Molecular Analysis of Breast Cancer in Minority Women Breast cancer remains the most common malignancy in females in the United States and is a major public health problem. Although progress has been made in prevention, early detection, and therapy, 37,500 women die of this malignancy annually. Although incidence of breast cancer is lower in minority women, significant health disparities exist for mortality, late diagnosis and triple negative disease. Analysis of breast cancer families resulted in the identification of two major loci, BRCA1 and BRCA2. These genes and several minor high-penetrant loci (PTEN, CHEK2, TP53) together account for 45-60% of disease in multiplex families. Therefore, there remain additional genes conferring risk for breast cancer. By establishing cohorts of minority women with breast cancer we hope to address some of these issues. e have begun collecting African American samples from Howard University and Hispanic samples from Puerto Rico. In addition we initiated a nationwide cohort of Hispanic breast cancer and have initiated recruitment. A collaboration with the Instituto Cancerologia in Guatemala City has also been established and a protocol submitted to collect samples and data. 2. Prostate Cancer: Validation of Exome Sequencing and Application We applied Roche/454 exome sequencing technology to the sequencing of normal DNA and DNA from five different metastatic lesions in a single prostate cancer patient. More than 3 million reads were obtained on each of the normal and metastatic tumors resulting in greater than 25-fold coverage. Prediction of variants was carried out in each sample, and more than 500 variants that were present in three or more of the metastatic lesions were identified. We identified mutations in the TET2 gene, a gene previously know to be mutated solely in hematopoetic cancers. Analysis of the promoter region has identified the start site of the gene and major promoter elements. In addition we have performed binding partner analysis and identified new protein interactors. 3. Kidney Tumor Exome and Transcriptome Sequencing To apply the technologies of high-throughput sequencing to renal cancer, we have used Illumina Solexa instrument for both transcriptome and exome sequencing. The Illumina exome approach uses an Agilent solution capture technology. DNA from two sporadic clear cell tumors were exome captured and sequenced to an average depth of 75-fold. From the sequence analysis, we identified a list of 101 genes with a newly described variant affecting the coding region, after eliminating genes from certain large, variable gene families, such as olfactory receptors. We further refined this list by analyzing the following characteristics: predicted severity of the mutation using Polyphen, SIFT, and other programs;presence of the same gene mutated in three out of five or more of the five genomes analyzed;presence of a mutation in that gene in the COSMIC database of cancer-related mutations;involvement of the gene in interactions with cancer-related proteins;and presence of loss of heterozygosity in the gene region in the tumors sequenced. From this combined analysis, we selected 16 genes as top priority for follow-up analysis. We have followed up on mutations of the PBRM1 gene and shown the gene to be mutated in approximately 40% of kidney tumors. We have undertaken expression analysis of these same tumors to understand the role of mutations in PBRM1 and VHL in expression in renal cancer. 4. Retinoblastoma in Latin America-Epidemiology and Genetic Analysis Retinoblastoma is one of the most common pediatric solid tumors in Mexico and Central America, accounting for up to 10% of all diagnosed cases, as opposed to 23% of all cases in the United States and Europe. Incidence calculations of retinoblastoma in Mexico have shown that the incidence varies within regions of the country and is highest in the Chiapas region bordering Guatemala. To further understand the factors involved in the higher prevalence, we performed an analysis of 246 consecutive cases treated over 8 years at the Unidad Nacional de Oncologia Pediatrica (UNOP), the sole pediatric cancer hospital in Guatemala. Data on age at diagnosis, birth region, laterality, ethnicity, and fathers occupation were captured, and this cohort was compared to a cohort of all cases with acute lymphocytic leukemia and as controls, children examined and found to be cancer-free. From this data we calculated the incidence of retinoblastoma to be 8.1 cases/million children under the age of 14 in the Guatemala City region. This incidence is elevated twofold over the incidence in the United States and Europe, and is similar in indigenous and admixed populations in the capital region. The elevated incidence is not due to an increase in familial cases, suggesting an environmental contributor. Analysis of retinoblastoma incidence in indigenous and admixed populations demonstrates a lower incidence in indigenous children in rural areas farther from the capitol. This disparity is even more pronounced in acute lymphocytic leukemia. Unilateral retinoblastoma accounted for 72% of cases. The average age of diagnosis and stage at diagnosis are advanced, resulting in reduced survival. To understand the spectrum of mutations in Guatemalan retinoblastoma cases, we mutation scanned and sequenced all 27 exons of the RB1 gene in 14 retinoblastoma tumors. Five different germline oncogenic mutations were detected in patients. In addition we developed a sensitive assay for methylation of the RB1 promoter and validated this assay on tissue samples.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC011300-02
Application #
8349453
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2011
Total Cost
$867,725
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Perez-Andreu, Virginia; Roberts, Kathryn G; Xu, Heng et al. (2015) A genome-wide association study of susceptibility to acute lymphoblastic leukemia in adolescents and young adults. Blood 125:680-6
Nickerson, Michael L; Dancik, Garrett M; Im, Kate M et al. (2014) Concurrent alterations in TERT, KDM6A, and the BRCA pathway in bladder cancer. Clin Cancer Res 20:4935-48
Dean, Michael; Bendfeldt, Giovana; Lou, Hong et al. (2014) Increased incidence and disparity of diagnosis of retinoblastoma patients in Guatemala. Cancer Lett 351:59-63
Jiménez-Morales, Silvia; Jiménez-Ruíz, Juan Luis; Del Río-Navarro, Blanca Estela et al. (2014) CHRM2 but not CHRM1 or CHRM3 polymorphisms are associated with asthma susceptibility in Mexican patients. Mol Biol Rep 41:2109-17
Guardado-Estrada, Mariano; Juárez-Torres, Eligia; Román-Bassaure, Edgar et al. (2014) The distribution of high-risk human papillomaviruses is different in young and old patients with cervical cancer. PLoS One 9:e109406
Dean, Michael; Lou, Hong (2013) Genetics and genomics of prostate cancer. Asian J Androl 15:309-13
Nickerson, Michael L; Bosley, Allen D; Weiss, Jayne S et al. (2013) The UBIAD1 prenyltransferase links menaquinone-4 [corrected] synthesis to cholesterol metabolic enzymes. Hum Mutat 34:317-29
Perez-Andreu, Virginia; Roberts, Kathryn G; Harvey, Richard C et al. (2013) Inherited GATA3 variants are associated with Ph-like childhood acute lymphoblastic leukemia and risk of relapse. Nat Genet 45:1494-8
Xu, Heng; Yang, Wenjian; Perez-Andreu, Virginia et al. (2013) Novel susceptibility variants at 10p12.31-12.2 for childhood acute lymphoblastic leukemia in ethnically diverse populations. J Natl Cancer Inst 105:733-42
Guo, Guangwu; Sun, Xiaojuan; Chen, Chao et al. (2013) Whole-genome and whole-exome sequencing of bladder cancer identifies frequent alterations in genes involved in sister chromatid cohesion and segregation. Nat Genet 45:1459-63

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