ZIA BC 004517 (ZIA) | |||
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Title | DNA Repair in Human Cancer-Prone Genetic Diseases | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Kraemer, Kenneth | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $1,141,540 | Project Dates | null - null |
Fiscal Year | 2018 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Aging (15.0%) Cancer (100.0%) Cancer Survivorship (25.0%) Chemoprevention (30.0%) Genetic Testing (50.0%) Childhood Cancers (50.0%) |
Brain (14.0%) Central Nervous System - Not Including Brain (4.0%) Eye (20.0%) Melanoma (40.0%) Nervous System (23.0%) |
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Research Type | |||
Interactions of Genes and/or Genetic Polymorphisms with Exogenous and/or Endogenous Factors Interventions to Prevent Cancer: Personal Behaviors (Non-Dietary) that Affect Cancer Risk |
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Abstract | |||
1. XERODERMA PIGMENTOSUM We have been examining XP patients at NIH since 1971. We performed long term follow-up studies of cancer, of hearing loss and of eye abnormalities in XP patients. We found that the XP patients under age 20 years had a 10,000-fold increased risk of non-melanoma skin cancer (NMSK) and a 2000-fold increased risk of melanoma. In our natural history protocol we ascertained and intensively examined 105 XP or Cockayne Syndrome (CS) patients and 206 family members at NIH and are collaborating with international researchers to study additional patients. We published detailed autopsy reports of 4 XP patients - including the first autopsy of an XP-D patient. The XP-A and XP-D patients were adults with severe neurological degeneration and were found to have infant sized brains. We have now identified mutations in all of the 9 currently known DNA nucleotide excision repair (NER) genes (XPA, XPB, XPC, XPD, XPE, XPF, XPG, ERCC1 and TTDA), in the error-prone polymerase, pol eta and in TTDN1 in nearly 200 XP or TTD patients. We have established several hundred carefully documented cell lines and contributed them to cell banks for use of the general scientific community. We are using array comparative genome hybridization (aCGH) and whole exome sequencing to look for mutations in other genes in cells from XP and TTD patients who do not have mutations in these genes. Our laboratory is the major center in the US for basic, clinical and translational expertise concerning DNA repair related disorders. We are actively seeking and have developed the expertise to recognize unusual patients who have unique disease features that provide insights into the functioning of DNA repair genes. These studies have enabled us to identify some remarkable XP patients and better characterize different mechanisms of DNA repair. For example, we found XPC patients with splice lariat branch point mutations who had 3 to 5% of XPC mRNA but mild disease indicating that only a small amount of XPC is sufficient for some cancer protection. We found that NER proteins accumulate and persist at sites of DNA damage in XP-B cells. In contrast, these NER proteins rapidly accumulate but fail to persist in UV damaged XP-E cells. We found that the melanomas and nevi in the XP patients were different from those in the general population both clinically and histologically. They had a high proportion of mutations in the PTEN tumor suppressor gene (90% UV type), a lower frequency of mutations in BRAF, NRAS or KIT and rarely had the BRAF V600E mutation found in the general population. We plan to develop a protocol to attempt to reduce the melanoma risk in the XP patients by inhibition of the PTEN, mTOR pathway. About 12% of genetic diseases involve premature stop codons (PTC). We developed sensitive assay systems to detect readthrough of premature stop codons using cells from our collection with PTC in the XPC DNA repair gene. We found the aminoglycoside, gentamycin, can improve DNA repair in selected patients, permitting precise targeting of therapy to responsive individual cell lines. We are performing pre-clinical tests to determine if topical aminoglycosides can increase DNA repair without systemic toxicity. We are collaborating with NCI epidemiologists to study clinically normal family members of XP patients to determine if XP heterozygotes, who are much more frequent than XP patients, have increased cancer risk. We have 257 XP patients and family members in 54 families enrolled in this protocol. 2. TRICHOTHIODYSTROPHY In contrast to the profound environmental influence of sun exposure on XP, TTD is a disease of altered development. In our current natural history protocol we have ascertained and intensively examined 58 TTD or XP/TTD patients and 116 TTD family members. This is the largest cohort of patients with this rare disorder in the world.We found that TTD patients with mutations in the TTDN1 gene had a distinct phenotype. In collaboration with gynecologi |