DNA Damage Response Pathways and Cancer

Published on 04/03/2015 by admin

Filed under Hematology, Oncology and Palliative Medicine

Last modified 04/03/2015

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Chapter 10

DNA Damage Response Pathways and Cancer

Summary of Key Points

• DNA repair and the cellular response to DNA damage are critical for maintaining genomic stability.

• Defects in DNA repair or the response to DNA damage encountered from endogenous or external sources results in an increased rate of genetic mutations, often leading to the development of cancer.

• Inherited mutations in DNA damage response pathway genes often result in cancer susceptibility.

• The major active pathways for DNA repair in humans are nucleotide excision repair, base excision repair, mismatch DNA repair, translesional DNA synthesis, and homologous recombination or nonhomologous end joining processes for double-strand break repair.

• Inherited defects in nucleotide excision repair lead to the skin cancer–prone syndrome xeroderma pigmentosum, as well as Cockayne syndrome and trichothiodystrophy.

• Inherited defects in base excision repair can result in colorectal cancer susceptibility.

• Inherited defects in mismatch repair result in Lynch syndrome (hereditary nonpolyposis colorectal cancer syndrome), leading to increased incidence of gastrointestinal cancers, endometrial cancer, and other malignancies.

• Inherited defects in DNA double-strand break repair and response pathways underlie a number of cancer prone disorders, including ataxia-telangiectasia, Nijmegen breakage syndrome, Bloom syndrome, Werner syndrome, Rothmund-Thomson syndrome, and Fanconi anemia.

• Persons with Li-Fraumeni syndrome, who are highly prone to cancer because of inherited p53 mutations, and persons with breast-ovarian cancer syndrome, who are highly prone to cancer because of inherited mutations of the BRCA1 and BRCA2 genes, exhibit defects in multiple DNA repair and DNA damage response pathways.

• Because most cancer therapeutic agents that are currently used damage DNA, understanding how normal cells and tumor cells respond to and repair DNA damage is an important aspect of understanding cancer therapeutic responses and toxicities of treatment.

• The presence of mutations in DNA damage response and repair pathways in tumors present opportunities for developing therapeutics that target alternative damage response pathways and can be selectively lethal to the mutated tumor cells, an approach called “synthetic lethality.”