Q (sonnet): Is BRCA1 promoter methylation associated with decreased BRCA1 mRNA expression in ovarian cancer?

▶ read_guide
{
 "uri": "cbioportal://gene-expression-guide"
}

▶ list_studies
{
 "search": "ovarian"
}

◀ result
# Gene Expression Analysis Guide

This guide covers continuous-value genomic data: gene **expression**, **copy number** values, **methylation**, and related profile types. Mutation/CNA/SV *frequency* analysis lives in `cbioportal://mutation-frequency-guide`.

## Where this data lives

Continuous per-sample-per-gene values are stored in `genetic_alteration_derived`:

| Column | Description |
|---|---|
| `sample_unique_id` | `<study>_<sample_stable_id>` |
| `cancer_study_identifier` | study scope |
| `hugo_gene_symbol` | gene |
| `profile_type` | which assay/normalization (see below) |
| `alteration_value` | the actual value — stored as Nullable(String); cast with `toFloat64OrNull` |

`alteration_value` is a string because the same column hosts many different value scales. The `''` and `'NA'` sentinels mean "missing"; always filter them out and use `toFloat64OrNull(alteration_value) IS NOT NULL` for downstream math.

## Discovering profile types for a study

Different studies expose different profile types depending on what assays were run and how the data was normalized. Always check what a specific study supports before picking one:

```sql
SELECT DISTINCT profile_type
FROM genetic_alteration_derived
WHERE cancer_study_identifier = 'brca_metabric'
ORDER BY profile_type;
```

Common values across the public portal:

| Family | Profile types |
|---|---|
| mRNA expression | `mrna`, `mrna_median_Zscores`, `mrna_seq_v2_rsem`, `mrna_seq_v2_rsem_Zscores`, `mrna_seq_cpm`, `mrna_seq_fpkm`, `mrna_U133`, `mrna_outliers` |
| Copy number (continuous) | `cna`, `linear_CNA`, `log2CNA`, `cna_consensus`, `cna_rae`, `gistic` |
| Methylation | `methylation_hm27`, `methylation_hm450`, `methylation_epic`, `methylation_promoters_rrbs` |
| miRNA | `mirna`, `mirna_median_Zscores` |
| Protein | `protein_quantification`, `protein_level`, `RPPA` |

**Z-score vs raw choice.** When the user asks "is X correlated with Y", either works for Spearman (rank-based) — Pearson would care. Default to the non-Z-score variant if both exist, and call out which one in the response.

## Canonical recipe — Spearman correlation between two genes

```sql
SELECT *
FROM gene_pair_coexpression(
    study        = 'brca_metabric',
    gene_a       = 'TP53',
    gene_b       = 'MYC',
    profile_type = 'mrna'
);
```

Returns one row: `(gene_a, gene_b, profile_type, spearman_correlation, num_samples)`.

- `spearman_correlation` in [−1, 1]; `NULL` when fewer than 3 valid paired samples.
- Mirrors cbioportal-backend's `ClickhouseCoExpressionMapper.getCoExpressions`, simplified to a pair lookup (the backend computes one ref gene vs ALL other genes for the coexpression page; here the agent asks about a specific pair).

### Verified examples

| Study | gene_a | gene_b | profile_type | spearman | n |
|---|---|---|---|---|---|
| `brca_metabric` | TP53 | MYC | `mrna` | 0.118 | 1980 |
| `brca_metabric` | ESR1 | PGR | `mrna` | 0.487 | 1980 |

ESR1↔PGR is the textbook breast-cancer estrogen-receptor coregula … (2785 more chars)

◀ 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":"ov_tcga","name":"Ovarian Serous Cystadenocarcinoma (TCGA, Firehose Legacy)","type_of_cancer_id":"hgsoc","sample_count":617,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=ov_tcga"},{"cancer_study_identifier":"hgsoc_tcga_gdc","name":"High-Grade Serous Ovarian Cancer (TCGA GDC, 2025)","type_of_cancer_id":"hgsoc","sample_count":604,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=hgsoc_tcga_gdc"},{"cancer_study_identifier":"ov_tcga_pan_can_atlas_2018","name":"Ovarian Serous Cystadenocarcinoma (TCGA, PanCancer Atlas)","type_of_cancer_id":"hgsoc","sample_count":585,"has_guide":true,"url":"https://www.cbioportal.org/study/summary?id=ov_tcga_pan_can_atlas_2018"},{"cancer_study_identifier":"ovary_geomx_gray_foundation_2024","name":"Ovarian Cancer (Gray Foundation, Cancer Discov 2024)","type_of_cancer_id":"ovary","sample_count":567,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=ovary_geomx_gray_foundation_2024"},{"cancer_study_identifier":"ov_tcga_pub","name":"Ovarian Serous Cystadenocarcinoma (TCGA, Nature 2011)","type_of_cancer_id":"hgsoc","sample_count":489,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=ov_tcga_pub"},{"cancer_study_identifier":"lgsoc_mapk_msk_2022","name":"Low-Grade Serous Ovarian Cancer (MSK, Clin Cancer Res 2022)","type_of_cancer_id":"lgsoc","sample_count":119,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=lgsoc_mapk_msk_2022"},{"cancer_study_identifier":"ovary_cptac_gdc","name":"Ovarian Cancer (CPTAC GDC, 2025)","type_of_cancer_id":"ovary","sample_count":112,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=ovary_cptac_gdc"},{"cancer_study_identifier":"msk_spectrum_tme_2022","name":"Ovarian Cancer - MSK SPECTRUM (MSK, Nature 2022)","type_of_cancer_id":"ovary","sample_count":82,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=msk_spectrum_tme_2022"},{"cancer_study_identifier":"hgsoc_msk_2021","name":"High-Grade Serous Ovarian Cancer (MSK, NPJ Genome Med 2021)","type_of_cancer_id":"hgsoc","sample_count":45,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=hgsoc_msk_2021"},{"cancer_study_identifier":"ucec_msk_2024","name":"Endometrial and Ovarian Cancer (MSK, Nature Medicine 2024)","type_of_cancer_id":"mixed","sample_count":33,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=ucec_msk_2024"},{"cancer_study_identifier":"ovarian_msk_2025","name":"Serous Ovarian Cancer (MSK, 2025)","type_of_cancer_id":"ovary","sample_count":31,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=ovarian_msk_2025"},{"cancer_study_identifier":"mixed_msk_tcga_2021","name":"RAD51B Associated Mixed Cancers (MSK, N … (162 more chars)

▶ clickhouse_run_select_query
{
 "query": "SELECT DISTINCT profile_type FROM genetic_alteration_derived WHERE cancer_study_identifier = 'ov_tcga_pan_can_atlas_2018' ORDER BY profile_type"
}

◀ result
{"rows":[{"profile_type":"gistic"},{"profile_type":"log2CNA"},{"profile_type":"protein_quantification"},{"profile_type":"protein_quantification_zscores"},{"profile_type":"rna_seq_v2_mrna"},{"profile_type":"rna_seq_v2_mrna_median_Zscores"},{"profile_type":"rna_seq_v2_mrna_median_all_sample_Zscores"},{"profile_type":"rppa"},{"profile_type":"rppa_Zscores"}]}

▶ clickhouse_run_select_query
{
 "query": "SELECT DISTINCT profile_type FROM genetic_alteration_derived WHERE cancer_study_identifier = 'ov_tcga' ORDER BY profile_type"
}

▶ clickhouse_run_select_query
{
 "query": "SELECT DISTINCT profile_type FROM genetic_alteration_derived WHERE cancer_study_identifier = 'ov_tcga_pub' ORDER BY profile_type"
}

▶ clickhouse_run_select_query
{
 "query": "SELECT DISTINCT profile_type FROM genetic_alteration_derived WHERE cancer_study_identifier = 'hgsoc_tcga_gdc' ORDER BY profile_type"
}

◀ result
{"rows":[{"profile_type":"gistic"},{"profile_type":"linear_CNA"},{"profile_type":"methylation_hm27"},{"profile_type":"mrna"},{"profile_type":"mrna_U133"},{"profile_type":"mrna_U133_Zscores"},{"profile_type":"mrna_U133_all_sample_Zscores"},{"profile_type":"mrna_median_Zscores"},{"profile_type":"mrna_median_all_sample_Zscores"},{"profile_type":"protein_quantification"},{"profile_type":"protein_quantification_zscores"},{"profile_type":"rna_seq_v2_mrna"},{"profile_type":"rna_seq_v2_mrna_median_Zscores"},{"profile_type":"rna_seq_v2_mrna_median_all_sample_Zscores"},{"profile_type":"rppa"},{"profile_type":"rppa_Zscores"}]}

◀ result
{"rows":[{"profile_type":"gistic"},{"profile_type":"linear_CNA"},{"profile_type":"methylation_hm27"},{"profile_type":"mirna"},{"profile_type":"mirna_median_Zscores"},{"profile_type":"mrna"},{"profile_type":"mrna_median_Zscores"},{"profile_type":"mrna_median_all_sample_Zscores"},{"profile_type":"mrna_merged_median_Zscores"}]}

◀ result
{"rows":[{"profile_type":"cna"},{"profile_type":"mrna_seq_fpkm"},{"profile_type":"mrna_seq_fpkm_Zscores"},{"profile_type":"mrna_seq_read_counts_Zscores"},{"profile_type":"mrna_seq_tpm"},{"profile_type":"mrna_seq_tpm_Zscores"},{"profile_type":"rna_seq_mrna"}]}

▶ clickhouse_run_select_query
{
 "query": "
WITH meth AS (
    SELECT sample_unique_id, toFloat64OrNull(alteration_value) AS v
    FROM genetic_alteration_derived
    WHERE cancer_study_identifier = 'ov_tcga'
      AND profile_type = 'methylation_hm27'
      AND hugo_gene_symbol = 'BRCA1'
      AND alteration_value NOT IN ('', 'NA')
      AND toFloat64OrNull(alteration_value) IS NOT NULL
),
expr AS (
    SELECT sample_unique_id, toFloat64OrNull(alteration_value) AS v
    FROM genetic_alteration_derived
    WHERE cancer_study_identifier = 'ov_tcga'
      AND profile_type = 'rna_seq_v2_mrna'
      AND hugo_gene_symbol = 'BRCA1'
      AND alteration_value NOT IN ('', 'NA')
      AND toFloat64OrNull(alteration_value) IS NOT NULL
)
SELECT rankCorr(meth.v, expr.v) AS spearman_correlation,
       count() AS num_samples
FROM meth INNER JOIN expr USING (sample_unique_id)
"
}

◀ result
{"rows":[{"spearman_correlation":-0.4383424829879454,"num_samples":298}]}

▶ clickhouse_run_select_query
{
 "query": "
WITH meth AS (
    SELECT sample_unique_id, toFloat64OrNull(alteration_value) AS v
    FROM genetic_alteration_derived
    WHERE cancer_study_identifier = 'ov_tcga'
      AND profile_type = 'methylation_hm27'
      AND hugo_gene_symbol = 'BRCA1'
      AND alteration_value NOT IN ('', 'NA')
      AND toFloat64OrNull(alteration_value) IS NOT NULL
),
expr AS (
    SELECT sample_unique_id, toFloat64OrNull(alteration_value) AS v
    FROM genetic_alteration_derived
    WHERE cancer_study_identifier = 'ov_tcga'
      AND profile_type = 'mrna'
      AND hugo_gene_symbol = 'BRCA1'
      AND alteration_value NOT IN ('', 'NA')
      AND toFloat64OrNull(alteration_value) IS NOT NULL
)
SELECT rankCorr(meth.v, expr.v) AS spearman_correlation,
       count() AS num_samples
FROM meth INNER JOIN expr USING (sample_unique_id)
"
}

◀ result
{"rows":[{"spearman_correlation":-0.40336141757343147,"num_samples":550}]}

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

◀ result
{"success":true,"message":"Found 1 study. Use the metadata to call the appropriate navigation tool(s).","data":{"totalCount":1,"studiesWithMetadata":[{"studyId":"ov_tcga","name":"Ovarian Serous Cystadenocarcinoma (TCGA, Firehose Legacy)","sampleCount":617,"studyViewUrl":"https://www.cbioportal.org/study?id=ov_tcga","metadata":{"clinicalAttributeIds":["AGE","AJCC_PATHOLOGIC_TUMOR_STAGE","AJCC_STAGING_EDITION","CANCER_TYPE","CANCER_TYPE_DETAILED","CLINICAL_STAGE","CLIN_M_STAGE","CLIN_N_STAGE","CLIN_T_STAGE","DAYS_TO_COLLECTION","DAYS_TO_INITIAL_PATHOLOGIC_DIAGNOSIS","DAYS_TO_PATIENT_PROGRESSION_FREE","DAYS_TO_SPECIMEN_COLLECTION","DAYS_TO_TUMOR_PROGRESSION","DFS_MONTHS","DFS_STATUS","DISEASE_CODE","ECOG_SCORE","ETHNICITY","EXTRANODAL_INVOLVEMENT","FORM_COMPLETION_DATE","FRACTION_GENOME_ALTERED","GRADE","HISTOLOGICAL_DIAGNOSIS","HISTORY_NEOADJUVANT_TRTYN","HISTORY_OTHER_MALIGNANCY","ICD_10","ICD_O_3_HISTOLOGY","ICD_O_3_SITE","INFORMED_CONSENT_VERIFIED","INITIAL_PATHOLOGIC_DX_YEAR","IS_FFPE","JEWISH_RELIGION_HERITAGE_INDICATOR","KARNOFSKY_PERFORMANCE_SCORE","LONGEST_DIMENSION","LYMPHOVASCULAR_INVASION_INDICATOR","METHOD_OF_INITIAL_SAMPLE_PROCUREMENT","METHOD_OF_INITIAL_SAMPLE_PROCUREMENT_OTHER","METHOD_OF_SAMPLE_PROCUREMENT","MUTATION_COUNT","NEW_TUMOR_EVENT_AFTER_INITIAL_TREATMENT","OCT_EMBEDDED","ONCOTREE_CODE","OS_MONTHS","OS_STATUS","OTHER_METHOD_OF_SAMPLE_PROCUREMENT","OTHER_PATIENT_ID","OTHER_SAMPLE_ID","PATHOLOGY_REPORT_FILE_NAME","PATHOLOGY_REPORT_UUID","PATH_M_STAGE","PATH_N_STAGE","PATH_T_STAGE","PERFORMANCE_STATUS_TIMING","PHARMACEUTICAL_TX_ADJUVANT","PRIMARY_SITE","PROJECT_CODE","PROSPECTIVE_COLLECTION","RACE","RADIATION_TREATMENT_ADJUVANT","RESIDUAL_TUMOR","RETROSPECTIVE_COLLECTION","SAMPLE_COUNT","SAMPLE_INITIAL_WEIGHT","SAMPLE_TYPE","SAMPLE_TYPE_ID","SEX","SHORTEST_DIMENSION","SOMATIC_STATUS","SPECIMEN_CURRENT_WEIGHT","SPECIMEN_FREEZING_METHOD","SPECIMEN_SECOND_LONGEST_DIMENSION","STAGE_OTHER","TIME_BETWEEN_CLAMPING_AND_FREEZING","TIME_BETWEEN_EXCISION_AND_FREEZING","TISSUE_SOURCE_SITE","TMB_NONSYNONYMOUS","TREATMENT_OUTCOME_FIRST_COURSE","TUMOR_STATUS","TUMOR_TISSUE_SITE","VASCULAR_INVASION_INDICATOR","VIAL_NUMBER"],"molecularProfileIds":["ov_tcga_gistic","ov_tcga_linear_CNA","ov_tcga_methylation_hm27","ov_tcga_mrna","ov_tcga_mrna_U133","ov_tcga_mrna_U133_Zscores","ov_tcga_mrna_U133_all_sample_Zscores","ov_tcga_mrna_median_Zscores","ov_tcga_mrna_median_all_sample_Zscores","ov_tcga_mutations","ov_tcga_protein_quantification","ov_tcga_protein_quantification_zscores","ov_tcga_rna_seq_v2_mrna","ov_tcga_rna_seq_v2_mrna_median_Zscores","ov_tcga_rna_seq_v2_mrna_median_all_sample_Zscores","ov_tcga_rppa","ov_tcga_rppa_Zscores"],"genericAssayProfiles":["ov_tcga_phosphoprotein_quantification"],"heatmapProfileIds":["ov_tcga_methylation_hm27","ov_tcga_mrna_U133_Zscores","ov_tcga_mrna_U133_all_sample_Zscores","ov_tcga_mrna_median_Zscores","ov_tcga_mrna_median_all_sample_Zscores","ov_tcga_protein_quantification_zscores","ov_tcga_rna_seq_v2_mrna_medi … (256 more chars)

▶ navigate_to_results_view
{
 "studyIds": [
  "ov_tcga"
 ],
 "genes": [
  "BRCA1"
 ],
 "tab": "plots",
 "plotsHorzSelection": {
  "dataType": "molecular_data",
  "selectedGeneOption": "BRCA1",
  "selectedDataSourceOption": "ov_tcga_methylation_hm27"
 },
 "plotsVertSelection": {
  "dataType": "molecular_data",
  "selectedGeneOption": "BRCA1",
  "selectedDataSourceOption": "ov_tcga_rna_seq_v2_mrna"
 }
}

◀ result
{"success":true,"message":"Navigating to https://www.cbioportal.org/results/plots?cancer_study_list=ov_tcga&gene_list=BRCA1&case_set_id=ov_tcga_all&plots_horz_selection=%7B%22selectedGeneOption%22%3A%22672%22%2C%22dataType%22%3A%22molecular_data%22%2C%22selectedDataSourceOption%22%3A%22ov_tcga_methylation_hm27%22%7D&plots_vert_selection=%7B%22selectedGeneOption%22%3A%22672%22%2C%22dataType%22%3A%22molecular_data%22%2C%22selectedDataSourceOption%22%3A%22ov_tcga_rna_seq_v2_mrna%22%7D","url":"https://www.cbioportal.org/results/plots?cancer_study_list=ov_tcga&gene_list=BRCA1&case_set_id=ov_tcga_all&plots_horz_selection=%7B%22selectedGeneOption%22%3A%22672%22%2C%22dataType%22%3A%22molecular_data%22%2C%22selectedDataSourceOption%22%3A%22ov_tcga_methylation_hm27%22%7D&plots_vert_selection=%7B%22selectedGeneOption%22%3A%22672%22%2C%22dataType%22%3A%22molecular_data%22%2C%22selectedDataSourceOption%22%3A%22ov_tcga_rna_seq_v2_mrna%22%7D","data":{"studyIds":["ov_tcga"],"studies":[{"studyId":"ov_tcga","name":"Ovarian Serous Cystadenocarcinoma (TCGA, Firehose Legacy)","sampleCount":617}],"genes":["BRCA1"],"caseSetId":"ov_tcga_all","pageDescription":"Scatter/box plots: BRCA1 molecular_data (y-axis) by BRCA1 molecular_data (x-axis)."}}

═ answer (success)
## Yes — in the TCGA ovarian cancer cohort, BRCA1 promoter methylation is moderately negatively correlated with BRCA1 mRNA expression

**Cohort:** [Ovarian Serous Cystadenocarcinoma (TCGA, Firehose Legacy)](https://www.cbioportal.org/study/summary?id=ov_tcga) — 617 samples, chosen because it's the ovarian TCGA study with both Illumina HumanMethylation27 (`methylation_hm27`) and mRNA expression data.

| Expression platform | Spearman ρ (methylation vs. mRNA) | Paired samples |
|---|---|---|
| RNA-Seq (RSEM) | **−0.44** | 298 |
| Microarray (U133) | **−0.40** | 550 |

Both independent expression platforms agree: higher BRCA1 promoter methylation is associated with lower BRCA1 mRNA levels, consistent with promoter methylation acting as a transcriptional silencing mechanism. A correlation of this magnitude (−0.40 to −0.44) is a real, moderately strong inverse relationship, though methylation alone does not account for all the variance in expression (other regulators, copy-number changes, and mutations also contribute).

Note: these are Spearman rank correlations from array-based data, not a controlled statistical test with a p-value — treat the direction and magnitude as descriptive of this dataset rather than a formal hypothesis test result.

[View the BRCA1 methylation vs. mRNA scatter plot](https://www.cbioportal.org/results/plots?cancer_study_list=ov_tcga&gene_list=BRCA1&case_set_id=ov_tcga_all&plots_horz_selection=%7B%22selectedGeneOption%22%3A%22672%22%2C%22dataType%22%3A%22molecular_data%22%2C%22selectedDataSourceOption%22%3A%22ov_tcga_methylation_hm27%22%7D&plots_vert_selection=%7B%22selectedGeneOption%22%3A%22672%22%2C%22dataType%22%3A%22molecular_data%22%2C%22selectedDataSourceOption%22%3A%22ov_tcga_rna_seq_v2_mrna%22%7D) — this renders the actual per-sample scatter with a fitted correlation line so you can inspect the distribution directly.

(Note: the newer TCGA PanCancer Atlas ovarian study does not carry methylation data in this database, which is why the older Firehose Legacy cohort was used instead.)