Whole–genome characterization of chemoresistant ovarian cancer

Abstract

Patients with high-grade serous ovarian cancer (HGSC) have experienced little improvement in overall survival, and standard treatment has not advanced beyond platinum-based combination chemotherapy, during the past 30 years. To understand the drivers of clinical phenotypes better, here we use whole-genome sequencing of tumour and germline DNA samples from 92 patients with primary refractory, resistant, sensitive and matched acquired resistant disease. We show that gene breakage commonly inactivates the tumour suppressors RB1, NF1, RAD51B and PTEN in HGSC, and contributes to acquired chemotherapy resistance. CCNE1 amplification was common in primary resistant and refractory disease. We observed several molecular events associated with acquired resistance, including multiple independent reversions of germline BRCA1 or BRCA2 mutations in individual patients, loss of BRCA1 promoter methylation, an alteration in molecular subtype, and recurrent promoter fusion associated with overexpression of the drug efflux pump MDR1.

Long Noncoding RNAs CUPID1 and CUPID2 Mediate Breast Cancer Risk at 11q13 by Modulating the Response to DNA Damage

“…Somatic structural variants (SVs) were identified with the qsv tool, and for genomes with >200 SV events, distinct patterns or clusters of breakpoint distributions were determined as described previously. [19][20][21] For the characterization of genomic breakpoint distributions, chromosomes bearing a significantly clustered distribution of breakpoints (as described in Korbel and Campbell 22 ; goodness-of-fit threshold p < 0.00001) and those containing outlying high numbers of rearrangement events were identified (outliers had a breakpoint-per-megabase rate exceeding 5 times the length of the inter-quartile range from the 75 th percentile for each sample with a minimum threshold of 30 breakpoints per chromosome). Genomes with fewer than 8 chromosomes with significantly clustered breakpoints and at least 1 containing an extreme outlying density of breakpoints were classified as containing focal rearrangement events.…”

Genetic and epigenetic heterogeneity of epithelial ovarian cancer and the clinical implications for molecular targeted therapy

“…TP53 mutations are almost invariably present in HGSOC 15, 18, 20 (Table 1). The early loss of P53 function observed in sporadic cancers could create a permissive environment for the loss of BRCA1 or BRCA2 function (or other phenotypes of DNA repair deficiency), which would otherwise lead to apoptosis because of checkpoint activation 29.…”

“…BRCA2 can also be down‐regulated through silencing of its upstream regulator, FANCF, by promoter methylation 69, 70. Although patients with BRCA1/2 mutations and low protein/mRNA expression of BRCA1 tend to show a favourable response to treatment20 and a better outcome 40, BRCA1 promoter methylation is significantly correlated with resistance to treatment 20 and a poorer prognosis 68 in patients with EOC. Thus, methylation is not functionally equivalent to a germline mutation in mediating chemotherapy sensitivity.…”

Identification of novel cyclin gene fusion transcripts in endometrioid ovarian carcinomas

“…Though the fusions ESSRA‐C11orf20 ,16 CDKN2D‐WDFY2 14 and BCAM‐AKT2 17 were initially described as recurrent in HGSC at rates of 15%, 20% and 7%, respectively, the findings have not been validated by other groups or in different series 18. More than 700 samples were screened in other studies and fusion transcripts were found at frequencies ranging from 0.5% ( KAT6B‐ADK ) to 2.7% ( CRHR1‐KANSL1 ) 4, 5, 6, 7. It is worthy of note in the context that most studies focused on HGSC, whereas the other four types of ovarian carcinoma were less often investigated; only 63 endometrioid carcinomas, 36 clear cell carcinomas, and six mucinous carcinomas had been analyzed for fusion genes prior to this study 7, 16.…”

“…Two studies used the genomic data produced by the Cancer Genome Atlas project4, 5 to find that three fusion transcripts were recurrent in HGSC carcinomas: CCDC6‐ANK3 (found in 4 samples or 1% of the tumors), and COL14A1‐DEPTOR and KAT6B‐ADK (each found in 2 samples or 0.5%). Patch et al 6. analyzed 114 samples from chemoresistant HGSC and found promoter swapping affecting the SLC25A40‐ABCB1 transcript in six samples (5%).…”