Q (sonnet): what other genes are altered in kras mutant crc or luad

▶ 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)

▶ list_studies
{
 "search": "Colorectal Adenocarcinoma TCGA PanCancer"
}

▶ list_studies
{
 "search": "Lung Adenocarcinoma TCGA PanCancer"
}

◀ result
{"result":[{"cancer_study_identifier":"coadread_tcga_pan_can_atlas_2018","name":"Colorectal Adenocarcinoma (TCGA, PanCancer Atlas)","type_of_cancer_id":"coadread","sample_count":594,"has_guide":true,"url":"https://www.cbioportal.org/study/summary?id=coadread_tcga_pan_can_atlas_2018"}]}

◀ result
{"result":[{"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"}]}

▶ clickhouse_run_select_query
{
 "query": "SELECT * FROM co_altered_genes_in_study(study = 'coadread_tcga_pan_can_atlas_2018', gene = 'KRAS', top_n = 20)"
}

▶ clickhouse_run_select_query
{
 "query": "SELECT * FROM co_altered_genes_in_study(study = 'luad_tcga_pan_can_atlas_2018', gene = 'KRAS', top_n = 20)"
}

◀ result
{"rows":[{"hugo_gene_symbol":"APC","mutant_altered":182,"mutant_profiled":218,"mutant_pct":83.5,"wildtype_altered":205,"wildtype_profiled":316,"wildtype_pct":64.9,"pct_difference":18.6},{"hugo_gene_symbol":"PIK3CA","mutant_altered":83,"mutant_profiled":218,"mutant_pct":38.1,"wildtype_altered":64,"wildtype_profiled":316,"wildtype_pct":20.3,"pct_difference":17.8},{"hugo_gene_symbol":"BRAF","mutant_altered":6,"mutant_profiled":218,"mutant_pct":2.8,"wildtype_altered":56,"wildtype_profiled":316,"wildtype_pct":17.7,"pct_difference":-14.9},{"hugo_gene_symbol":"COL7A1","mutant_altered":7,"mutant_profiled":218,"mutant_pct":3.2,"wildtype_altered":40,"wildtype_profiled":316,"wildtype_pct":12.7,"pct_difference":-9.5},{"hugo_gene_symbol":"PCBP1","mutant_altered":20,"mutant_profiled":218,"mutant_pct":9.2,"wildtype_altered":5,"wildtype_profiled":316,"wildtype_pct":1.6,"pct_difference":7.6},{"hugo_gene_symbol":"ABCA13","mutant_altered":22,"mutant_profiled":218,"mutant_pct":10.1,"wildtype_altered":55,"wildtype_profiled":316,"wildtype_pct":17.4,"pct_difference":-7.3},{"hugo_gene_symbol":"DOCK3","mutant_altered":11,"mutant_profiled":218,"mutant_pct":5,"wildtype_altered":38,"wildtype_profiled":316,"wildtype_pct":12,"pct_difference":-7},{"hugo_gene_symbol":"YLPM1","mutant_altered":6,"mutant_profiled":218,"mutant_pct":2.8,"wildtype_altered":31,"wildtype_profiled":316,"wildtype_pct":9.8,"pct_difference":-7},{"hugo_gene_symbol":"ZNF469","mutant_altered":11,"mutant_profiled":218,"mutant_pct":5,"wildtype_altered":38,"wildtype_profiled":316,"wildtype_pct":12,"pct_difference":-7},{"hugo_gene_symbol":"CHD7","mutant_altered":7,"mutant_profiled":218,"mutant_pct":3.2,"wildtype_altered":32,"wildtype_profiled":316,"wildtype_pct":10.1,"pct_difference":-6.9},{"hugo_gene_symbol":"ARID1A","mutant_altered":15,"mutant_profiled":218,"mutant_pct":6.9,"wildtype_altered":43,"wildtype_profiled":316,"wildtype_pct":13.6,"pct_difference":-6.7},{"hugo_gene_symbol":"CELSR2","mutant_altered":6,"mutant_profiled":218,"mutant_pct":2.8,"wildtype_altered":30,"wildtype_profiled":316,"wildtype_pct":9.5,"pct_difference":-6.7},{"hugo_gene_symbol":"NRAS","mutant_altered":5,"mutant_profiled":218,"mutant_pct":2.3,"wildtype_altered":28,"wildtype_profiled":316,"wildtype_pct":8.9,"pct_difference":-6.6},{"hugo_gene_symbol":"TMPRSS15","mutant_altered":19,"mutant_profiled":218,"mutant_pct":8.7,"wildtype_altered":7,"wildtype_profiled":316,"wildtype_pct":2.2,"pct_difference":6.5},{"hugo_gene_symbol":"DNAH1","mutant_altered":14,"mutant_profiled":218,"mutant_pct":6.4,"wildtype_altered":40,"wildtype_profiled":316,"wildtype_pct":12.7,"pct_difference":-6.3},{"hugo_gene_symbol":"SCN3A","mutant_altered":9,"mutant_profiled":218,"mutant_pct":4.1,"wildtype_altered":33,"wildtype_profiled":316,"wildtype_pct":10.4,"pct_difference":-6.3},{"hugo_gene_symbol":"CACNA1F","mutant_altered":4,"mutant_profiled":218,"mutant_pct":1.8,"wildtype_altered":25,"wildtype_profiled":316,"wildtype_pct":7.9,"pct_difference":-6.1},{"hugo_gene_symbol" … (505 more chars)

◀ result
{"rows":[{"hugo_gene_symbol":"TP53","mutant_altered":62,"mutant_profiled":168,"mutant_pct":36.9,"wildtype_altered":233,"wildtype_profiled":398,"wildtype_pct":58.5,"pct_difference":-21.6},{"hugo_gene_symbol":"EGFR","mutant_altered":1,"mutant_profiled":168,"mutant_pct":0.6,"wildtype_altered":69,"wildtype_profiled":398,"wildtype_pct":17.3,"pct_difference":-16.7},{"hugo_gene_symbol":"STK11","mutant_altered":38,"mutant_profiled":168,"mutant_pct":22.6,"wildtype_altered":37,"wildtype_profiled":398,"wildtype_pct":9.3,"pct_difference":13.3},{"hugo_gene_symbol":"ATM","mutant_altered":28,"mutant_profiled":168,"mutant_pct":16.7,"wildtype_altered":19,"wildtype_profiled":398,"wildtype_pct":4.8,"pct_difference":11.9},{"hugo_gene_symbol":"MUC16","mutant_altered":84,"mutant_profiled":168,"mutant_pct":50,"wildtype_altered":158,"wildtype_profiled":398,"wildtype_pct":39.7,"pct_difference":10.3},{"hugo_gene_symbol":"NF1","mutant_altered":8,"mutant_profiled":168,"mutant_pct":4.8,"wildtype_altered":58,"wildtype_profiled":398,"wildtype_pct":14.6,"pct_difference":-9.8},{"hugo_gene_symbol":"CSMD1","mutant_altered":48,"mutant_profiled":168,"mutant_pct":28.6,"wildtype_altered":77,"wildtype_profiled":398,"wildtype_pct":19.3,"pct_difference":9.3},{"hugo_gene_symbol":"CNTNAP2","mutant_altered":32,"mutant_profiled":168,"mutant_pct":19,"wildtype_altered":39,"wildtype_profiled":398,"wildtype_pct":9.8,"pct_difference":9.2},{"hugo_gene_symbol":"RIMS2","mutant_altered":32,"mutant_profiled":168,"mutant_pct":19,"wildtype_altered":40,"wildtype_profiled":398,"wildtype_pct":10.1,"pct_difference":8.9},{"hugo_gene_symbol":"LRP1B","mutant_altered":69,"mutant_profiled":168,"mutant_pct":41.1,"wildtype_altered":132,"wildtype_profiled":398,"wildtype_pct":33.2,"pct_difference":7.9},{"hugo_gene_symbol":"LRRC7","mutant_altered":34,"mutant_profiled":168,"mutant_pct":20.2,"wildtype_altered":49,"wildtype_profiled":398,"wildtype_pct":12.3,"pct_difference":7.9},{"hugo_gene_symbol":"TNR","mutant_altered":19,"mutant_profiled":168,"mutant_pct":11.3,"wildtype_altered":76,"wildtype_profiled":398,"wildtype_pct":19.1,"pct_difference":-7.8},{"hugo_gene_symbol":"BRAF","mutant_altered":3,"mutant_profiled":168,"mutant_pct":1.8,"wildtype_altered":38,"wildtype_profiled":398,"wildtype_pct":9.5,"pct_difference":-7.7},{"hugo_gene_symbol":"RP1L1","mutant_altered":37,"mutant_profiled":168,"mutant_pct":22,"wildtype_altered":60,"wildtype_profiled":398,"wildtype_pct":15.1,"pct_difference":6.9},{"hugo_gene_symbol":"ZFHX4","mutant_altered":63,"mutant_profiled":168,"mutant_pct":37.5,"wildtype_altered":122,"wildtype_profiled":398,"wildtype_pct":30.7,"pct_difference":6.8},{"hugo_gene_symbol":"HECTD4","mutant_altered":18,"mutant_profiled":168,"mutant_pct":10.7,"wildtype_altered":16,"wildtype_profiled":398,"wildtype_pct":4,"pct_difference":6.7},{"hugo_gene_symbol":"KMT2C","mutant_altered":15,"mutant_profiled":168,"mutant_pct":8.9,"wildtype_altered":62,"wildtype_profiled":398,"wildtype_pct":15.6,"pct_difference":-6.7},{"hugo_gene_ … (513 more chars)

▶ resolve_and_route
{
 "studyIds": [
  "coadread_tcga_pan_can_atlas_2018",
  "luad_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":"coadread_tcga_pan_can_atlas_2018","name":"Colorectal Adenocarcinoma (TCGA, PanCancer Atlas)","sampleCount":594,"studyViewUrl":"https://www.cbioportal.org/study?id=coadread_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":["coadread_tcga_pan_can_atlas_2018_gistic","coadread_tcga_pan_can_atlas_2018_log2CNA","coadread_tcga_pan_can_atlas_2018_mutations","coadread_tcga_pan_can_atlas_2018_protein_quantification","coadread_tcga_pan_can_atlas_2018_protein_quantification_zscores","coadread_tcga_pan_can_atlas_2018_rna_seq_v2_mrna","coadread_tcga_pan_can_atlas_2018_rna_seq_v2_mrna_median_Zscores","coadread_tcga_pan_can_atlas_2018_rna_seq_v2_mrna_median_all_sample_Zscores","coadread_tcga_pan_can_atlas_2018_rna_seq_v2_mrna_median_all_sample_ref_normal_Zscores","coadread_tcga_pan_can_atlas_2018_rppa","coadread_tcga_pan_can_atlas_2018_rppa_Zscores","coadread_tcga_pan_can_atlas_2018_structural_variants"],"genericAssayProfiles":["coadread_tcga_pan_can_atlas_2018_armlevel_cna","coadread_tcga_pan_can_atlas_2018_genetic_ancestry","coadread_tcga_pan_can_atlas_2018_methylation_hm27_hm450_merge","coadread_tcga_pan_can_atlas_2018_methylation_hm450"],"heatmapProfileIds":["coadread_tcga_pan_can_atlas_2018_protein_quantification_zscores","coadread_tcga_pan_can_atlas_2018_rna_seq_v2_mrna_median_Zscores","coadread_tcga_pan_can_atlas_2018_rna_seq_v2_mrna_median_all_sample_Zscores","coadread_tcga_pan_can_atlas_2018_rna_seq_v2_mrna_median_all_sample_ref_normal_Zscores","coadread_tcga_pan_can_atlas_2018_rp … (2852 more chars)

▶ navigate_to_results_view
{
 "studyIds": [
  "coadread_tcga_pan_can_atlas_2018"
 ],
 "genes": [
  "KRAS",
  "APC",
  "PIK3CA",
  "BRAF",
  "TP53"
 ],
 "tab": "comparison/alterations",
 "comparisonSelectedGroups": [
  "KRAS"
 ]
}

◀ result
{"success":true,"message":"Navigating to https://www.cbioportal.org/results/comparison/alterations?cancer_study_list=coadread_tcga_pan_can_atlas_2018&gene_list=KRAS%0AAPC%0APIK3CA%0ABRAF%0ATP53&case_set_id=coadread_tcga_pan_can_atlas_2018_all&comparison_selectedGroups=%5B%22KRAS%22%5D","url":"https://www.cbioportal.org/results/comparison/alterations?cancer_study_list=coadread_tcga_pan_can_atlas_2018&gene_list=KRAS%0AAPC%0APIK3CA%0ABRAF%0ATP53&case_set_id=coadread_tcga_pan_can_atlas_2018_all&comparison_selectedGroups=%5B%22KRAS%22%5D","data":{"studyIds":["coadread_tcga_pan_can_atlas_2018"],"studies":[{"studyId":"coadread_tcga_pan_can_atlas_2018","name":"Colorectal Adenocarcinoma (TCGA, PanCancer Atlas)","sampleCount":594}],"genes":["KRAS","APC","PIK3CA","BRAF","TP53"],"caseSetId":"coadread_tcga_pan_can_atlas_2018_all","pageDescription":"Genomic alteration rates compared across KRAS-altered."}}

▶ navigate_to_results_view
{
 "studyIds": [
  "luad_tcga_pan_can_atlas_2018"
 ],
 "genes": [
  "KRAS",
  "TP53",
  "STK11",
  "EGFR",
  "ATM"
 ],
 "tab": "comparison/alterations",
 "comparisonSelectedGroups": [
  "KRAS"
 ]
}

◀ result
{"success":true,"message":"Navigating to https://www.cbioportal.org/results/comparison/alterations?cancer_study_list=luad_tcga_pan_can_atlas_2018&gene_list=KRAS%0ATP53%0ASTK11%0AEGFR%0AATM&case_set_id=luad_tcga_pan_can_atlas_2018_all&comparison_selectedGroups=%5B%22KRAS%22%5D","url":"https://www.cbioportal.org/results/comparison/alterations?cancer_study_list=luad_tcga_pan_can_atlas_2018&gene_list=KRAS%0ATP53%0ASTK11%0AEGFR%0AATM&case_set_id=luad_tcga_pan_can_atlas_2018_all&comparison_selectedGroups=%5B%22KRAS%22%5D","data":{"studyIds":["luad_tcga_pan_can_atlas_2018"],"studies":[{"studyId":"luad_tcga_pan_can_atlas_2018","name":"Lung Adenocarcinoma (TCGA, PanCancer Atlas)","sampleCount":566}],"genes":["KRAS","TP53","STK11","EGFR","ATM"],"caseSetId":"luad_tcga_pan_can_atlas_2018_all","pageDescription":"Genomic alteration rates compared across KRAS-altered."}}

═ answer (success)
Co-alteration patterns in KRAS-mutant tumors (mutation-only comparison, patient/sample counts are mutation-profiled samples), each from the **TCGA PanCancer Atlas** cohort, comparing KRAS-mutant vs KRAS-wild-type mutation rates:

## Colorectal Adenocarcinoma (COADREAD, n=594 samples; 218 KRAS-mutant / 316 wild-type profiled)

| Gene | KRAS-mutant | KRAS-WT | Difference |
|---|---|---|---|
| **APC** | 182/218 (83.5%) | 205/316 (64.9%) | **+18.6 pts** (enriched with KRAS) |
| **PIK3CA** | 83/218 (38.1%) | 64/316 (20.3%) | **+17.8 pts** (enriched with KRAS) |
| **BRAF** | 6/218 (2.8%) | 56/316 (17.7%) | **−14.9 pts** (depleted — largely mutually exclusive, as expected since both activate the MAPK pathway) |
| NRAS | 5/218 (2.3%) | 28/316 (8.9%) | −6.6 pts |

APC and PIK3CA mutations co-occur with KRAS more often than in KRAS-wild-type tumors, while BRAF mutations are notably rarer in KRAS-mutant cases — consistent with both genes acting in the same RAS/MAPK pathway (mutual exclusivity here is a descriptive pattern, not a statistically tested claim).

## Lung Adenocarcinoma (LUAD, n=566 samples; 168 KRAS-mutant / 398 wild-type profiled)

| Gene | KRAS-mutant | KRAS-WT | Difference |
|---|---|---|---|
| **STK11** | 38/168 (22.6%) | 37/398 (9.3%) | **+13.3 pts** (enriched with KRAS) |
| **ATM** | 28/168 (16.7%) | 19/398 (4.8%) | **+11.9 pts** (enriched) |
| TP53 | 62/168 (36.9%) | 233/398 (58.5%) | −21.6 pts (depleted) |
| **EGFR** | 1/168 (0.6%) | 69/398 (17.3%) | **−16.7 pts** (largely mutually exclusive with KRAS, as expected — both are alternative RTK/RAS-pathway drivers) |

STK11 (LKB1) and ATM co-mutation is notably enriched in KRAS-mutant LUAD (the STK11/KRAS co-mutant subgroup is a recognized molecular subtype in the literature, though I'm not asserting a clinical implication here). EGFR mutations are nearly absent in KRAS-mutant tumors, consistent with the general pattern of mutually exclusive oncogenic drivers.

*Note: these are descriptive percentage-point differences in raw mutation frequency, not statistically tested co-occurrence/exclusivity (no p-values computed). Mutation-only — copy number and structural variants are excluded.*

[View KRAS co-alterations — Colorectal Adenocarcinoma](https://www.cbioportal.org/results/comparison/alterations?cancer_study_list=coadread_tcga_pan_can_atlas_2018&gene_list=KRAS%0AAPC%0APIK3CA%0ABRAF%0ATP53&case_set_id=coadread_tcga_pan_can_atlas_2018_all&comparison_selectedGroups=%5B%22KRAS%22%5D)

[View KRAS co-alterations — Lung Adenocarcinoma](https://www.cbioportal.org/results/comparison/alterations?cancer_study_list=luad_tcga_pan_can_atlas_2018&gene_list=KRAS%0ATP53%0ASTK11%0AEGFR%0AATM&case_set_id=luad_tcga_pan_can_atlas_2018_all&comparison_selectedGroups=%5B%22KRAS%22%5D)

Both links open the Comparison/Alterations tab with the Altered (KRAS-mutant) group pre-selected against the Unaltered group, where you can run the formal mutual exclusivity/co-occurrence test.