Assessing Recurrent Genomic Aberrations Linked to Ethnicity
| Institution: | University of California, San Francisco | ||
| Investigator(s): |
Koie Chin , M.D., Ph.D. -
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| Award Cycle: | 2004 (Cycle 10) | Grant #: 10IB-0195 | Award: $100,000 |
| Award Type: | IDEA | ||
| Research Priorities | |||
| Disparities>Disparities: eliminating the unequal burden of breast cancer | |||
Initial Award Abstract (2004)
The National Cancer Institute reports the lifetime risk of breast cancer for women in the US is 13.3%. While the incidence of breast cancer in African Americans is about 20% lower than that in Caucasians, the prognosis in African-Americans with breast cancer is 20% poorer than in Caucasians. Population-based studies have shown that African-American women tend to have tumors that are larger, more advanced in stage and have higher lymph node involvement and more distant metastasis compared to Caucasian women. Some of these differences can be related to socio-economic and reproductive differences. However, these factors do not explain why breast cancers in African American are more poor-differentiated and estrogen receptor-negative, regardless of menopausal status. We postulate that these characteristics are due to fundamental differences in cancer genotype that arise during tumor development. If true, different approaches to treatment may be warranted. We have analyzed genome copy number aberrations in about 150 breast cancers using microarray-based Comparative Genomic Hybridization (array CGH). These analyses suggest that some genomic differences do exist between African American and Caucasian tumors, although only 11 tumors from African-Americans were included in the study compared to tumors from 108 Caucasians. The purpose of this study is to validate these findings in a larger set of tumors and to test the hypothesis that ethnicity related aberrations cause gene expression changes that contribute to biological events that are associated with reduced survival in African American women with breast cancer. These studies also will identify gene expression differences between tumors from Caucasian and African American women that are caused by epigenetic and other non-genomic events. I will use array CGH to identify map gene dosage aberrations and Affymetrix gene expression arrays to compare breast tumors from African American and Caucasian women. I will focus on poorly differentiated tumors with estrogen receptor-negative that is dominant type in African American tumors. I will obtain 50 matched tumor samples each of African American and Caucasian from the UCSF Cancer Center and the University of Alabama to identify the racial difference in recurrent genomic aberrations and gene expression. DNA for the CGH study and RNA for the expression assay will be extracted from same tumor samples. The gene expression will be measured using Affymetrix GeneChip? microarrays to assess the expression of ~40,000 genes in each sample. CGH arrays will interrogate copy number over the genome with ~1 MB resolution along the genomic distance. This project will apply state-of-the-art technologies to identify genomic and gene expression differences between breast cancers that arise in African Americans and Caucasians. These will be the first comparative genomic and gene expression analyses on these tumor types. These studies will identify the extent to which prognostic markers and therapeutic strategies developed through analyses of tumors from Caucasian women will apply to tumors that arise in African American women.
Final Report (2008)
We assessed genome copy number changes using array CGH (Comparative Genomic Hybridization) and gene expression profiles using Affymetrix GeneChip® in High Throughput Array (HTA) system to identify recurrent genomic aberrations in 120 breast tumors from African Americans (AA tumors) and 106 tumors from Caucasians (White tumors) collected through University of California, San Francisco (UCSF) and University of Alabama at Birmingham (UAB). We compared those recurrent genetic events between AA tumors and White tumors to find genes that may lead specific features in African American’s breast tumors; larger, advanced stage, higher lymph node involvement, distant metastasis, resulted in poor prognosis. We initially proposed to analyze 50 breast tumors each from AA and White. We tried to collect as many as possible breast tumors to increase statistical power. We finally assessed 122 AA tumors and 106 White tumors, collectively total 228 breast tumors. The major objectives of Aim 1 (Fine mapping of genomic copy number in breast cancers in African-American and Caucasian) were completely accomplished. In those tumors, we found that gained chromosome locations were 1q, 3q, 4q, 5p, 6p, 7pq, 8q, 9p, 10p, 11q, 12p, 16p, 17q, 18p, 19q, 20q and 21q, and lost chromosome locations were 1p, 3p, 4p, 5q, 7q, 8p, 9q, 13q, 14q, 15q, 16q, 17p, 18q. Those locations were relatively common between AA tumors and White tumors. Increased copy number at 2p25, 9p24, 9p21, 9p13, 17q13, 18p11 and 21q22 were significant in AA tumors and decreased copy number at 2q37, 3p14, 16p13 and 20p13 were significant in AA tumors as well. On the other hand, significant regions in white tumors were chromosomes 3p13, 3q12, 5q33, 15q21 and 16p13 with gains and chromosome 13q31 with loss. We also assessed disease free survival in both racial groups by Kaplan-Meier plotting. There was no significance in disease free survival between African American and Caucasian. AA tumors and White tumors were successfully classified into three genomic subtypes; simple type, amplifying type and complex type based on their genome copy number profiles. Disease free survival according to genomic subtypes was also measured; we were unable to find significance between AA tumors and White tumors. The major objectives of Aim 2 (High-density gene expression profiling in breast cancers analyzed in Aim 1.) were also accomplished. We assessed degree of expression in >20,000 genes using Affymetrix GeneChip in HTA system. We carefully compared two data sets from AA tumors and White tumors because HTA system we used in this study was pre-commercial version under development. In this analysis, we found >40 genes were significantly up-regulated in AA tumors compared to White tumors. A combined analysis of genomic copy number and gene expression will be conducted further.
Symposium Abstract (2005)
Advances on several fronts have led to increases in survival duration and in reduced mortality in patients with breast cancer. These include improved procedures for earlier detection, optimization of combined surgical and radiotherapy and from use of optimized selective estrogen receptor modifiers (SERMS) and new chemotherapeutic strategies including gene targeted therapies. In addition, molecular stratification strategies have been developed that stratify patients according to outcome. Stratification based on measurement of expression signatures have been particularly effective and seem likely to reduce over treatment of patients. Patients at increased risk of progressive disease can then be offered standard of care chemotherapy. However, some of these patients do not respond well to these treatments and current stratification strategies provide little information to guide treatment of these patients. This study of tumors from patients treated according the standard of care at the University of California San Francisco and California Pacific Medical Centers identifies genomic and coordinated transcriptional aberrations - especially amplification at 11q, and 20q in tumors with the luminal A expression phenotype and at 17q in tumors associated with the ERBB2 expression phenotype - that are strongly associated with poor response to the current standard of care. Our study identifies genes in these regions of amplification that can be assessed to identify patients that will respond poorly to the current standard of care and that are targets for therapies that will be effective against these poorly responding tumors. Interesting, this study also shows that patients with basal-like tumors do not have substantially shorter survival durations than patients with luminal-like tumors suggesting that basal-like tumors respond well to the adjuvant Doxorubicin hydrochloride and Cyclophosphamide therapies employed during their treatment.
Symposium Abstract (2007)
The incidence of breast cancer in African American women is about 20% lower than that in Caucasians, and the 5-year disease specific survival rate in African Americans is also about 20% lower than in Caucasians. Some the differences in incidence and survival may be explained by socio-economic factors. However, these factors are unlikely to explain why reasons breast tumors in African American tend to be more frequently poorly differentiated and estrogen receptor-negative that tumors in Caucasian women. The goal of this project is to identify genes in the regions that recurrently exhibit copy number aberrations and deregulation of their expression contributing to the poor prognosis in African American women with breast cancer. The correlation between gene copy number and gene expression will be assessed to identify candidate genes that may be driving the differences in breast tumors between African American and Caucasian women. These analyses may suggest models of the molecular mechanisms that result in higher mortality with poor-differentiation and negative ER status in breast cancers in African-American women. It is important to understand the mechanisms of how these abnormalities occur and how genes are associated with functions that drive the development of breast cancer pathophysiology. We analyzed ~120 breast tumors in African American women and ~110 breast tumors in Caucasian women for genome copy number abnormalities using array-based comparative genomic hybridization (array CGH) and for gene expression using GeneChip (U133A, High Throughput System, Affymetrix). The samples were collected from the University of California, San Francisco and the University of Alabama at Birmingham. We assessed the recurrent abnormalities of genome copy numbers and deregulated gene expression to identify genomic events that might contribute to cancer pathophysiology. The genomic loci that exhibit recurrent genome copy number aberrations (CNAs) in African American women are similar to genome CNAs in Caucasian women. These are briefly copy number gains of chromosomes 1q, 8p11-12, 8q, 10p, 11q13-14, 12q13-14, 17q11-12, 17q21-24, 20q13 and copy number losses of 1p, 3p, 8p, 13q, 16q, 17p. Also we found coamplification of 8q24 and 20q13 and coamplification of 11q12-14, 12q13-14, 17q11-12 and 17q21-24 which regions include ERBB2, MYC, CCND1 and MDM2. The results suggest there are some differences at the level of genome copy number and at the extent of high-level copy number gains between breast cancers in African American and Caucasian women. Most samples from African Americans and Caucasians were successfully segregated into three genomic subtypes (1q /16q, amplifying and comples) by unsupervised hierarchical clustering for genome copy number. We will explore the detail of combined analyses of genome copy number and gene expression and present the significance of our study for breast cancers in African American women.
