Q (sonnet): compare egfr mutations between lung and brain cancer

▶ read_guide
{
 "uri": "cbioportal://mutation-frequency-guide"
}

▶ list_studies
{
 "search": "lung"
}

◀ 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)

▶ list_studies
{
 "search": "glioblastoma"
}

◀ result
{"result":[{"cancer_study_identifier":"msk_met_2021","name":"MSK MetTropism (MSK, Cell 2021)","type_of_cancer_id":"mixed","sample_count":25775,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=msk_met_2021"},{"cancer_study_identifier":"luad_mskcc_2023_met_organotropism","name":"Lung Adenocarcinoma Met Organotropism (MSK, Cancer Cell 2023)","type_of_cancer_id":"luad","sample_count":2653,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=luad_mskcc_2023_met_organotropism"},{"cancer_study_identifier":"nsclc_ctdx_msk_2022","name":"Metastatic Non-Small Cell Lung Cancer (MSK, Nature Medicine 2022)","type_of_cancer_id":"nsclc","sample_count":2621,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=nsclc_ctdx_msk_2022"},{"cancer_study_identifier":"nsclc_tcga_broad_2016","name":"Pan-Lung Cancer (TCGA, Nat Genet 2016)","type_of_cancer_id":"nsclc","sample_count":1144,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=nsclc_tcga_broad_2016"},{"cancer_study_identifier":"lung_msk_2017","name":"Non-Small Cell Cancer (MSK, Cancer Discov 2017)","type_of_cancer_id":"luad","sample_count":915,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=lung_msk_2017"},{"cancer_study_identifier":"luad_mskcc_2020","name":"Lung Adenocarcinoma (MSK, J Thorac Oncol 2020)","type_of_cancer_id":"luad","sample_count":604,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=luad_mskcc_2020"},{"cancer_study_identifier":"luad_tcga","name":"Lung Adenocarcinoma (TCGA, Firehose Legacy)","type_of_cancer_id":"luad","sample_count":586,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=luad_tcga"},{"cancer_study_identifier":"luad_tcga_gdc","name":"Lung Adenocarcinoma (TCGA GDC, 2025)","type_of_cancer_id":"luad","sample_count":571,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=luad_tcga_gdc"},{"cancer_study_identifier":"luad_tcga_pan_can_atlas_2018","name":"Lung Adenocarcinoma (TCGA, PanCancer Atlas)","type_of_cancer_id":"luad","sample_count":566,"has_guide":true,"url":"https://www.cbioportal.org/study/summary?id=luad_tcga_pan_can_atlas_2018"},{"cancer_study_identifier":"lusc_tcga","name":"Lung Squamous Cell Carcinoma (TCGA, Firehose Legacy)","type_of_cancer_id":"lusc","sample_count":511,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=lusc_tcga"},{"cancer_study_identifier":"lusc_tcga_gdc","name":"Lung Squamous Cell Carcinoma (TCGA GDC, 2025)","type_of_cancer_id":"lusc","sample_count":503,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=lusc_tcga_gdc"},{"cancer_study_identifier":"lusc_tcga_pan_can_atlas_2018","name":"Lung Squamous Cell Carcinoma (TCGA, PanCancer Atlas)","type_of_cancer_id":"lusc","sample_count":487,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=lusc_tcga_pan_can_atlas_2018"},{"cancer_study_identifier":"nsclc_tracerx_2017","name":"Non-Small Cell Lung Cancer (TRACERx, NEJM & N … (1826 more chars)

◀ result
{"result":[{"cancer_study_identifier":"gbm_tcga","name":"Glioblastoma Multiforme (TCGA, Firehose Legacy)","type_of_cancer_id":"difg","sample_count":619,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=gbm_tcga"},{"cancer_study_identifier":"gbm_tcga_gdc","name":"Glioblastoma Multiforme (TCGA GDC, 2025)","type_of_cancer_id":"difg","sample_count":611,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=gbm_tcga_gdc"},{"cancer_study_identifier":"gbm_tcga_pan_can_atlas_2018","name":"Glioblastoma Multiforme (TCGA, PanCancer Atlas)","type_of_cancer_id":"difg","sample_count":592,"has_guide":true,"url":"https://www.cbioportal.org/study/summary?id=gbm_tcga_pan_can_atlas_2018"},{"cancer_study_identifier":"gbm_tcga_pub2013","name":"Glioblastoma (TCGA, Cell 2013)","type_of_cancer_id":"difg","sample_count":577,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=gbm_tcga_pub2013"},{"cancer_study_identifier":"gbm_tcga_pub","name":"Glioblastoma (TCGA, Nature 2008)","type_of_cancer_id":"difg","sample_count":206,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=gbm_tcga_pub"},{"cancer_study_identifier":"gbm_cptac_2021","name":"Glioblastoma (CPTAC, Cell 2021)","type_of_cancer_id":"difg","sample_count":99,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=gbm_cptac_2021"},{"cancer_study_identifier":"gbm_columbia_2019","name":"Glioblastoma (Columbia, Nat Med. 2019)","type_of_cancer_id":"difg","sample_count":42,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=gbm_columbia_2019"},{"cancer_study_identifier":"gbm_iatlas_prins_2019","name":"Glioblastoma (Randomized Clinical Trial, Nat Med. 2019) - iAtlas Harmonized","type_of_cancer_id":"adifg","sample_count":30,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=gbm_iatlas_prins_2019"}]}

▶ clickhouse_run_select_query
{
 "query": "SELECT * FROM gene_mutation_frequency_in_study(study = 'luad_tcga_pan_can_atlas_2018', gene = 'EGFR')"
}

◀ result
{"rows":[{"cancer_type":"Non-Small Cell Lung Cancer","altered_samples":70,"profiled_samples":566,"frequency_pct":12.4}]}

▶ clickhouse_run_select_query
{
 "query": "SELECT * FROM gene_mutation_frequency_in_study(study = 'gbm_tcga_pan_can_atlas_2018', gene = 'EGFR')"
}

◀ result
{"rows":[{"cancer_type":"Glioblastoma","altered_samples":94,"profiled_samples":397,"frequency_pct":23.7}]}

▶ clickhouse_run_select_query
{
 "query": "SELECT * FROM gene_mutation_variants_in_study(study = 'luad_tcga_pan_can_atlas_2018', gene = 'EGFR') ORDER BY altered_samples DESC LIMIT 10"
}

◀ result
{"rows":[{"mutation_variant":"L858R","mutation_type":"Missense_Mutation","altered_samples":23,"profiled_samples":566,"frequency_pct":4.1,"total_mutation_events":23},{"mutation_variant":"E746_A750del","mutation_type":"In_Frame_Del","altered_samples":16,"profiled_samples":566,"frequency_pct":2.8,"total_mutation_events":16},{"mutation_variant":"E709_T710delinsD","mutation_type":"In_Frame_Del","altered_samples":3,"profiled_samples":566,"frequency_pct":0.5,"total_mutation_events":3},{"mutation_variant":"L861Q","mutation_type":"Missense_Mutation","altered_samples":3,"profiled_samples":566,"frequency_pct":0.5,"total_mutation_events":3},{"mutation_variant":"T790M","mutation_type":"Missense_Mutation","altered_samples":2,"profiled_samples":566,"frequency_pct":0.4,"total_mutation_events":2},{"mutation_variant":"L747_A750delinsP","mutation_type":"In_Frame_Del","altered_samples":2,"profiled_samples":566,"frequency_pct":0.4,"total_mutation_events":2},{"mutation_variant":"L62R","mutation_type":"Missense_Mutation","altered_samples":2,"profiled_samples":566,"frequency_pct":0.4,"total_mutation_events":2},{"mutation_variant":"S768I","mutation_type":"Missense_Mutation","altered_samples":2,"profiled_samples":566,"frequency_pct":0.4,"total_mutation_events":2},{"mutation_variant":"L747_T751del","mutation_type":"In_Frame_Del","altered_samples":2,"profiled_samples":566,"frequency_pct":0.4,"total_mutation_events":2},{"mutation_variant":"G719A","mutation_type":"Missense_Mutation","altered_samples":2,"profiled_samples":566,"frequency_pct":0.4,"total_mutation_events":2}]}

▶ clickhouse_run_select_query
{
 "query": "SELECT * FROM gene_mutation_variants_in_study(study = 'gbm_tcga_pan_can_atlas_2018', gene = 'EGFR') ORDER BY altered_samples DESC LIMIT 10"
}

◀ result
{"rows":[{"mutation_variant":"A289V","mutation_type":"Missense_Mutation","altered_samples":16,"profiled_samples":397,"frequency_pct":4,"total_mutation_events":16},{"mutation_variant":"G598V","mutation_type":"Missense_Mutation","altered_samples":15,"profiled_samples":397,"frequency_pct":3.8,"total_mutation_events":15},{"mutation_variant":"R222C","mutation_type":"Missense_Mutation","altered_samples":6,"profiled_samples":397,"frequency_pct":1.5,"total_mutation_events":6},{"mutation_variant":"A289T","mutation_type":"Missense_Mutation","altered_samples":6,"profiled_samples":397,"frequency_pct":1.5,"total_mutation_events":6},{"mutation_variant":"A289D","mutation_type":"Missense_Mutation","altered_samples":5,"profiled_samples":397,"frequency_pct":1.3,"total_mutation_events":5},{"mutation_variant":"V774M","mutation_type":"Missense_Mutation","altered_samples":5,"profiled_samples":397,"frequency_pct":1.3,"total_mutation_events":5},{"mutation_variant":"R108K","mutation_type":"Missense_Mutation","altered_samples":4,"profiled_samples":397,"frequency_pct":1,"total_mutation_events":4},{"mutation_variant":"S645C","mutation_type":"Missense_Mutation","altered_samples":3,"profiled_samples":397,"frequency_pct":0.8,"total_mutation_events":3},{"mutation_variant":"G63R","mutation_type":"Missense_Mutation","altered_samples":3,"profiled_samples":397,"frequency_pct":0.8,"total_mutation_events":3},{"mutation_variant":"R252C","mutation_type":"Missense_Mutation","altered_samples":3,"profiled_samples":397,"frequency_pct":0.8,"total_mutation_events":3}]}

▶ resolve_and_route
{
 "studyIds": [
  "luad_tcga_pan_can_atlas_2018",
  "gbm_tcga_pan_can_atlas_2018"
 ]
}

◀ result
{"success":true,"message":"Found 2 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":2,"studiesWithMetadata":[{"studyId":"luad_tcga_pan_can_atlas_2018","name":"Lung Adenocarcinoma (TCGA, PanCancer Atlas)","sampleCount":566,"studyViewUrl":"https://www.cbioportal.org/study?id=luad_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":["luad_tcga_pan_can_atlas_2018_gistic","luad_tcga_pan_can_atlas_2018_log2CNA","luad_tcga_pan_can_atlas_2018_mutations","luad_tcga_pan_can_atlas_2018_rna_seq_v2_mrna","luad_tcga_pan_can_atlas_2018_rna_seq_v2_mrna_median_Zscores","luad_tcga_pan_can_atlas_2018_rna_seq_v2_mrna_median_all_sample_Zscores","luad_tcga_pan_can_atlas_2018_rna_seq_v2_mrna_median_all_sample_ref_normal_Zscores","luad_tcga_pan_can_atlas_2018_rppa","luad_tcga_pan_can_atlas_2018_rppa_Zscores","luad_tcga_pan_can_atlas_2018_structural_variants"],"genericAssayProfiles":["luad_tcga_pan_can_atlas_2018_armlevel_cna","luad_tcga_pan_can_atlas_2018_genetic_ancestry","luad_tcga_pan_can_atlas_2018_methylation_hm27_hm450_merge","luad_tcga_pan_can_atlas_2018_methylation_hm450"],"heatmapProfileIds":["luad_tcga_pan_can_atlas_2018_rna_seq_v2_mrna_median_Zscores","luad_tcga_pan_can_atlas_2018_rna_seq_v2_mrna_median_all_sample_Zscores","luad_tcga_pan_can_atlas_2018_rna_seq_v2_mrna_median_all_sample_ref_normal_Zscores","luad_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":"gbm_tcga_pan_can_atlas_2018","name":"Glioblastoma Multif … (2394 more chars)

▶ navigate_to_results_view
{
 "studyIds": [
  "luad_tcga_pan_can_atlas_2018",
  "gbm_tcga_pan_can_atlas_2018"
 ],
 "genes": [
  "EGFR: MUT"
 ],
 "tab": "mutations"
}

◀ result
{"success":true,"message":"Navigating to https://www.cbioportal.org/results/mutations?cancer_study_list=luad_tcga_pan_can_atlas_2018%2Cgbm_tcga_pan_can_atlas_2018&gene_list=EGFR%3A+MUT&case_set_id=all","url":"https://www.cbioportal.org/results/mutations?cancer_study_list=luad_tcga_pan_can_atlas_2018%2Cgbm_tcga_pan_can_atlas_2018&gene_list=EGFR%3A+MUT&case_set_id=all","data":{"studyIds":["luad_tcga_pan_can_atlas_2018","gbm_tcga_pan_can_atlas_2018"],"studies":[{"studyId":"luad_tcga_pan_can_atlas_2018","name":"Lung Adenocarcinoma (TCGA, PanCancer Atlas)","sampleCount":566},{"studyId":"gbm_tcga_pan_can_atlas_2018","name":"Glioblastoma Multiforme (TCGA, PanCancer Atlas)","sampleCount":592}],"genes":["EGFR"],"caseSetId":"all","pageDescription":"Detailed mutation table with lollipop plot showing mutation positions, types, and frequencies for queried genes."}}

▶ navigate_to_group_comparison
{
 "studyIds": [
  "luad_tcga_pan_can_atlas_2018",
  "gbm_tcga_pan_can_atlas_2018"
 ],
 "groups": [
  {
   "name": "Lung Adenocarcinoma (TCGA)",
   "studyViewFilter": {
    "studyIds": [
     "luad_tcga_pan_can_atlas_2018"
    ]
   }
  },
  {
   "name": "Glioblastoma (TCGA)",
   "studyViewFilter": {
    "studyIds": [
     "gbm_tcga_pan_can_atlas_2018"
    ]
   }
  }
 ],
 "tab": "mutations",
 "selectedGene": "EGFR"
}

◀ result
{"success":true,"message":"Navigating to https://www.cbioportal.org/comparison/mutations?comparisonId=6ab81ca2e497aad53593c5c5&selectedGene=EGFR","url":"https://www.cbioportal.org/comparison/mutations?comparisonId=6ab81ca2e497aad53593c5c5&selectedGene=EGFR","data":{"description":"Group comparison (2 custom groups)","studies":["luad_tcga_pan_can_atlas_2018","gbm_tcga_pan_can_atlas_2018"],"totalGroups":2,"groups":[{"name":"Lung Adenocarcinoma (TCGA)","sampleCount":566},{"name":"Glioblastoma (TCGA)","sampleCount":592}],"studyViewUrl":"https://www.cbioportal.org/study?id=luad_tcga_pan_can_atlas_2018%2Cgbm_tcga_pan_can_atlas_2018","groupUrls":[{"groupName":"Lung Adenocarcinoma (TCGA)","url":"https://www.cbioportal.org/study?id=luad_tcga_pan_can_atlas_2018"},{"groupName":"Glioblastoma (TCGA)","url":"https://www.cbioportal.org/study?id=gbm_tcga_pan_can_atlas_2018"}],"pageDescription":"Mutation frequency (protein change) compared across Lung Adenocarcinoma (TCGA) (566) vs Glioblastoma (TCGA) (592)."}}

═ answer (success)
## EGFR Mutation Frequency: Lung Adenocarcinoma vs. Glioblastoma (TCGA PanCancer Atlas)

I used the TCGA PanCancer Atlas as the reference cohort for each: [Lung Adenocarcinoma](https://www.cbioportal.org/study/summary?id=luad_tcga_pan_can_atlas_2018) (566 samples) and [Glioblastoma Multiforme](https://www.cbioportal.org/study/summary?id=gbm_tcga_pan_can_atlas_2018) (592 samples). Frequencies below are sample-level (altered / profiled).

| Cohort | EGFR-mutant samples | Profiled samples | Frequency |
|---|---|---|---|
| Lung Adenocarcinoma (LUAD) | 70 | 566 | **12.4%** |
| Glioblastoma (GBM) | 94 | 397 | **23.7%** |

EGFR mutations are roughly **twice as frequent in glioblastoma** as in lung adenocarcinoma in these cohorts — but the *type* of mutation differs sharply between the two diseases:

**Lung adenocarcinoma — kinase-domain hotspots** (classic activating mutations):
- L858R: 23/566 (4.1%)
- E746_A750del (exon 19 deletion): 16/566 (2.8%)
- T790M (resistance mutation): 2/566 (0.4%)
- G719A, L861Q, S768I: sensitizing hotspots, ~0.4–0.5% each

**Glioblastoma — extracellular-domain mutations** (distinct biology from LUAD):
- A289V: 16/397 (4.0%)
- G598V: 15/397 (3.8%)
- R222C, A289T, A289D, V774M: 1.3–1.5% each

Note: GBM's EGFR profiled-sample denominator (397) is smaller than its total cohort (592) — some samples weren't sequenced/profiled for this gene. Also, cBioPortal's structural-variant/CNA data would be needed to capture **EGFRvIII** (the classic GBM in-frame deletion variant) and **EGFR amplification**, which are common in glioblastoma and not reflected in the point-mutation table above — let me know if you'd like me to pull those too.

**Explore further:**
- [Mutations tab — lollipop plot, both cohorts](https://www.cbioportal.org/results/mutations?cancer_study_list=luad_tcga_pan_can_atlas_2018%2Cgbm_tcga_pan_can_atlas_2018&gene_list=EGFR%3A+MUT&case_set_id=all) — compare mutation position/type distributions side by side.
- [Group Comparison — LUAD vs GBM, EGFR mutations](https://www.cbioportal.org/comparison/mutations?comparisonId=6ab81ca2e497aad53593c5c5&selectedGene=EGFR) — statistical comparison of mutation spectrum between the two cohorts.

Any claim of statistical significance for this frequency difference would need a formal test (e.g., Fisher's exact) — the Group Comparison link above can run that for you.