Q (haiku): tell me about IDH1 mutations in glioma ▶ read_guide { "uri": "cbioportal://mutation-frequency-guide" } ▶ search_oncotree { "search_term": "glioma" } ◀ result # Mutation Frequency Analysis Guide ## IMPORTANT: Reporting Mutation Frequencies - **ALWAYS report frequencies as percentages**, not raw counts: `frequency = (altered_samples / total_profiled_samples) × 100` - For quick frequency lookups, **prefer the TCGA Pan-Cancer Atlas study first**, then offer to expand to other studies - When reporting across multiple studies, show **ranges** (e.g., "TP53 is mutated in 30–60% of samples") rather than a single average - **NEVER** sum mutation events across studies to compute an aggregate frequency — this can exceed 100% due to double-counting - Warn users that samples may overlap across cohorts (e.g., MSK studies may share patients) - **Choose and state the counting unit**: use patient-level frequencies for prevalence/rate questions unless the user explicitly asks for samples; use sample-level frequencies when the user asks about samples. - **For "across cancer types" questions**, jump to the [Cross-Cancer-Type Mutation Frequency](#cross-cancer-type-mutation-frequency) section below — there is one correct recipe and several common wrong ones. ## Counting Unit: Samples vs Patients Before answering any mutation count or frequency question, decide whether the unit is samples or patients and state that choice in the answer. | User wording | Counting unit | |--------------|---------------| | "prevalence", "rate", "fraction of patients", "patients with", "how common is" | Patient-level: `COUNT(DISTINCT patient_unique_id)` | | "samples", "specimens", "biopsies", sample-level cohort composition | Sample-level: `COUNT(DISTINCT sample_unique_id)` | | Ambiguous | Ask, or default to patient-level for prevalence/rate language and say so | ### Cross-study sample-count caveat When an answer touches more than one study and reports a sample count, prepend a one-line caveat: > Sample IDs are unique within cBioPortal study prefixes, not guaranteed biological-sample identifiers across studies; overlapping cohorts can count the same patient/sample more than once. Prefer one of these safer approaches: - Use a shipped `cancer_study_query_preferences` cohort such as `pan_cancer_tcga` or `all_studies_non_redundant`. - Restrict to one named study. - Aggregate by `patient_unique_id` when the biological question is patient prevalence. ## STOP rule: a frequency above 100% means your query is wrong If your query returns a frequency over 100%, **do not try to debug or explain the data inconsistency to the user**. The cause is always one of these query bugs: - Summing mutation events instead of `COUNT(DISTINCT sample_unique_id)` for the numerator - Using a study-wide sample count as the denominator instead of the gene-specific profiled count - Cross-study aggregation where the same biological sample appears under multiple `sample_unique_id` values (e.g., MSK-IMPACT and MSK-CHORD share patients) - **Joining the profiled CTE through `gene_panel` / `gene_panel_list` without a WES branch.** `gene_panel_id = 'WES'` is *not* a row in … (35166 more chars) ▶ resolve_and_route { "studyKeywords": [ "glioma" ] } ◀ result {"result":[{"code":"AGNG","name":"Anaplastic Ganglioglioma","score":65,"mainType":"Glioma","tissue":"CNS/Brain","hierarchy":"BRAIN > ENCG > AGNG"},{"code":"APXA","name":"Anaplastic Pleomorphic Xanthoastrocytoma","score":65,"mainType":"Glioma","tissue":"CNS/Brain","hierarchy":"BRAIN > ENCG > APXA"},{"code":"ASTR","name":"Astrocytoma, IDH-Mutant","score":65,"mainType":"Glioma","tissue":"CNS/Brain","hierarchy":"BRAIN > DIFG > ADIFG > ASTR","replacedCodes":["AASTR"]},{"code":"DASTR","name":"Diffuse Astrocytoma, MYB- or MYBL1-Altered","score":65,"mainType":"Glioma","tissue":"CNS/Brain","hierarchy":"BRAIN > DIFG > PDIFLG > DASTR"},{"code":"DIFG","name":"Diffuse Glioma","score":65,"mainType":"Glioma","tissue":"CNS/Brain","hierarchy":"BRAIN > DIFG"},{"code":"DNT","name":"Dysembryoplastic Neuroepithelial Tumor","score":65,"mainType":"Glioma","tissue":"CNS/Brain","hierarchy":"BRAIN > ENCG > DNT"},{"code":"ENCG","name":"Encapsulated Glioma","score":65,"mainType":"Glioma","tissue":"CNS/Brain","hierarchy":"BRAIN > ENCG"},{"code":"EPM","name":"Ependymoma","score":65,"mainType":"Glioma","tissue":"CNS/Brain","hierarchy":"BRAIN > EPMT > EPM"},{"code":"GB","name":"Glioblastoma, IDH-Wildtype","score":65,"mainType":"Glioma","tissue":"CNS/Brain","hierarchy":"BRAIN > DIFG > ADIFG > GB","replacedCodes":["GBM"]},{"code":"GNC","name":"Gangliocytoma","score":65,"mainType":"Glioma","tissue":"CNS/Brain","hierarchy":"BRAIN > ENCG > GNC"},{"code":"GNG","name":"Ganglioglioma","score":65,"mainType":"Glioma","tissue":"CNS/Brain","hierarchy":"BRAIN > ENCG > GNG"},{"code":"GNOS","name":"Glioma, NOS","score":65,"mainType":"Glioma","tissue":"CNS/Brain","hierarchy":"BRAIN > DIFG > GNOS","replacedCodes":["AOAST","OAST"]},{"code":"GSARC","name":"Gliosarcoma","score":65,"mainType":"Glioma","tissue":"CNS/Brain","hierarchy":"BRAIN > DIFG > ADIFG > GB > GSARC"},{"code":"HGGNOS","name":"High-Grade Glioma, NOS","score":65,"mainType":"Glioma","tissue":"CNS/Brain","hierarchy":"BRAIN > DIFG > HGGNOS"},{"code":"LGGNOS","name":"Low-Grade Glioma, NOS","score":65,"mainType":"Glioma","tissue":"CNS/Brain","hierarchy":"BRAIN > ENCG > LGGNOS"},{"code":"ODG","name":"Oligodendroglioma, IDH-mutant, and 1p/19q-Codeleted","score":65,"mainType":"Glioma","tissue":"CNS/Brain","hierarchy":"BRAIN > DIFG > ADIFG > ODG","replacedCodes":["AODG"]},{"code":"PAST","name":"Pilocytic Astrocytoma","score":65,"mainType":"Glioma","tissue":"CNS/Brain","hierarchy":"BRAIN > ENCG > PAST"},{"code":"PMA","name":"Pilomyxoid Astrocytoma","score":65,"mainType":"Glioma","tissue":"CNS/Brain","hierarchy":"BRAIN > ENCG > PMA"},{"code":"PXA","name":"Pleomorphic Xanthoastrocytoma","score":65,"mainType":"Glioma","tissue":"CNS/Brain","hierarchy":"BRAIN > ENCG > PXA"},{"code":"SCGBM","name":"Small Cell Glioblastoma","score":65,"mainType":"Glioma","tissue":"CNS/Brain","hierarchy":"BRAIN > DIFG > ADIFG > GB > SCGBM"},{"code":"ADIFG","name":"Adult-Type Diffuse Glioma","score":50,"mainType":"Gliomas, Glioneuronal Tumors, and Neuronal Tumors","t … (782 more chars) ◀ result {"success":true,"message":"Found 16 matching studies (top 5 with full metadata, rest with basic info). Pick the best match (prefer TCGA → prefer PanCancer Atlas), use its metadata to call the appropriate navigation tool(s) and generate URLs immediately. Present other studies as alternatives.","data":{"totalCount":16,"studiesWithMetadata":[{"studyId":"glioma_mskcc_2019","name":"Glioma (MSK, Clin Cancer Res 2019)","sampleCount":1004,"studyViewUrl":"https://www.cbioportal.org/study?id=glioma_mskcc_2019","metadata":{"clinicalAttributeIds":["ACQUIRED_AFTER_ALKALATOR_TREATMENT","ACQUIRED_AFTER_ANY_SYSTEMIC_TREATMENT","ACQUIRED_AFTER_RADIOTHERAPY","ACTIONABLE_LESION1","AGE","CANCER_TYPE","CANCER_TYPE_DETAILED","ENHANCING","FRACTION_GENOME_ALTERED","GENE_PANEL","HIGHEST_ONCOKB_LEVEL","HISTOLOGY","MGMT_STATUS","MUTATION_COUNT","ONCOTREE_CODE","OS_MONTHS","OS_STATUS","PATIENT_DISPLAY_NAME","PFS_MONTHS","PFS_STATUS","PRIOR_LINES_OF_THERAPY","RECEIVED_TARGETED_TX","SAMPLE_COUNT","SAMPLE_TYPE","SEX","SOMATIC_STATUS","SURGERY_DATE_RELATIVE_TO_DX_MONTHS","TMB_NONSYNONYMOUS","TMZ_HYPERMUTATED","TUMOR_SURGERY_NUMBER","WHO_CLASSIFICATION_OF_DX_TUMOR","WHO_GRADE"],"molecularProfileIds":["glioma_mskcc_2019_gistic","glioma_mskcc_2019_mutations","glioma_mskcc_2019_structural_variants"],"availableComparisonTabs":["overlap","clinical","survival","alterations","mutations"]}},{"studyId":"difg_glass","name":"Diffuse Glioma (GLASS Consortium)","sampleCount":693,"studyViewUrl":"https://www.cbioportal.org/study?id=difg_glass","metadata":{"clinicalAttributeIds":["AGE","ALIQUOT_ANALYSIS_TYPE","ALKYLATING_AGENT_TX","CANCER_TYPE","CANCER_TYPE_DETAILED","CASE_PROJECT","CODEL_STATUS","DNA_ALIQUOT_BARCODE","ESTIMATE_SCORE","FRACTION_GENOME_ALTERED","HISTOLOGY","IDH_CODEL_STATUS","IDH_STATUS","IMMUNE_SCORE","MGMT_METHYLATION","MGMT_METHYLATION_METHOD","MUTATION_COUNT","ONCOTREE_CODE","OS_MONTHS","OS_STATUS","PURITY","RNA_ALIQUOT_BARCODE","SAMPLE_COUNT","SAMPLE_TYPE","SEX","STROMAL_SCORE","SURGERY_EXTENT_OF_RESECTION","SURGERY_INDICATION","SURGERY_LATERALITY","SURGERY_LOCATION","SURGERY_TYPE","TISSUE_SOURCE","TREATMENT_CONCURRENT_TMZ","TREATMENT_RADIATION_DOSE_GY","TREATMENT_RADIOTHERAPY","TREATMENT_TMZ","TREATMENT_TMZ_CYCLES","TREATMENT_TMZ_CYCLES_6","TUMOR_CLASSIFICATION","TUMOR_GRADE"],"molecularProfileIds":["difg_glass_cna","difg_glass_mrna_seq_tpm_all_sample_Zscores","difg_glass_mutations","difg_glass_rna_seq_mrna"],"heatmapProfileIds":["difg_glass_mrna_seq_tpm_all_sample_Zscores"],"availableComparisonTabs":["overlap","clinical","survival","alterations","mutations","mrna"]}},{"studyId":"lgg_tcga","name":"Brain Lower Grade Glioma (TCGA, Firehose Legacy)","sampleCount":530,"studyViewUrl":"https://www.cbioportal.org/study?id=lgg_tcga","metadata":{"clinicalAttributeIds":["AGE","ANIMAL_INSECT_ALLERGY_AGE","ANIMAL_INSECT_ALLERGY_HIST","ASTHMA_ECZEMA_ALLERGY_FIRST_DIAGNOSIS","ASTHMA_HISTORY","CANCER_TYPE","CANCER_TYPE_DETAILED","DAYS_TO_COLLECTION","DAYS_TO_INITIAL_PATHOLOGIC_DIAGNOSIS" … (9592 more chars) ▶ clickhouse_run_select_query { "query": " SELECT * FROM gene_mutation_frequency_by_cancer_type( preference = 'pan_cancer_tcga', gene = 'IDH1' ) ORDER BY frequency_pct DESC; ", "max_rows": 50 } ▶ resolve_and_route { "studyIds": [ "lgg_tcga_pan_can_atlas_2018", "glioma_mskcc_2019", "difg_glass" ] } ◀ result {"rows":[{"cancer_type":"Glioma","altered_samples":395,"profiled_samples":514,"frequency_pct":76.8},{"cancer_type":"Leukemia","altered_samples":19,"profiled_samples":200,"frequency_pct":9.5},{"cancer_type":"Glioblastoma","altered_samples":25,"profiled_samples":397,"frequency_pct":6.3},{"cancer_type":"Melanoma","altered_samples":26,"profiled_samples":440,"frequency_pct":5.9},{"cancer_type":"Endometrial Cancer","altered_samples":20,"profiled_samples":574,"frequency_pct":3.5},{"cancer_type":"Bladder Cancer","altered_samples":9,"profiled_samples":410,"frequency_pct":2.2},{"cancer_type":"Hepatobiliary Cancer","altered_samples":8,"profiled_samples":366,"frequency_pct":2.2},{"cancer_type":"Colorectal Cancer","altered_samples":9,"profiled_samples":534,"frequency_pct":1.7},{"cancer_type":"Prostate Cancer","altered_samples":5,"profiled_samples":494,"frequency_pct":1},{"cancer_type":"Non-Small Cell Lung Cancer","altered_samples":9,"profiled_samples":1050,"frequency_pct":0.9},{"cancer_type":"Head and Neck Cancer","altered_samples":4,"profiled_samples":515,"frequency_pct":0.8},{"cancer_type":"Esophagogastric Cancer","altered_samples":5,"profiled_samples":618,"frequency_pct":0.8},{"cancer_type":"Thymic Epithelial Tumor","altered_samples":1,"profiled_samples":123,"frequency_pct":0.8},{"cancer_type":"Sarcoma","altered_samples":2,"profiled_samples":255,"frequency_pct":0.8},{"cancer_type":"Pancreatic Cancer","altered_samples":1,"profiled_samples":179,"frequency_pct":0.6},{"cancer_type":"Breast Cancer","altered_samples":6,"profiled_samples":1066,"frequency_pct":0.6},{"cancer_type":"Renal Clear Cell Carcinoma","altered_samples":2,"profiled_samples":402,"frequency_pct":0.5},{"cancer_type":"Ovarian Epithelial Tumor","altered_samples":1,"profiled_samples":523,"frequency_pct":0.2}]} ◀ result {"success":true,"message":"Found 3 matching studies. Pick the best match (prefer TCGA → prefer PanCancer Atlas), use its metadata to call the appropriate navigation tool(s) and generate URLs immediately. Present other studies as alternatives.","data":{"totalCount":3,"studiesWithMetadata":[{"studyId":"lgg_tcga_pan_can_atlas_2018","name":"Brain Lower Grade Glioma (TCGA, PanCancer Atlas)","sampleCount":514,"studyViewUrl":"https://www.cbioportal.org/study?id=lgg_tcga_pan_can_atlas_2018","metadata":{"clinicalAttributeIds":["AGE","AJCC_PATHOLOGIC_TUMOR_STAGE","AJCC_STAGING_EDITION","ANEUPLOIDY_SCORE","BUFFA_HYPOXIA_SCORE","CANCER_TYPE","CANCER_TYPE_ACRONYM","CANCER_TYPE_DETAILED","DAYS_LAST_FOLLOWUP","DAYS_TO_BIRTH","DAYS_TO_INITIAL_PATHOLOGIC_DIAGNOSIS","DFS_MONTHS","DFS_STATUS","DSS_MONTHS","DSS_STATUS","ETHNICITY","FORM_COMPLETION_DATE","FRACTION_GENOME_ALTERED","GENETIC_ANCESTRY_LABEL","GRADE","HISTORY_NEOADJUVANT_TRTYN","ICD_10","ICD_O_3_HISTOLOGY","ICD_O_3_SITE","INFORMED_CONSENT_VERIFIED","IN_PANCANPATHWAYS_FREEZE","MSI_SCORE_MANTIS","MSI_SENSOR_SCORE","MUTATION_COUNT","NEW_TUMOR_EVENT_AFTER_INITIAL_TREATMENT","ONCOTREE_CODE","OS_MONTHS","OS_STATUS","OTHER_PATIENT_ID","PATH_M_STAGE","PATH_N_STAGE","PATH_T_STAGE","PERSON_NEOPLASM_CANCER_STATUS","PFS_MONTHS","PFS_STATUS","PRIMARY_LYMPH_NODE_PRESENTATION_ASSESSMENT","PRIOR_DX","RACE","RADIATION_THERAPY","RAGNUM_HYPOXIA_SCORE","SAMPLE_COUNT","SAMPLE_TYPE","SEX","SOMATIC_STATUS","SUBTYPE","TBL_SCORE","TISSUE_PROSPECTIVE_COLLECTION_INDICATOR","TISSUE_RETROSPECTIVE_COLLECTION_INDICATOR","TISSUE_SOURCE_SITE","TISSUE_SOURCE_SITE_CODE","TMB_NONSYNONYMOUS","TUMOR_TISSUE_SITE","TUMOR_TYPE","WEIGHT","WINTER_HYPOXIA_SCORE"],"molecularProfileIds":["lgg_tcga_pan_can_atlas_2018_gistic","lgg_tcga_pan_can_atlas_2018_log2CNA","lgg_tcga_pan_can_atlas_2018_mutations","lgg_tcga_pan_can_atlas_2018_rna_seq_v2_mrna","lgg_tcga_pan_can_atlas_2018_rna_seq_v2_mrna_median_Zscores","lgg_tcga_pan_can_atlas_2018_rna_seq_v2_mrna_median_all_sample_Zscores","lgg_tcga_pan_can_atlas_2018_rppa","lgg_tcga_pan_can_atlas_2018_rppa_Zscores","lgg_tcga_pan_can_atlas_2018_structural_variants"],"genericAssayProfiles":["lgg_tcga_pan_can_atlas_2018_armlevel_cna","lgg_tcga_pan_can_atlas_2018_genetic_ancestry","lgg_tcga_pan_can_atlas_2018_methylation_hm27_hm450_merge","lgg_tcga_pan_can_atlas_2018_methylation_hm450"],"heatmapProfileIds":["lgg_tcga_pan_can_atlas_2018_rna_seq_v2_mrna_median_Zscores","lgg_tcga_pan_can_atlas_2018_rna_seq_v2_mrna_median_all_sample_Zscores","lgg_tcga_pan_can_atlas_2018_rppa_Zscores"],"availableComparisonTabs":["overlap","clinical","survival","alterations","mutations","mrna","protein","generic_assay_armlevel_cna","generic_assay_genetic_ancestry","generic_assay_methylation"]}},{"studyId":"glioma_mskcc_2019","name":"Glioma (MSK, Clin Cancer Res 2019)","sampleCount":1004,"studyViewUrl":"https://www.cbioportal.org/study?id=glioma_mskcc_2019","metadata":{"clinicalAttributeIds":["ACQUIRED_AFTER_ALKALATOR_TREATMENT","ACQUIRED_A … (2000 more chars) ▶ clickhouse_run_select_query { "query": " SELECT * FROM gene_mutation_variants_in_study(study = 'lgg_tcga_pan_can_atlas_2018', gene = 'IDH1') ORDER BY altered_samples DESC; ", "max_rows": 20 } ◀ result {"rows":[{"mutation_variant":"R132H","mutation_type":"Missense_Mutation","altered_samples":358,"profiled_samples":514,"frequency_pct":69.6,"total_mutation_events":358},{"mutation_variant":"R132C","mutation_type":"Missense_Mutation","altered_samples":17,"profiled_samples":514,"frequency_pct":3.3,"total_mutation_events":17},{"mutation_variant":"R132G","mutation_type":"Missense_Mutation","altered_samples":11,"profiled_samples":514,"frequency_pct":2.1,"total_mutation_events":11},{"mutation_variant":"R132S","mutation_type":"Missense_Mutation","altered_samples":9,"profiled_samples":514,"frequency_pct":1.8,"total_mutation_events":9}]} ▶ navigate_to_results_view { "studyIds": [ "lgg_tcga_pan_can_atlas_2018" ], "genes": [ "IDH1" ], "tab": "mutations" } ◀ result {"success":true,"message":"Navigating to https://www.cbioportal.org/results/mutations?cancer_study_list=lgg_tcga_pan_can_atlas_2018&gene_list=IDH1&case_set_id=lgg_tcga_pan_can_atlas_2018_all","url":"https://www.cbioportal.org/results/mutations?cancer_study_list=lgg_tcga_pan_can_atlas_2018&gene_list=IDH1&case_set_id=lgg_tcga_pan_can_atlas_2018_all","data":{"studyIds":["lgg_tcga_pan_can_atlas_2018"],"studies":[{"studyId":"lgg_tcga_pan_can_atlas_2018","name":"Brain Lower Grade Glioma (TCGA, PanCancer Atlas)","sampleCount":514}],"genes":["IDH1"],"caseSetId":"lgg_tcga_pan_can_atlas_2018_all","pageDescription":"Detailed mutation table with lollipop plot showing mutation positions, types, and frequencies for queried genes."}} ═ answer (success) Perfect! Here's a comprehensive overview of **IDH1 mutations in glioma**: --- ## Mutation Frequency **IDH1 is a defining hallmark of adult diffuse gliomas.** In the TCGA Pan-Cancer cohort: | Cancer Type | IDH1-Mutated | Profiled | Frequency | |---|---|---|---| | **Glioma** | 395 | 514 | **76.8%** | | Glioblastoma | 25 | 397 | 6.3% | The "Glioma" category here represents **lower-grade gliomas** (primarily WHO grades II-III: diffuse astrocytomas and oligodendrogliomas), where IDH1 is the most common somatic mutation. IDH1 is far rarer in other cancer types (0.2%–9.5% across leukemia, melanoma, endometrial cancer, etc.), making it essentially a glioma-defining mutation. ## Most Common Variants In the **Brain Lower Grade Glioma (TCGA PanCancer Atlas, n=514)**: | Protein Change | Type | Samples | Frequency | |---|---|---|---| | **R132H** | Missense | 358 | **69.6%** | | R132C | Missense | 17 | 3.3% | | R132G | Missense | 11 | 2.1% | | R132S | Missense | 9 | 1.8% | **R132H dominates**, accounting for ~90% of all IDH1-mutated samples (358/395). The other variants (R132C, G, S) collectively represent the remaining ~10%. ## Key Clinical Context - **IDH1 R132H** is an arginine-to-histidine substitution at residue 132 in the isocitrate dehydrogenase 1 catalytic domain, resulting in production of the oncometabolite 2-hydroxyglutarate (2-HG). - **IDH mutant status** is a major prognostic and diagnostic marker in adult gliomas (WHO 2021 classification), associated with **better outcomes** than IDH-wildtype glioblastomas. - **Co-alterations**: IDH-mutant diffuse gliomas often co-occur with **TP53** and/or **1p/19q co-deletion** (the latter defining oligodendrogliomas). --- ## Explore the Data [View IDH1 mutations in Brain Lower Grade Glioma (TCGA PanCancer Atlas)](https://www.cbioportal.org/results/mutations?cancer_study_list=lgg_tcga_pan_can_atlas_2018&gene_list=IDH1&case_set_id=lgg_tcga_pan_can_atlas_2018_all) This Mutations tab shows a lollipop plot of all IDH1 protein changes, their frequencies, and sample counts. **Alternative cohorts** (if you'd like to compare): - [MSK Glioma Study (n=1,004 samples)](https://www.cbioportal.org/study?id=glioma_mskcc_2019) - [GLASS Consortium Diffuse Glioma (n=693 samples)](https://www.cbioportal.org/study?id=difg_glass) — includes longitudinal tracking of IDH mutations across recurrence