID: 38983151), but has not been biochemically characterized and therefore, its effect on Fgfr2 protein function is unknown (PubMed, Nov 2024).
FLT3 D895Y missense unknown FLT3 D895Y lies within the protein kinase domain of the Flt3 protein (UniProt.org). D895Y has been identified in sequencing studies (PMID: 22810696), but has not been biochemically characterized and therefore, its effect on Flt3 protein function is unknown (PubMed, Apr 2024).
FLT3 S71I missense unknown FLT3 S71I lies within the extracellular domain of the Flt3 protein (UniProt.org). S71I has been identified in sequencing studies (PMID: 22810696), but has not been biochemically characterized and therefore, its effect on Flt3 protein function is unknown (PubMed, May 2024).
IDH2 I441T missense unknown IDH2 I441T does not lie within any known functional domains of the Idh2 protein (UniProt.org). I441T has been identified in sequencing studies (PMID: 22810696), but has not been biochemically characterized and therefore, its effect on Idh2 protein function is unknown (PubMed, May 2024).
JAK1 K527N missense unknown JAK1 K527N lies within the SH2 domain of the Jak1 protein (UniProt.org). K527N has been identified in sequencing studies (PMID: 22810696), but has not been biochemically characterized and therefore, its effect on Jak1 protein function is unknown (PubMed, Nov 2024).
JAK2 R215Q missense unknown JAK2 R215Q lies within the FERM domain of the Jak2 protein (UniProt.org). R215Q has been identified in sequencing studies (PMID: 22810696), but has not been biochemically characterized and therefore, its effect on Jak2 protein function is unknown (PubMed, Jun 2024).
KMT2A E1060D missense unknown KMT2A E1060D does not lie within any known functional domains of the Kmt2a protein (UniProt.org). E1060D has been identified in sequencing studies (PMID: 22810696), but has not been biochemically characterized and therefore, its effect on Kmt2a protein function is unknown (PubMed, Jul 2024).
KMT2A E3448K missense unknown KMT2A E3448K does not lie within any known functional domains of the Kmt2a protein (UniProt.org). E3448K has been identified in sequencing studies (PMID: 22810696), but has not been biochemically characterized and therefore, its effect on Kmt2a protein function is unknown (PubMed, Aug 2024).
KMT2A G3376D missense unknown KMT2A G3376D does not lie within any known functional domains of the Kmt2a protein (UniProt.org). G3376D has been identified in sequencing studies (PMID: 22810696), but has not been biochemically characterized and therefore, its effect on Kmt2a protein function is unknown (PubMed, Aug 2024).
KMT2A P3095Q missense unknown KMT2A P3095Q does not lie within any known functional domains of the Kmt2a protein (UniProt.org). P3095Q has been identified in sequencing studies (PMID: 22810696), but has not been biochemically characterized and therefore, its effect on Kmt2a protein function is unknown (PubMed, Aug 2024).
KMT2A R736M missense unknown KMT2A R736M does not lie within any known functional domains of the Kmt2a protein (UniProt.org). R736M has been identified in sequencing studies (PMID: 22810696, PMID: 32732356), but has not been biochemically characterized and therefore, its effect on Kmt2a protein function is unknown (PubMed, Aug 2024).
KMT2A S3576F missense unknown KMT2A S3576F does not lie within any known functional domains of the Kmt2a protein (UniProt.org). S3576F has been identified in sequencing studies (PMID: 22810696), but has not been biochemically characterized and therefore, its effect on Kmt2a protein function is unknown (PubMed, Jan 2025).
KMT2A S534L missense unknown KMT2A S534L does not lie within any known functional domains of the Kmt2a protein (UniProt.org). S534L has been identified in sequencing studies (PMID: 22810696), but has not been biochemically characterized and therefore, its effect on Kmt2a protein function is unknown (PubMed, Oct 2024).
MLH1 E703A missense unknown MLH1 E703A lies within the C-terminal dimerization domain of the Mlh1 protein (PMID: 22753075). E703A has been identified in sequencing studies (PMID: 22810696), but has not been biochemically characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Nov 2024).
MLH1 R9Q missense unknown MLH1 R9Q lies within the ATPase domain of the Mlh1 protein (PMID: 22753075). R9Q has been identified in sequencing studies (PMID: 22810696), but has not been biochemically characterized and therefore, its effect on Mlh1 protein function is unknown (PubMed, Nov 2024).
MSH2 K550T missense unknown MSH2 K550T lies within the clamp domain of the Msh2 protein (PMID: 17531815). K550T has been identified in sequencing studies (PMID: 22810696), but has not been biochemically characterized and therefore, its effect on Msh2 protein function is unknown (PubMed, Nov 2024).
MSH2 N412H missense unknown MSH2 N412H lies within the lever domain of the Msh2 protein (PMID: 17531815). N412H has been identified in sequencing studies (PMID: 22810696), but has not been biochemically characterized and therefore, its effect on Msh2 protein function is unknown (PubMed, Nov 2024).
MSH6 A457D missense unknown MSH6 A457D lies within the mismatch binding domain of the Msh6 protein (PMID: 17531815). A457D has been identified in sequencing studies (PMID: 22810696), but has not been biochemically characterized and therefore, its effect on Msh6 protein function is unknown (PubMed, Jun 2024).
MSH6 K185T missense unknown MSH6 K185T does not lie within any known functional domains of the Msh6 protein (UniProt.org). K185T has been identified in sequencing studies (PMID: 22810696), but has not been biochemically characterized and therefore, its effect on Msh6 protein function is unknown (PubMed, Apr 2024).
MSH6 L979V missense unknown MSH6 L979V lies within the clamp domain of the Msh6 protein (PMID: 17531815). L979V has been identified in sequencing studies (PMID: 22810696), but has not been biochemically characterized and therefore, its effect on Msh6 protein function is unknown (PubMed, Jun 2024).
PIK3CA R777M missense unknown PIK3CA R777M lies within the PI3K/PI4K catalytic domain of the Pik3ca protein (UniProt.org). R777M has been identified in sequencing studies (PMID: 22810696), but has not been biochemically characterized and therefore, its effect on Pik3ca protein function is unknown (PubMed, Mar 2024).
RB1 M695V missense unknown RB1 M695V lies within domain B of the Rb1 protein (UniProt.org). M695V has been identified in sequencing studies (PMID: 22810696), but has not been biochemically characterized and therefore, its effect on Rb1 protein function is unknown (PubMed, May 2024).
RET R77H missense unknown RET R77H lies within the extracellular domain of the Ret protein (UniProt.org). R77H has been identified in sequencing studies (PMID: 27626691, PMID: 22810696), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Apr 2024).
ROS1 A1964T missense unknown ROS1 A1964T lies within the protein kinase domain of the Ros1 protein (UniProt.org). A1964T has been identified in sequencing studies (PMID: 22810696), but has not been biochemically characterized and therefore, its effect on Ros1 protein function is unknown (PubMed, Mar 2024).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
MLH1 inact mut colorectal cancer not applicable N/A Preclinical Emerging In a preclinical study, MLH1 inactivation through hypermethylation was associated with high microsatellite instability (MSI-H) colorectal carcinoma by whole genome sequencing of tumor samples (PMID: 22810696), suggesting it may be a potential biomarker. 22810696