Reduction of setup uncertainties and tumor motion in the radiation therapy of lung tumors

Because the goal of radiation therapy is to deliver a lethal dose to the tumor, accurate information on the location of the tumor needs to be known. Margins are placed around the tumor to account for variations in the daily position of the tumor. If tumor motion and patient setup uncertainties can be reduced, margins that account for such uncertainties in tumor location in can be reduced allowing dose escalation, which in turn could potentially improve survival rates. ^ In the first part of this study, we monitor the location of fiducials implanted in the periphery of lung tumors to determine the extent of non-gated and gated fiducial motion, and to quantify patient setup uncertainties. In the second part we determine where the tumor is when different methods of image-guided patient setup and respiratory gating are employed. In the final part we develop, validate, and implement a technique in which patient setup uncertainties are reduced by aligning patients based upon fiducial locations in projection images. ^ Results from the first part indicate that respiratory gating reduces fiducial motion relative to motion during normal respiration and setup uncertainties when the patients were aligned each day using externally placed skin marks are large. The results from the second part indicate that current margins that account for setup uncertainty and tumor motion result in less than 2% of the tumor outside of the planning target volume (PTV) when the patient is aligned using skin marks. In addition, we found that if respiratory gating is going to be used, it is most effective if used in conjunction with image-guided patient setup. From the third part, we successfully developed, validated, and implemented on a patient a technique for aligning a moving target prior to treatment to reduce the uncertainties in tumor location. ^ In conclusion, setup uncertainties and tumor motion are a significant problem when treating tumors located within the thoracic region. Image-guided patient setup in conjunction with treatment delivery using respiratory gating reduces these uncertainties in tumor locations. In doing so, margins around the tumor used to generate the PTV can be reduced, which may allow for dose escalation to the tumor. ^

Characterization and subchromosomal location of a novel tumor suppressor gene on human chromosome 7

Alterations in oncogenes and tumor suppressor genes (TSGs) are considered to be critical steps in oncogenesis. Consistent deletions and loss of heterozygosity (LOH) of polymorphic markers in a determinate chromosomal fragment are known to be indicative of a closely mapping TSG. Deletion of the long arm of chromosome 7 (hchr 7) is a frequent trait in many kinds of human primary tumors. LOH was studied with an extensive set of markers on chromosome 7q in several types of human neoplasias (primary breast, prostate, colon, ovarian and head and neck carcinomas) to determine the location of a putative TSG. The extent of LOH varied depending the type of tumor studied but all the LOH curves we obtained had a peak at (C-A)$\sb{\rm n}$ microsatellite repeat D7S522 at 7q31.1 and showed a Gaussian distribution. The high incidence of LOH in all tumor types studied suggests that a TSG relevant to the development of epithelial cancers is present on the 7q31.1. To investigate whether the putative TSG is conserved in the syntenic mouse locus, we studied LOH of 30 markers along mouse chromosome 6 (mchr 6) in chemically induced squamous cell carcinomas (SCCs). Tumors were obtained from SENCAR and C57BL/6 x DBA/2 F1 females by a two-stage carcinogenesis protocol. The high incidence of LOH in the tumor types studied suggests that a TSG relevant to the development of epithelial cancers is present on mchr 6 A1. Since this segment is syntenic with the hchr 7q31, these data indicate that the putative TSG is conserved in both species. Functional evidence for the existence of a TSG in hchr 7 was obtained by microcell fusion transfer of a single hchr 7 into a murine SCC-derived cell line. Five out of seven hybrids had two to three-fold longer latency periods for in vivo tumorigenicity assays than parental cells. One of the unrepressed hybrids had a deletion in the introduced chromosome 7 involving q31.1-q31.3, confirming the LOH data. ^

Mitotic mapping of a novel tumor suppressor locus on human chromosome 3q important in osteosarcoma tumorigenesis

Tumor-specific loss of constitutional heterozygosity by deletion, mitotic recombination or nondisjunction is a common mechanism for tumor suppressor allele inactivation. When loss of heterozygosity is the result of mitotic recombination, or a segmental deletion event, only a portion of the chromosome is lost. This information can be used to map the location of new tumor suppressor genes. In osteosarcoma, the highest frequencies of loss of heterozygosity have been reported for chromosomes 3q, 13q, 17p. On chromosomes 13q and 17p, allelic losses are associated with loss of function at the retinoblastoma susceptibility locus (RB1) and the p53 locus, respectively. Chromosome 3q is also of particular interest because the high percent of loss of heterozygosity (62%-75%) suggests the presence of another tumor suppressor important for osteosarcoma tumorigenesis. To localize this putative tumor suppressor gene, we used polymorphic markers on chromosome 3q to find the smallest common region of allele loss. This putative tumor suppressor was localized to a 700 kb region on chromosome 3q26.2 between the polymorphic loci D3S1282 and D3S1246. ^

Delineation of a novel genetic region at 5q11 harboring tumor suppressor gene(s) and identification of the telomeric DNA as a marker for human prostate cancer

Prostate cancer is the most commonly diagnosed cancer and the second leading cause of cancer mortality in American men. The distinction between those cases of prostate cancer destined to progress rapidly to lethal metastatic disease and those with little likelihood of causing morbidity and mortality is a major goal of current research. Some type of diagnostic method is urgently needed to identify which histological prostate cancers have completed the progression to a stage that will produce a life-threatening disease, thus requiring immediate therapeutic intervention. The objectives of this dissertation are to delineate a novel genetic region harboring tumor suppressor gene(s) and to identify a marker for prostate tumorigenesis. I first established an in vitro cell model system from a human prostate epithelial cells derived from tissue fragments surrounding a prostate tumor in a patient with prostatic adenocarcinoma. Since chromosome 5 abnormality was present in early, middle and late passages of this cell model system, I examined long-term established prostate cancer cell lines for this chromosome abnormality. The results implicated the region surrounding marker D5S2068 as the locus of interest for further experimentation and location of a tumor suppressor gene in human prostate cancer. ^ Cancer is a group of complex genetic diseases with uncontrolled cell; division and prostate cancer is no exception. I determined if telomeric DNA, and telomerase activity, alone or together, could serve as biomarkers of prostate tumorigenesis. I studied three newly established human prostate cancer cell lines and three fibroblast cell cultures derived from prostate tissues. In conclusion, my data reveal that in the presence of telomerase activity, telomeric repeats are maintained at a certain optimal length, and analysis of telomeric DNA variations might serve as early diagnostic and prognostic biomarkers for prostate cancer. (Abstract shortened by UMI.)^