Q (sonnet): Which KRAS mutations are most common in colorectal cancer?

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

▶ search_oncotree
{
 "search_term": "colorectal"
}

◀ 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)

◀ result
{"result":[{"code":"COADREAD","name":"Colorectal Adenocarcinoma","score":60,"mainType":"Colorectal Cancer","tissue":"Bowel","hierarchy":"BOWEL > COADREAD"},{"code":"CAIS","name":"Colon Adenocarcinoma In Situ","score":45,"mainType":"Colorectal Cancer","tissue":"Bowel","hierarchy":"BOWEL > COADREAD > CAIS"},{"code":"CMC","name":"Medullary Carcinoma of the Colon","score":45,"mainType":"Colorectal Cancer","tissue":"Bowel","hierarchy":"BOWEL > CMC"},{"code":"COAD","name":"Colon Adenocarcinoma","score":45,"mainType":"Colorectal Cancer","tissue":"Bowel","hierarchy":"BOWEL > COADREAD > COAD"},{"code":"MACR","name":"Mucinous Adenocarcinoma of the Colon and Rectum","score":45,"mainType":"Colorectal Cancer","tissue":"Bowel","hierarchy":"BOWEL > COADREAD > MACR"},{"code":"READ","name":"Rectal Adenocarcinoma","score":45,"mainType":"Colorectal Cancer","tissue":"Bowel","hierarchy":"BOWEL > COADREAD > READ"},{"code":"SRCCR","name":"Signet Ring Cell Adenocarcinoma of the Colon and Rectum","score":45,"mainType":"Colorectal Cancer","tissue":"Bowel","hierarchy":"BOWEL > COADREAD > SRCCR"}]}

▶ list_studies
{
 "search": "colorectal pan_can_atlas"
}

◀ 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"}]}

▶ clickhouse_run_select_query
{
 "query": "SELECT * FROM gene_mutation_variants_in_study(study = 'coadread_tcga_pan_can_atlas_2018', gene = 'KRAS') ORDER BY altered_samples DESC LIMIT 25"
}

◀ result
{"rows":[{"mutation_variant":"G12D","mutation_type":"Missense_Mutation","altered_samples":58,"profiled_samples":534,"frequency_pct":10.9,"total_mutation_events":58},{"mutation_variant":"G12V","mutation_type":"Missense_Mutation","altered_samples":49,"profiled_samples":534,"frequency_pct":9.2,"total_mutation_events":49},{"mutation_variant":"G13D","mutation_type":"Missense_Mutation","altered_samples":37,"profiled_samples":534,"frequency_pct":6.9,"total_mutation_events":37},{"mutation_variant":"A146T","mutation_type":"Missense_Mutation","altered_samples":16,"profiled_samples":534,"frequency_pct":3,"total_mutation_events":16},{"mutation_variant":"G12C","mutation_type":"Missense_Mutation","altered_samples":15,"profiled_samples":534,"frequency_pct":2.8,"total_mutation_events":15},{"mutation_variant":"G12A","mutation_type":"Missense_Mutation","altered_samples":10,"profiled_samples":534,"frequency_pct":1.9,"total_mutation_events":10},{"mutation_variant":"G12S","mutation_type":"Missense_Mutation","altered_samples":8,"profiled_samples":534,"frequency_pct":1.5,"total_mutation_events":8},{"mutation_variant":"K117N","mutation_type":"Missense_Mutation","altered_samples":4,"profiled_samples":534,"frequency_pct":0.7,"total_mutation_events":4},{"mutation_variant":"Q61H","mutation_type":"Missense_Mutation","altered_samples":4,"profiled_samples":534,"frequency_pct":0.7,"total_mutation_events":4},{"mutation_variant":"Q61K","mutation_type":"Missense_Mutation","altered_samples":3,"profiled_samples":534,"frequency_pct":0.6,"total_mutation_events":3},{"mutation_variant":"G13C","mutation_type":"Missense_Mutation","altered_samples":2,"profiled_samples":534,"frequency_pct":0.4,"total_mutation_events":2},{"mutation_variant":"Q61R","mutation_type":"Missense_Mutation","altered_samples":2,"profiled_samples":534,"frequency_pct":0.4,"total_mutation_events":2},{"mutation_variant":"G12R","mutation_type":"Missense_Mutation","altered_samples":2,"profiled_samples":534,"frequency_pct":0.4,"total_mutation_events":2},{"mutation_variant":"L19F","mutation_type":"Missense_Mutation","altered_samples":1,"profiled_samples":534,"frequency_pct":0.2,"total_mutation_events":1},{"mutation_variant":"A59T","mutation_type":"Missense_Mutation","altered_samples":1,"profiled_samples":534,"frequency_pct":0.2,"total_mutation_events":1},{"mutation_variant":"Q22K","mutation_type":"Missense_Mutation","altered_samples":1,"profiled_samples":534,"frequency_pct":0.2,"total_mutation_events":1},{"mutation_variant":"A155D","mutation_type":"Missense_Mutation","altered_samples":1,"profiled_samples":534,"frequency_pct":0.2,"total_mutation_events":1},{"mutation_variant":"E98*","mutation_type":"Nonsense_Mutation","altered_samples":1,"profiled_samples":534,"frequency_pct":0.2,"total_mutation_events":1},{"mutation_variant":"Q61L","mutation_type":"Missense_Mutation","altered_samples":1,"profiled_samples":534,"frequency_pct":0.2,"total_mutation_events":1},{"mutation_variant":"A11_G12dup","mutation_type":"In_Frame_Ins","alter … (851 more chars)

▶ resolve_and_route
{
 "studyIds": [
  "coadread_tcga_pan_can_atlas_2018"
 ]
}

◀ result
{"success":true,"message":"Found 1 study. Use the metadata to call the appropriate navigation tool(s).","data":{"totalCount":1,"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_rppa_Zscores"],"availableComparisonTabs":["overlap","clinical","survival","alterations","mutations","mrna","protein","generic_assay_armlevel_c … (70 more chars)

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

◀ result
{"rows":[{"cancer_type":"Colorectal Cancer","altered_samples":218,"profiled_samples":534,"frequency_pct":40.8}]}

▶ navigate_to_results_view
{
 "studyIds": [
  "coadread_tcga_pan_can_atlas_2018"
 ],
 "genes": [
  "KRAS"
 ],
 "tab": "mutations"
}

◀ result
{"success":true,"message":"Navigating to https://www.cbioportal.org/results/mutations?cancer_study_list=coadread_tcga_pan_can_atlas_2018&gene_list=KRAS&case_set_id=coadread_tcga_pan_can_atlas_2018_all","url":"https://www.cbioportal.org/results/mutations?cancer_study_list=coadread_tcga_pan_can_atlas_2018&gene_list=KRAS&case_set_id=coadread_tcga_pan_can_atlas_2018_all","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"],"caseSetId":"coadread_tcga_pan_can_atlas_2018_all","pageDescription":"Detailed mutation table with lollipop plot showing mutation positions, types, and frequencies for queried genes."}}

═ answer (success)
## KRAS mutations in colorectal cancer

Using the [Colorectal Adenocarcinoma (TCGA, PanCancer Atlas)](https://www.cbioportal.org/study/summary?id=coadread_tcga_pan_can_atlas_2018) cohort (594 samples; 534 profiled for mutations), **KRAS is mutated in 218/534 samples (40.8%)**.

The most frequent specific protein-level variants (sample-level, % of 534 KRAS-profiled samples) are all clustered in classic hotspot codons 12/13, plus a smaller peak at A146:

| Variant | Samples | % of profiled |
|---|---|---|
| **G12D** | 58 | 10.9% |
| **G12V** | 49 | 9.2% |
| **G13D** | 37 | 6.9% |
| A146T | 16 | 3.0% |
| G12C | 15 | 2.8% |
| G12A | 10 | 1.9% |
| G12S | 8 | 1.5% |
| Q61H | 4 | 0.7% |
| K117N | 4 | 0.7% |
| Q61K | 3 | 0.6% |

Beyond these, there's a long tail of rare variants (G12R, G13C, Q61R/L/E/P, A155D, A11_G12dup, etc.), each seen in only 1–2 samples.

**Summary:** G12D, G12V, and G13D — all in the canonical codon 12/13 hotspot — together account for roughly 27% of all colorectal tumors profiled, making them by far the dominant KRAS alterations in this disease. A146T is a distinct, less common hotspot outside the classic G12/G13/Q61 cluster.

[View KRAS mutations (lollipop plot & variant table)](https://www.cbioportal.org/results/mutations?cancer_study_list=coadread_tcga_pan_can_atlas_2018&gene_list=KRAS&case_set_id=coadread_tcga_pan_can_atlas_2018_all) — detailed mutation table with lollipop plot showing mutation positions, types, and frequencies.

[View cohort overview](https://www.cbioportal.org/study?id=coadread_tcga_pan_can_atlas_2018) for the full Colorectal Adenocarcinoma TCGA PanCancer Atlas study.