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BRCA1 promoter hypermethylation on circulating tumor DNA correlates with improved survival of patients with ovarian cancer.

ABSTRACT: Methylation of the BRCA1 promoter is an epigenetic gene expression regulator and is frequently observed in ovarian cancer; however, conversion of methylation status is thought to drive disease recurrence. Therefore, longitudinal monitoring of methylation status by liquid biopsy in cell-free DNA may be a predictive marker. In total, 135 plasma samples were collected from 69 ovarian cancer patients before and during systemic treatment. Our liquid biopsy assay could detect down to a single molecule of methylated DNA in a high background of normal DNA (0.03%) with perfect specificity in control samples. We found that 60% of the cancer patients exhibited BRCA1 promoter hypermethylation at one point, although 24% lost hypermethylation during treatment. Multivariate survival analyses indicate that relapses are independent events and that hypermethylation and methylation conversion are independently correlated to longer relapse-free survival. We present a highly sensitive and specific methylation-specific quantitative PCR-based liquid biopsy assay. BRCA1 promoter hypermethylation is frequently found in ovarian cancer and is often reversed upon recurrence, indicating the selection of therapy-resistant clones and unfavorable clinical outcome.

SUBMITTER: Elazezy M

PROVIDER: S-EPMC8637552 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundOncology applications of cell-free DNA analysis are often limited by the amount of circulating tumor DNA and the fraction of cell-free DNA derived from tumor cells in a blood sample. This circulating tumor fraction varies widely between individuals and cancer types. Clinical factors that influence tumor fraction have not been completely elucidated.Methods and findingsCirculating tumor fraction was determined for breast, lung, and colorectal cancer participant samples in the first substudy of the Circulating Cell-free Genome Atlas study (CCGA; NCT02889978; multi-cancer early detection test development) and was related to tumor and patient characteristics. Linear models were created to determine the influence of tumor size combined with mitotic or metabolic activity (as tumor mitotic volume or excessive lesion glycolysis, respectively), histologic type, histologic grade, and lymph node status on tumor fraction. For breast and lung cancer, tumor mitotic volume and excessive lesion glycolysis (primary lesion volume scaled by percentage positive for Ki-67 or PET standardized uptake value minus 1.0, respectively) were the only statistically significant covariates. For colorectal cancer, the surface area of tumors invading beyond the subserosa was the only significant covariate. The models were validated with cases from the second CCGA substudy and show that these clinical correlates of circulating tumor fraction can predict and explain the performance of a multi-cancer early detection test.ConclusionsPrognostic clinical variables, including mitotic or metabolic activity and depth of invasion, were identified as correlates of circulating tumor DNA by linear models that relate clinical covariates to tumor fraction. The identified correlates indicate that faster growing tumors have higher tumor fractions. Early cancer detection from assays that analyze cell-free DNA is determined by circulating tumor fraction. Results support that early detection is particularly sensitive for faster growing, aggressive tumors with high mortality, many of which have no available screening today.

Project description:BackgroundPoly(adenosine diphosphate-ribose) polymerase 1 (PARP-1) and the balance between BRCA1 and 53BP1 play a key role in the DNA repair and cell stress response. PARP inhibitors show promising clinical activity in metastatic triple negative (TN) or BRCA-mutated breast cancer. However, a comprehensive analysis of PARP-1 activity, BRCA1 promoter methylation and 53BP1 expression in tumours without known BRCA1 mutation has not yet been carried out.MethodsWe investigated cytosolic PARP-1 activity, 53BP1 protein levels and BRCA1 promoter methylation in 155 surgical breast tumour samples from patients without familial breast cancer history or known BRCA1 mutations who were treated between January 2006 and November 2009 and evaluated their statistical association with classical predictive and prognostic factors.ResultsThe mitotic count score was the only parameter clearly associated with PARP-1 activity. BRCA1 promoter hypermethylation (15.4% of all cancers) was significantly associated with uPA and PAI-1 levels, tumour grade, mitotic count score, hormone receptor and HER2 negative status and TN profile (29% of TN tumours showed BRCA1 promoter hypermethylation compared to 5% of grade II-III hormone receptor-positive/HER2-negative and 2% of HER2-positive tumours). No statistical association was found between BRCA1 promoter hypermethylation and PARP-1 activity. High 53BP1 protein levels correlated with lymph node positivity, hormone receptor positivity, molecular grouping, unmethylated BRCA1 promoter and PARP-1 activity. In TN tumours, BRCA1 promoter methylation was only marginally associated with age, PARP-1 activity was not associated with any of the tested clinico-pathological factors and high 53BP1 protein levels were significantly associated with lymph node positivity. Only 3 of the 14 TN tumours with BRCA1 promoter hypermethylation presented high 53BP1 protein levels.ConclusionsBreast cancers that harbour simultaneously high 53BP1 protein level and BRCA1 promoter hypermethylation and are the putative target population of drugs targeting DNA repair appear to be restricted to a small subgroup of TN tumours.

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BRCA1 promoter hypermethylation on circulating tumor DNA correlates with improved survival of patients with ovarian cancer.

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