Figure 6.

Integrative analyses

(A–D) BRCA1 (A) and RAD51C (B) HRDetect scores (left) and expression values (right) for breast and ovarian samples with or without promoter methylation in BRCA1 or RAD51C. Samples with deleterious alterations in five key HR genes (BRCA1, BRCA2, ATM, PALB2, and RAD51C) are colored orange (somatic) and green (germline and somatic). Haplotype-specific DNA methylation frequencies at the BRCA1/NBR2 (C) and RAD51C (D) promoter regions in HRD samples (HRDetect score ≥ 0.7) with promoter methylation. Germline refers to a matched blood sample from the same individual.

(E) Haplotype-specific DNA methylation at the MLH1 promoter in a lung squamous cell carcinoma sample with MLH1 germline epimutation.

(F) Haplotype-specific DNA methylation frequencies at the MLH1 promoter region in a lung squamous cell carcinoma sample with MLH1 germline epimutation (top) and in a uterine endometrioid carcinoma sample with somatic MLH1 promoter methylation (bottom).

(G) Haplotype-specific methylation and copy number for NRG1 in breast cancer sample POG816. The 3′ amplification was included within an ecDNA. Promoter aDMRs are highlighted in yellow.

(H) Haplotype-phased long reads mapped to the ecDNA region.

(I) Circos plot of the NRG1-containing ecDNA, highlighting DMRs and methylation states. Inner track: gene annotations, with NRG1 highlighted. Outer tracks: binned counts of aDMRs, showing substantial enrichment at the 5′ end of NRG1.