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Fam Cancer. 2016 Jul;15(3):359-66. doi: 10.1007/s10689-016-9883-7.

Hereditary cancer syndromes: utilizing DNA repair deficiency as therapeutic target.

Author information

1
Department of Internal Medicine, CHI Health Creighton University Medical Center, Omaha, NE, USA.
2
Class of 2017, Creighton University School of Medicine, Omaha, NE, USA.
3
Division of Hematology/Oncology, CHI Health Creighton University Medical Center and VA Nebraska-Western Iowa Health Care System, Omaha, NE, USA. PeterSilberstein@creighton.edu.

Abstract

Human cells have numerous repair mechanisms to counteract various insults incurred on the DNA. Any mutation in these repair mechanisms can lead to accumulation of DNA errors and carcinogenesis. This review aims to discuss the therapeutic options in the two most common DNA repair deficient cancer syndromes, namely Lynch syndrome (hereditary non-polyposis colorectal cancer) and breast cancer susceptibility gene (BRCA) associated ovarian and breast cancer. Deficiency in DNA repair mechanisms renders these tumors with increased sensitivity to platinum agents. There has been increasing amount of information on the utility of the defects in DNA repair as targets for cancer therapy in these syndromes. Novel therapies like poly (ADP-ribose) polymerase (PARP) inhibitors are one of such example where the induction of double stranded breaks in DNA leads to tumoricidal effect in patients with homologous DNA repair deficiency. Interestingly, patients with DNA repair deficiencies tend to have a more favorable prognosis than sporadic malignancies. In microsatellite high colorectal cancer patients, this has been attributed to increased recruitment of CD8+ T lymphocytes in tumor microenvironment. However, these tumors are able to limit the host immune response by activation of immune checkpoints that seem like attractive targets of therapy in the future.

KEYWORDS:

BRCA; DNA repair; Hereditary cancer; Lynch syndrome; Microsatellite high; PARP

PMID:
26873719
PMCID:
PMC4901091
DOI:
10.1007/s10689-016-9883-7
[Indexed for MEDLINE]
Free PMC Article

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