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    Awarded Grants
    Genetic Basis of DNA Repair Deficiency in Sporadic Breast Cancer

    Scientific Abstract:
    Genomic instability is a hallmark of all cancer, including breast cancer. It has been suggested that early development of genomic instability is necessary for a cell to be able to accumulate all of the genetic alterations required to confer the transformed or tumorigenic phenotype. Using a unique cell culture method developed and patented in our laboratory, we have been able to perform functional analyses of DNA repair directly in breast tumor and normal tissue. We found that all (17/17) sporadic early stage breast tumors analyzed were deficient in nucleotide excision repair (NER), a complex and very generalizable DNA repair pathway that remediates any type of DNA damage that causes a distortion in the DNA double helix. This includes intrastrand lesions caused by UV or mimetic drugs such as cis-Pt, and bulky adducts, such as those caused by adduction of polyaromatic hydrocarbons (PAHs) found in combustion byproducts (smoking, diesel exhaust) and some types of cancer chemotherapy (e.g., AAAF). More recently, we have similarly analyzed samples of the histologically normal tissue from the same breasts as 12 of these tumors. These samples were intended as patient controls, to demonstrate that the observed NER deficiency was intrinsic to the somatic development of the tumor. And, indeed, in 4 cases this “non-tumor adjacent” (NTA) sample had normal levels of NER. In 8 cases, however, representing almost 70% of our matched tumors, the NER capacity of the “normal” tissue was just as low as that of the tumor. This suggests that women who develop “sporadic” breast tumors are far more likely to have been born with a low NER capacity than disease-free women. This effect is likely to have relatively low penetrance, and thus, has not been previously identified as a genetic factor in breast cancer incidence. However, these data suggest that screening for NER capacity could be an important tool for breast cancer risk assessment. Also, since NER plays a role in repairing the types of damage caused by some cancer chemotherapy drugs, knowing the NER capacity of the patient and the tumor may be useful in individually tailoring chemotherapy regimen to individual patients. Since these results have such important implications, we would like to first duplicate our initial observations, and extend them to a more accessible tissue. Thus, we propose to analyze NER capacity in 20 more stage 1 tumors and matching NTA tissue, and to add additional analyses in blood lymphocytes (which would allow for population screening), and in normal tissue from the uninvolved (contralateral) breast (which would be obtained from patients undergoing reconstructive plastic surgery on the uninvolved breast, normally a size reduction, in order to achieve a more symmetrical appearance). If these studies bear out our initial results that most breast cancer patients have low NER to begin with, we will attempt to develop a clinically applicable molecular test (which does not require growing cells or large tissue samples). The molecular test will be dependent on the basis of the low NER in these patients. One possibility is that they carry low activity variants, or polymorphisms, for genes in the NER pathway, and there is already evidence that such variants are involved in the development of other types of tumors. Indeed, clinically important polymorphisms have already been identified in a number of NER genes, and these will be the first we will screen for in our patient population. Another possibility is that haploinsufficiency for genes in the NER pathway could cause a predisposition to breast cancer. 50% reductions in NER activity have been associated with xeroderma pigmentosum, a hereditary disease characterized by sensitivity to UV light and high incidence of skin cancer. Also, it has recently been demonstrated that BRCA2 is the gene responsible for Fanconi anemia type D1, another example of a gene having different but very significant cancer-predisposition effects in both homozygotes and heterozygotes. In either case, we will develop a blood test that will identify women other than BRCA mutation carriers, that are at increased risk of breast cancer, and these data will provide a basis for developing interventional strategies for the prevention of their tumors.

    Lay Abstract:
    To become a tumor, a cell must undergo a number of changes that allow it to ignore both its own programming and signals from the rest of the body to maintain its specific function. These changes are so extensive that one of the most fundamental changes that must occur is the loss of a cell’s normal ability to repair its cellular blueprint, the DNA of the genome. Using a) a unique cell culture method, and b) a functional, rather than molecular assay, we have shown that all (17/17) sporadic early stage breast tumors are deficient in a process called nucleotide excision repair or NER. NER has historically been considered primarily a mechanism for repairing DNA damage caused by exposure to sunlight, but it is actually a complex and very generalizable pathway that repairs any DNA damage that causes a distortion in the DNA double helix, such as the attachment (or adduction) of tobacco smoke carcinogens. More recently, we have managed to culture and analyze histologically normal tissue from the same breasts as 12 of these tumors. We expected that the NER capacity of these samples would all be normal, because they were not involved in the process of tumor development. And, indeed, this was the case for 4 samples. In these cases, it would appear that the loss of NER activity occurred during the development of the tumor, and was restricted to the tumor itself. In 8 cases, however, representing almost 70% of our matched tumors, the NER capacity of the “normal” tissue was just as low as that of the tumor. This suggests that women who develop breast tumors are far more likely to have been born with low NER capacity than women who are more resistant to the development of breast cancer, and that screening for NER capacity could be an important tool for breast cancer risk assessment. Also, since NER plays a role in repairing the types of damage caused by some cancer chemotherapy drugs, knowing the NER capacity of the patient and their tumor may be useful in individually tailoring chemotherapy regimen to individual patients. Since these results have such important implications, we would like to first duplicate our initial observations, and extend them to a more accessible tissue. Thus, we propose to analyze NER capacity in 20 more stage 1 tumors and matching “non-tumor adjacent” tissue, and to add additional analyses in blood lymphocytes (which would allow for population screening), and in normal tissue from the uninvolved (contralateral) breast (which would be obtained from patients undergoing reconstructive plastic surgery on the uninvolved breast, normally a size reduction, in order to achieve a more symmetrical appearance). If these studies bear out our initial results that most breast cancer patients have low NER to begin with, we will attempt to develop a clinically applicable molecular test (which does not require growing cells or large tissue samples). The molecular test will be dependent on the basis of the low NER in these patients. One possibility is that they carry low activity variants, or polymorphisms for genes in the NER pathway, and there is already evidence that such variants are involved in the development of other types of tumors. Another possibility is that a single inactive copy of a gene in the NER pathway could cause a predisposition to breast cancer. This condition, called “haploinsufficiency” is normally not thought to produce a clinically important result, but, since the NER genes are so important (with 50% reductions in activity resulting in hereditary disease under the right circumstances) it is another molecular mechanism we will check for. In either case, we will develop a blood test that will identify women other than BRCA mutation carriers, that are at increased risk of breast cancer, and these data will provide a basis for developing interventional strategies for the prevention of their tumors.