Q (sonnet): List the top 20 mutated genes in study nbl_msk_2023. ▶ read_guide { "uri": "cbioportal://mutation-frequency-guide" } ◀ 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 … (36467 more chars) ▶ clickhouse_run_select_query { "query": "SELECT hugo_gene_symbol, total_mutation_events AS mutations, altered_samples, profiled_samples, frequency_pct FROM top_mutated_genes_in_study(study = 'nbl_msk_2023', top_n = 20)" } ▶ resolve_and_route { "studyIds": [ "nbl_msk_2023" ] } ◀ result {"rows":[{"hugo_gene_symbol":"ALK","mutations":34,"altered_samples":33,"profiled_samples":223,"frequency_pct":14.8},{"hugo_gene_symbol":"ATRX","mutations":24,"altered_samples":24,"profiled_samples":223,"frequency_pct":10.8},{"hugo_gene_symbol":"SMARCA4","mutations":9,"altered_samples":9,"profiled_samples":223,"frequency_pct":4},{"hugo_gene_symbol":"BRAF","mutations":8,"altered_samples":8,"profiled_samples":223,"frequency_pct":3.6},{"hugo_gene_symbol":"BRCA2","mutations":8,"altered_samples":8,"profiled_samples":223,"frequency_pct":3.6},{"hugo_gene_symbol":"TERT","mutations":7,"altered_samples":7,"profiled_samples":223,"frequency_pct":3.1},{"hugo_gene_symbol":"CREBBP","mutations":8,"altered_samples":6,"profiled_samples":223,"frequency_pct":2.7},{"hugo_gene_symbol":"FAT1","mutations":6,"altered_samples":6,"profiled_samples":223,"frequency_pct":2.7},{"hugo_gene_symbol":"KMT2D","mutations":9,"altered_samples":6,"profiled_samples":223,"frequency_pct":2.7},{"hugo_gene_symbol":"KRAS","mutations":6,"altered_samples":6,"profiled_samples":223,"frequency_pct":2.7},{"hugo_gene_symbol":"PTPN11","mutations":6,"altered_samples":6,"profiled_samples":223,"frequency_pct":2.7},{"hugo_gene_symbol":"ROS1","mutations":6,"altered_samples":6,"profiled_samples":223,"frequency_pct":2.7},{"hugo_gene_symbol":"CD79B","mutations":5,"altered_samples":5,"profiled_samples":223,"frequency_pct":2.2},{"hugo_gene_symbol":"IRS2","mutations":5,"altered_samples":5,"profiled_samples":223,"frequency_pct":2.2},{"hugo_gene_symbol":"KMT2B","mutations":5,"altered_samples":5,"profiled_samples":168,"frequency_pct":3},{"hugo_gene_symbol":"NCOR1","mutations":5,"altered_samples":5,"profiled_samples":223,"frequency_pct":2.2},{"hugo_gene_symbol":"NF1","mutations":6,"altered_samples":5,"profiled_samples":223,"frequency_pct":2.2},{"hugo_gene_symbol":"PDGFRA","mutations":5,"altered_samples":5,"profiled_samples":223,"frequency_pct":2.2},{"hugo_gene_symbol":"ARID1A","mutations":4,"altered_samples":4,"profiled_samples":223,"frequency_pct":1.8},{"hugo_gene_symbol":"AXL","mutations":4,"altered_samples":4,"profiled_samples":223,"frequency_pct":1.8}]} ✗ error The operation timed out. ▶ resolve_and_route { "studyIds": [ "nbl_msk_2023" ] } ◀ result {"success":true,"message":"Found 1 study. Use the metadata to call the appropriate navigation tool(s).","data":{"totalCount":1,"studiesWithMetadata":[{"studyId":"nbl_msk_2023","name":"Pediatric Neuroblastoma (MSK, Nat Genet 2023)","sampleCount":223,"studyViewUrl":"https://www.cbioportal.org/study?id=nbl_msk_2023","metadata":{"clinicalAttributeIds":["AGE_AT_DIAGNOSIS","AGE_AT_SEQ_REPORTED_YEARS","CANCER_TYPE","CANCER_TYPE_DETAILED","DISEASE_SUBTYPE","ETHNICITY","FRACTION_GENOME_ALTERED","GENE_PANEL","INSS_STAGE","INSTITUTE","MEDIAN_COVERAGE","METASTATIC_SITE","MSI_COMMENT","MSI_SCORE","MSI_TYPE","MUTATION_COUNT","ONCOTREE_CODE","OS_MONTHS","OS_STATUS","PRIMARY_SITE","RACE","SAMPLE_CLASS","SAMPLE_CODE","SAMPLE_COUNT","SAMPLE_COVERAGE","SAMPLE_TYPE","SEX","SOMATIC_STATUS","TIME_AT_LAST_FOLLOWUP_MONTHS","TMB_NONSYNONYMOUS","TUMOR_PLOIDY","TUMOR_PURITY","TUMOR_SITE","TUMOR_SITE_CATEGORY","TUMOR_SITE_DETAIL"],"molecularProfileIds":["nbl_msk_2023_cna","nbl_msk_2023_mutations","nbl_msk_2023_structural_variants"],"availableComparisonTabs":["overlap","clinical","survival","alterations","mutations"]}}]}} ▶ navigate_to_results_view { "studyIds": [ "nbl_msk_2023" ], "genes": [ "ALK", "ATRX", "SMARCA4", "BRAF", "BRCA2", "TERT", "CREBBP", "FAT1", "KMT2D", "KRAS", "PTPN11", "ROS1", "CD79B", "IRS2", "KMT2B", "NCOR1", "NF1", "PDGFRA", "ARID1A", "AXL" ], "tab": "oncoprint" } ◀ result {"success":true,"message":"Navigating to https://www.cbioportal.org/results/oncoprint?cancer_study_list=nbl_msk_2023&gene_list=ALK%0AATRX%0ASMARCA4%0ABRAF%0ABRCA2%0ATERT%0ACREBBP%0AFAT1%0AKMT2D%0AKRAS%0APTPN11%0AROS1%0ACD79B%0AIRS2%0AKMT2B%0ANCOR1%0ANF1%0APDGFRA%0AARID1A%0AAXL&case_set_id=nbl_msk_2023_all","url":"https://www.cbioportal.org/results/oncoprint?cancer_study_list=nbl_msk_2023&gene_list=ALK%0AATRX%0ASMARCA4%0ABRAF%0ABRCA2%0ATERT%0ACREBBP%0AFAT1%0AKMT2D%0AKRAS%0APTPN11%0AROS1%0ACD79B%0AIRS2%0AKMT2B%0ANCOR1%0ANF1%0APDGFRA%0AARID1A%0AAXL&case_set_id=nbl_msk_2023_all","data":{"studyIds":["nbl_msk_2023"],"studies":[{"studyId":"nbl_msk_2023","name":"Pediatric Neuroblastoma (MSK, Nat Genet 2023)","sampleCount":223}],"genes":["ALK","ATRX","SMARCA4","BRAF","BRCA2","TERT","CREBBP","FAT1","KMT2D","KRAS","PTPN11","ROS1","CD79B","IRS2","KMT2B","NCOR1","NF1","PDGFRA","ARID1A","AXL"],"caseSetId":"nbl_msk_2023_all","pageDescription":"Visual summary of alterations in queried genes across samples."}} ═ answer (success) ## Top 20 Mutated Genes — Pediatric Neuroblastoma (MSK, Nat Genet 2023) Study: **Pediatric Neuroblastoma (MSK, Nat Genet 2023)** (`nbl_msk_2023`), 223 samples profiled for mutations. Frequencies = altered samples / profiled samples (all genes profiled in 223 samples, except KMT2B in 168). | Rank | Gene | Mutation Events | Altered Samples | Profiled | Frequency | |---|---|---|---|---|---| | 1 | **ALK** | 34 | 33 | 223 | 14.8% | | 2 | **ATRX** | 24 | 24 | 223 | 10.8% | | 3 | SMARCA4 | 9 | 9 | 223 | 4.0% | | 4 | BRAF | 8 | 8 | 223 | 3.6% | | 5 | BRCA2 | 8 | 8 | 223 | 3.6% | | 6 | TERT | 7 | 7 | 223 | 3.1% | | 7 | KMT2B | 5 | 5 | 168 | 3.0% | | 8 | CREBBP | 8 | 6 | 223 | 2.7% | | 9 | FAT1 | 6 | 6 | 223 | 2.7% | | 10 | KMT2D | 9 | 6 | 223 | 2.7% | | 11 | KRAS | 6 | 6 | 223 | 2.7% | | 12 | PTPN11 | 6 | 6 | 223 | 2.7% | | 13 | ROS1 | 6 | 6 | 223 | 2.7% | | 14 | CD79B | 5 | 5 | 223 | 2.2% | | 15 | IRS2 | 5 | 5 | 223 | 2.2% | | 16 | NCOR1 | 5 | 5 | 223 | 2.2% | | 17 | NF1 | 6 | 5 | 223 | 2.2% | | 18 | PDGFRA | 5 | 5 | 223 | 2.2% | | 19 | ARID1A | 4 | 4 | 223 | 1.8% | | 20 | AXL | 4 | 4 | 223 | 1.8% | ALK and ATRX stand out as the two most frequently mutated genes, consistent with their established roles in neuroblastoma biology (ALK activating mutations, ATRX loss in high-risk/older-onset tumors) — note this is general background, not something computed from this query. [View OncoPrint of these 20 genes in nbl_msk_2023](https://www.cbioportal.org/results/oncoprint?cancer_study_list=nbl_msk_2023&gene_list=ALK%0AATRX%0ASMARCA4%0ABRAF%0ABRCA2%0ATERT%0ACREBBP%0AFAT1%0AKMT2D%0AKRAS%0APTPN11%0AROS1%0ACD79B%0AIRS2%0AKMT2B%0ANCOR1%0ANF1%0APDGFRA%0AARID1A%0AAXL&case_set_id=nbl_msk_2023_all) [View study overview](https://www.cbioportal.org/study?id=nbl_msk_2023)