epialleleR: an R/Bioconductor package for sensitive allele-specific methylation analysis in NGS data

Nikolaienko, Oleksii; Lønning, Per Eystein; Knappskog, Stian

doi:10.1093/gigascience/giad087

Cited by 2 publications

(1 citation statement)

References 43 publications

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“…Targeted DNA sequencing was performed on pretreatment tumor biopsies using a 360-gene panel, 18 as a preplanned analysis per protocol. 9 BRCA1 promoter methylation analysis was performed applying an amplicon-based next-generation sequencing assay as described previously [19][20][21] (see the Data Supplement, Supplementary Methods). BRCA1 promoter methylation was combined with HRR mutations to evaluate the prevalence of HRD by either wide (HRD-W) or strict definitions (HRD-S).…”

Section: Hrr Mutations Brca1 Methylation and Brcaness Analysesmentioning

confidence: 99%

Homologous Recombination Deficiency Across Subtypes of Primary Breast Cancer

Yndestad,

Engebrethsen,

Herencia-Ropero

et al. 2023

JCO Precis Oncol

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PURPOSE Homologous recombination deficiency (HRD) is highly prevalent in triple-negative breast cancer (TNBC) and associated with response to PARP inhibition (PARPi). Here, we studied the prevalence of HRD in non-TNBC to assess the potential for PARPi in a wider group of patients with breast cancer. METHODS HRD status was established using targeted gene panel sequencing (360 genes) and BRCA1 methylation analysis of pretreatment biopsies from 201 patients with primary breast cancer in the phase II PETREMAC trial (ClinicalTrials.gov identifier: NCT02624973 ). HRD was defined as mutations in BRCA1, BRCA2, BRIP1, BARD1, or PALB2 and/or promoter methylation of BRCA1 (strict definition; HRD-S). In secondary analyses, a wider definition (HRD-W) was used, examining mutations in 20 additional genes. Furthermore, tumor BRCAness (multiplex ligation-dependent probe amplification), PAM50 subtyping, RAD51 nuclear foci to test functional HRD, tumor-infiltrating lymphocyte (TIL), and PD-L1 analyses were performed. RESULTS HRD-S was present in 5% of non-TNBC cases (n = 9 of 169), contrasting 47% of the TNBC tumors (n = 15 of 32). HRD-W was observed in 23% of non-TNBC (n = 39 of 169) and 59% of TNBC cases (n = 19 of 32). Of 58 non-TNBC and 30 TNBC biopsies examined for RAD51 foci, 4 of 4 (100%) non-TNBC and 13 of 14 (93%) TNBC cases classified as HRD-S had RAD51 low scores. In contrast, 4 of 17 (24%) non-TNBC and 15 of 19 (79%) TNBC biopsies classified as HRD-W exhibited RAD51 low scores. Of nine non-TNBC tumors with HRD-S status, only one had a basal-like PAM50 signature. There was a high concordance between HRD-S and either BRCAness, high TIL density, or high PD-L1 expression (each P < .001). CONCLUSION The prevalence of HRD in non-TNBC suggests that therapy targeting HRD should be evaluated in a wider breast cancer patient population. Strict HRD criteria should be implemented to increase diagnostic precision with respect to functional HRD.

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Section: Hrr Mutations Brca1 Methylation and Brcaness Analysesmentioning

confidence: 99%

Homologous Recombination Deficiency Across Subtypes of Primary Breast Cancer

Yndestad,

Engebrethsen,

Herencia-Ropero

et al. 2023

JCO Precis Oncol

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Constitutional BRCA1 Epimutations: A Key for Understanding Basal‐Like Breast and High‐Grade Serous Ovarian Cancer

Lønning,

Nikolaienko,

Knappskog

2024

Human Mutation

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Germline pathogenic genetic variants in the BRCA1 and BRCA2 genes are the most frequent causes of familial breast and ovarian cancer. Contrasting BRCA2, epimutations in the BRCA1 gene are frequently detected in tissue from triple‐negative breast (TNBC) and high‐grade serous ovarian cancers (HGSOC). While studies over the last decade have reported BRCA1 epimutations in white blood cells (WBC) from breast and ovarian cancer patients, the potential hazard ratio for incident TNBC and HGSOC was not formally assessed until recently.Conducting a prospective nested case‐control study on women participating in the American Women’s Health Initiative Study, we provided firm evidence that mosaic WBC BRCA1 epimutations, even at allele frequencies < 0.1%, are associated with a significantly increased risk of both incident HGSOC and TNBC > 5 years after WBC collection. In a second study assessing BRCA1 epimutations in WBC and matched tumor samples from TNBC, our results indicated such epimutations to be the underlying cause of around 20% of TNBC, far exceeding the percentage of cases carrying BRCA1 germline pathogenic genetic variants.We detected primary constitutional BRCA1 epimutations in tissues derived from all three germ layers. They occur independently of BRCA1 promoter haplotypes but are present on the same allele in all WBC within affected individuals. Moreover, epimutations are consistently found on the same allele in normal and tumor breast tissue as well as in WBC. This finding, together with BRCA1 epimutations detected in WBC from newborns, strongly indicates an early embryonic event with clonal expansion affecting all germ layers.Future work in the field must lead to an understanding of exactly when and how the BRCA1 epimutations occur and, most importantly, whether primary constitutional epimutations in genes other than BRCA1 may cause an elevated risk of other cancer types.

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epialleleR: an R/Bioconductor package for sensitive allele-specific methylation analysis in NGS data

Cited by 2 publications

References 43 publications

Homologous Recombination Deficiency Across Subtypes of Primary Breast Cancer

Homologous Recombination Deficiency Across Subtypes of Primary Breast Cancer

Constitutional BRCA1 Epimutations: A Key for Understanding Basal‐Like Breast and High‐Grade Serous Ovarian Cancer

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