The BRCAness Landscape of Cancer

Abstract

BRCAness refers to the damaged homologous recombination (HR) function due to the defects in HR-involved non-BRCA1/2 genes. BRCAness is the important marker for the use of synthetic lethal-based PARP inhibitor therapy in breast and ovarian cancer treatment. The success provides an opportunity of applying PARP inhibitor therapy to treat other cancer types with BRCAness features. However, systematic knowledge is lack for BRCAness in different cancer types beyond breast and ovarian cancer. We performed a comprehensive characterization for 40 BRCAness-related genes in 33 cancer types with over 10,000 cancer cases, including pathogenic variation, homozygotic deletion, promoter hypermethylation, gene expression, and clinical correlation of BRCAness in each cancer type. Using BRCA1/BRCA2 mutated breast and ovarian cancer as the control, we observed that BRCAness is widely present in multiple cancer types. Based on the sum of the BRCAneass features in each cancer type, we identified the following 21 cancer types as the potential targets for PARPi therapy: adrenocortical carcinoma, bladder urothelial carcinoma, brain lower grade glioma, colon adenocarcinoma, esophageal carcinoma, head and neck squamous carcinoma, kidney chromophobe, kidney renal clear cell carcinoma, kidney renal papillary cell carcinoma, liver hepatocellular carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, mesothelioma, rectum adenocarcinoma, pancreatic adenocarcinoma, prostate adenocarcinoma, sarcoma, skin cutaneous melanoma, stomach adenocarcinoma, uterine carcinosarcoma, and uterine corpus endometrial carcinoma.

Keywords: BRCA1/2; BRCAness; PARP inhibitors; genetic defects; synthetic lethal.

Figure 1

Scheme of the analysis. (A) Functional enrichment analysis for BRCAness genes. It shows the barplot for the top 30 significant GO functional enriched biological processes (BPs), and KEGG pathways. (B) The number of patients included each cancer type.

Figure 2

Distribution of pathogenic variation of BRCAness genes in different cancer types. Left part shows the distribution of somatic and right part shows the germline pathogenic variants in BRCAness genes and cancer types. BRCA1 and BRCA2 in red show their corresponding distribution for comparison with BRCAness genes. Abbreviations: ACC, adrenocortical carcinoma; BLCA, bladder urothelial carcinoma; BRCA, breast invasive carcinoma; CESC, cervical squamous cell carcinoma and endocervical adenocarcinoma; CHOL, cholangiocarcinoma; COAD, colon adenocarcinoma; DLBC, lymphoid neoplasm diffuse large B-cell lymphoma; ESCA, esophageal carcinoma; GBM, glioblastoma multiforme; HNSC, head and neck squamous carcinoma; KICH, kidney chromophobe; KIRC, kidney renal clear cell carcinoma; KIRP, kidney renal papillary cell carcinoma; LAML, acute myeloid leukemia; LGG, brain lower grade glioma; LIHC, liver hepatocellular carcinoma; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; MESO, mesothelioma; OV, ovarian serous cystadenocarcinoma; PAAD, pancreatic adenocarcinoma; PCPG, pheochromocytoma and paraganglioma; PRAD, prostate adenocarcinoma; READ, rectum adenocarcinoma; SARC, sarcoma; SKCM, skin cutaneous melanoma; STAD, stomach adenocarcinoma; TGCT, testicular germ cell tumors; THCA, thyroid carcinoma; THYM, thymoma; UCEC, uterine corpus endometrial carcinoma; UCS, uterine carcinosarcoma; UVM, uveal melanoma.

Figure 3

Correlation of pathogenic variation of BRCAness genes across 33 cancer types. (A,B) Significant correlation for the frequencies of somatic and germline pathogenic variants between individual BRCAness gene and BRCA1. (C,D). Significant correlation for the frequencies of somatic and germline pathogenic variants between individual BRCAness gene and BRCA2. The pairs with p-value < 0.05 were regarded as significant. The pairs with an absolute coefficient > 0.5 were regarded as significantly correlated.

Figure 4

Homozygotic deletions of BRCAness genes in different cancer types. (A) The frequency of homozygotic deletion in each BRCAness gene across 33 cancer types (left) and in all cancer types (right). In the inset on right, we displayed gene list falling into each classification. For example, the genes list (FANCD2, BARD1, FANCC, BRCA1, RAD52, RAD51D, CDK12, PARP1, WEE1) in the blue region represent these genes have higher homozygotic variation frequency than BRCA1 in 5 to 10 cancer types. (B,C) The significance of the homozygotic frequencies between each BRCAness gene and BRCA1/2. The pairs with a p-value < 0.05 were regarded as significant. (D,E) The correlation of homozygotic frequencies between BRCAness genes and BRCA1/2. The pairs with an absolute coefficient > 0.4 were regarded as significantly correlated.

Figure 5

Methylation and transcriptional regulation of BRCAness genes. (A) Promoter methylation of BRCAness genes across 33 cancer types. It showed the mean beta value of all promoter methylation sites. Red: hypermethylated genes; blue: hypomethylated genes. By using BRCA2 as the cutoff, 18 BRCAness genes were hypermethylated and 24 were hypomethylated. (B) Altered expression of BRCAness genes in 19 cancer types with available expression data from normal controls. Red: up-regulated genes; blue: down-regulated genes. (C) Cancer type-specific silencing effects of promoter methylation in BRCAness genes. It showed that promoter methylation silenced the expression in the majority of BRCAness genes, except the enhanced expression in 13 BRCAness genes, and the silencing effects were highly cancer type specific. Blue: silencing; red: enhancing. Pearson’s correlation coefficient > 0.5 represents significant associations.

Figure 6

Clinical relevance of BRCAness genes across cancer types. (A) Correlation between expression of BRCAness genes and patient survival. OR, odds ratio; CI: confidence interval; Red p-values represents a higher expression of BRCAness genes associated with worse survival, and blue p-values represents an association with better survival. Only p values < 0.05 are shown. (B) Distribution of hazard ratios across different cancer types in AURKA and PTEN. Red: the cancer types for those the expression levels of AURKA or PTEN are risky factors; Blue: the cancer types for those the expression levels of PTEN are protective factors. (C) Heatmap showing the clustered expression of all BRCAness genes in KIRC cancer patients. Red, higher levels of gene expression; Green, lower levels of gene expression. (D) Kaplan–Meier survival plot of KIRC patients grouped by the altered expression patterns of BRCAness genes.