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DNA Repair Pathways in Clinical Practice: Lessons From Pediatric Cancer Susceptibility Syndromes

Richard D. Kennedy, Alan D. D'Andrea

From the Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA

Address reprint requests to Alan D. D'Andrea, MD, Dana-Farber Cancer Institute, Department of Radiation Oncology, Harvard Medical School, 44 Binney St, Boston, MA 02115; e-mail: alan_dandrea{at}dfci.harvard.edu

Human cancers exhibit genomic instability and an increased mutation rate due to underlying defects in DNA repair. Cancer cells are often defective in one of six major DNA repair pathways, namely: mismatch repair, base excision repair, nucleotide excision repair, homologous recombination, nonhomologous endjoining and translesion synthesis. The specific DNA repair pathway affected is predictive of the kinds of mutations, the tumor drug sensitivity, and the treatment outcome. The study of rare inherited DNA repair disorders, such as Fanconi anemia, has yielded new insights to drug sensitivity and treatment of sporadic cancers, such as breast or ovarian epithelial tumors, in the general population. The Fanconi anemia pathway is an example of how DNA repair pathways can be deregulated in cancer cells and how biomarkers of the integrity of these pathways could be useful as a guide to cancer management and may be used in the development of novel therapeutic agents.

Supported by a grant from the Susan G. Komen Breast Cancer Foundation (R.K.) and by National Institutes of Health Grants No. RO1HL52725, RO1 DK43889, P0150654, P50 CA105009-01, and PO1HL54785 (A.D.).

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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