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.”
1. True or false: Defects in genes involved in genomic stability or DNA repair are common in hereditary cancer syndromes.
2. DNA mismatch repair targets which lesions?
3. Lynch syndrome is associated with enhanced risk for which of the following malignancies?
4. How common are BRCA1 and BRCA2 mutations in the general population?
5. Microsatellite instability (MSI) is a feature of which malignancies?
A All colon cancers in Lynch syndrome
C Endometrial cancers in Lynch syndrome
6. Breast cancers that arise in BRCA1 mutation carriers are specifically sensitive to which therapies?
1. Answer: True. Inherited germline mutations in genes such as the DNA strand break repair genes BRCA1 and BRCA2 and the mismatch repair genes MLH1, MSH2, and MSH6 constitute a majority of hereditary cancer syndrome cases (breast-ovarian cancer syndrome and Lynch syndrome). Loss of heterozygosity mutations in these genes may lead to a mutator phenotype, resulting in additional cancer-causing mutations and an accelerated rate of tumorigenesis in multiple tissues in the carrier.
2. Answer: D. DNA mismatch repair proteins function as heterodimers to recognize and excise DNA replication errors that occur during normal cell division. Unlike other mechanisms for DNA repair, they do not actually sense a “damaged” base but rather an incorrectly paired base. However, through mechanisms that are still unclear, they are able to determine which of the two mismatched base pairs resides in the newly replicated DNA strand and thus is incorrect and needs replacement.
3. Answer: D. Lynch syndrome–associated malignancies include primarily colorectal and endometrial cancers, as well as stomach, ovarian, genitourinary tract, skin, and brain tumors. Cervical cancers have not been associated with Lynch syndrome.
4. Answer: B. Population-based estimates for BRCA1/2 carriage rates are 1 in 400 in most Western countries. Within the Ashkenazi Jewish population, mutation rates for the three founder BRCA1/2 mutations are 1 in 40.
5. Answer: E. MSI has been identified in colorectal and endometrial cancers associated with and diagnostic of Lynch syndrome. About half of breast cancers identified within Lynch syndrome families also exhibit MSI, unlike sporadic breast cancers.
6. Answer: E. The DNA repair defects conferred by BRCA1/2 mutations in breast cancers lead to enhanced sensitivity to DNA-damaging agents such as cisplatin but not to other classes of chemotherapeutic drugs such as taxanes. Base excision repair–inhibiting drugs such as PARP inhibitors exhibit synthetic lethality with BRCA1/2 mutations and are selectively toxic to these tumors.
7. Answer: D. MSI is present in about 20% of all colorectal cancers and is a good prognostic marker independent of stage and grade, although it is a poor predictive marker for response to 5-fluorouracil–based chemotherapies.
