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Genomic instability in breast and ovarian cancers: translation into clinical predictive biomarkers

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Abstract

Breast and ovarian cancer are among the most common malignancies diagnosed in women worldwide. Together, they account for the majority of cancer-related deaths in women. These cancer types share a number of features, including their association with hereditary cancer syndromes caused by heterozygous germline mutations in BRCA1 or BRCA2. BRCA-associated breast and ovarian cancers are hallmarked by genomic instability and high sensitivity to DNA double-strand break (DSB) inducing agents due to loss of error-free DSB repair via homologous recombination (HR). Recently, poly(ADP-ribose) polymerase inhibitors, a new class of drugs that selectively target HR-deficient tumor cells, have been shown to be highly active in BRCA-associated breast and ovarian cancers. This finding has renewed interest in hallmarks of HR deficiency and the use of other DSB-inducing agents, such as platinum salts or bifunctional alkylators, in breast and ovarian cancer patients. In this review we discuss the similarities between breast and ovarian cancer, the hallmarks of genomic instability in BRCA-mutated and BRCA-like breast and ovarian cancers, and the efforts to search for predictive markers of HR deficiency in order to individualize therapy in breast and ovarian cancer.

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Abbreviations

8-OHdG:

8-Hydroxy-2′-deoxyguanosine

aCGH:

Array comparative genomic hybridization

AC:

Adriamycin–cyclophosphamide

AR:

Androgen receptor

AT:

Doxorubicin–docetaxel

BCSS:

Breast cancer-specific survival

BER:

Base excision repair

BLBC:

Basal-like breast cancer

CIN:

Chromosomal instability

CK:

Cytokeratin

CNA:

Copy number aberration

CS:

Cockayne syndrome

CMF:

Cyclophosphamide–methotrexate–5-fluorouracil

DFS:

Disease-free survival

DSB:

Double-strand break

E2:

Estrogen

ERE:

Estrogen responsive element

ER:

Estrogen receptor

FA:

Fanconi anemia

FAC:

5-Fluorouracil–adriamycin–cyclophosphamide

FEC:

5-Fluorouracil–epirubicin–cyclophosphamide

FFPE:

Formalin-fixed paraffin-embedded

HER2:

Human epidermal growth factor receptor-2

HR:

Homologous recombination

HRT:

Hormone replacement therapy

IHC:

Immunohistochemistry

ILC:

Invasive lobular carcinoma

LBD:

Ligand binding domain

MMR:

Mismatch repair

MRN-complex:

MRE11–RAD50–NBS1 complex

NER:

Nucleotide excision repair

NHEJ:

Non-homologous end joining

PARP:

Poly(ADP-ribose) polymerase

PARPi:

PARP inhibitors

pCR:

Pathological complete remission

PFS:

Progression-free survival

PgR:

Progesterone receptor

PRE:

Progesterone binding element

OS:

Overall survival

RCT:

Randomized controlled trial

RFS:

Recurrence-free survival

SSB:

Single-strand break

TTD:

Trichothiodystrophy

TN:

Triple-negative

XP:

Xeroderma pigmentosum

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Acknowledgments

The work in the Linn lab was financially supported by grants from the Dutch Cancer Society (grant NKI 2006-3706) and A Sister’s Hope/Pink Ribbon. Work in the Jonkers lab was supported by the Dutch Cancer Society (grants NKI 2007-3772 and NKI 2008-4116), the Netherlands Organization for Scientific Research (Cancer Systems Biology Center grant and Horizon Breakthrough grant 40-41009-98-9109), CTMM (BreastCare project), TI Pharma (Kinases in Cancer project), and the European Commission project EuroSyStem.

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  1. Division of Molecular Biology, Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

    Marieke A. Vollebergh, Jos Jonkers & Sabine C. Linn

  2. Division of Medical Oncology, Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands

    Marieke A. Vollebergh & Sabine C. Linn

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  1. Marieke A. Vollebergh
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Correspondence to Jos Jonkers or Sabine C. Linn.

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Vollebergh, M.A., Jonkers, J. & Linn, S.C. Genomic instability in breast and ovarian cancers: translation into clinical predictive biomarkers. Cell. Mol. Life Sci. 69, 223–245 (2012). https://doi.org/10.1007/s00018-011-0809-0

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