Biomedical subjects

Jaya M Satagopan

Publications and source records attributed to Jaya M Satagopan.

13 recordsLinked to original sources

PubMed2006

Novel mutations of epidermal growth factor receptor in localized prostate cancer.

We recently demonstrated that EGFR protein overexpression is more common in African American (AA) prostate cancer patients compared to Caucasian patients. We further examine EGFR dysregulation by determining EGFR mutation status in the tyrosine kinase (TK) domain in prostate cancer patients of different ethnicity. Normal and tumor DNA from 89 radical prostatectomy cases were studied for mutations in the EGFR TK domain using genomic DNA sequencing. We identified 4 novel missense mutations in exons 19, 20 and 21 of EGFR TK domain: 3 in Koreans and 1 in Caucasian but none in AA. We also identified 5 distinct synonymous DNA sequence changes, which did not alter the encoded amino acid, in exons 20 and 21 in 31/89 (35%) patients. Interestingly, these synonymous sequence changes were not observed in normal DNA in 7(23%) patients, indicating the presence of de novo somatic mutation to a new synonymous sequence. Our data reveal that EGFR missense mutation in the TK domain occurs in localized prostate cancer. Our data also demonstrate the presence of somatic mutation to a new synonymous sequence in a subset of patients. Larger population-based studies are required to define the association between EGFR mutations and the ethnic background of patients.

Aged↗

PubMed2005

Quantitative trait locus study design from an information perspective.

We examine the efficiency of different genotyping and phenotyping strategies in inbred line crosses from an information perspective. This provides a mathematical framework for the statistical aspects of QTL experimental design, while guiding our intuition. Our central result is a simple formula that quantifies the fraction of missing information of any genotyping strategy in a backcross. It includes the special case of selectively genotyping only the phenotypic extreme individuals. The formula is a function of the square of the phenotype and the uncertainty in our knowledge of the genotypes at a locus. This result is used to answer a variety of questions. First, we examine the cost-information trade-off varying the density of markers and the proportion of extreme phenotypic individuals genotyped. Then we evaluate the information content of selective phenotyping designs and the impact of measurement error in phenotyping. A simple formula quantifies the information content of any combined phenotyping and genotyping design. We extend our results to cover multigenotype crosses, such as the F(2) intercross, and multiple QTL models. We find that when the QTL effect is small, any contrast in a multigenotype cross benefits from selective genotyping in the same manner as in a backcross. The benefit remains in the presence of a second unlinked QTL with small effect (explaining <20% of the variance), but diminishes if the second QTL has a large effect. Software for performing power calculations for backcross and F(2) intercross incorporating selective genotyping and marker spacing is available from http://www.biostat.ucsf.edu/sen.

Animals↗

PubMed2004

Frequency of BRCA1 and BRCA2 mutations in unselected Ashkenazi Jewish patients with colorectal cancer.

Mutations in BRCA1 and BRCA2 that predispose to breast and ovarian cancer are detected in approximately 2.5% of the Ashkenazi Jewish population. To explore whether carriers of Ashkenazi founder mutations in BRCA1 or BRCA2 have an increased risk for colorectal cancer, we screened 586 unselected Ashkenazi Jewish case patients with colorectal cancer for the three common founder mutations in BRCA1 and BRCA2. We identified six carriers (1.02%) among these case patients. After adjusting for age at diagnosis and sex by use of logistic regression analysis, we compared the incidence of carriers in this group of 586 case patients with that of 5012 Ashkenazi Jewish control subjects without a known history of colorectal cancer. The presence of a founder BRCA mutation was not associated with the risk of colorectal cancer (relative risk = 0.50, 95% confidence interval = 0.22 to 1.14). We thus recommend that counseling for colorectal cancer screening and prevention in individuals with BRCA mutations be based on the personal and family history of colorectal cancer or associated syndromic malignancies.

Adult↗

PubMed2004

Two-stage designs for gene-disease association studies with sample size constraints.

Gene-disease association studies based on case-control designs may often be used to identify candidate polymorphisms (markers) conferring disease risk. If a large number of markers are studied, genotyping all markers on all samples is inefficient in resource utilization. Here, we propose an alternative two-stage method to identify disease-susceptibility markers. In the first stage all markers are evaluated on a fraction of the available subjects. The most promising markers are then evaluated on the remaining individuals in Stage 2. This approach can be cost effective since markers unlikely to be associated with the disease can be eliminated in the first stage. Using simulations we show that, when the markers are independent and when they are correlated, the two-stage approach provides a substantial reduction in the total number of marker evaluations for a minimal loss of power. The power of the two-stage approach is evaluated when a single marker is associated with the disease, and in the presence of multiple disease-susceptibility markers. As a general guideline, the simulations over a wide range of parametric configurations indicate that evaluating all the markers on 50% of the individuals in Stage 1 and evaluating the most promising 10% of the markers on the remaining individuals in Stage 2 provides near-optimal power while resulting in a 45% decrease in the total number of marker evaluations.

Biometry↗

PubMed2003

Absence of a telomere maintenance mechanism as a favorable prognostic factor in patients with osteosarcoma.

There are two telomere maintenance mechanisms (TMMs) in human tumors, telomerase activation (TA) and, more rarely, the process termed alternative lengthening of telomeres (ALT). Unlike most carcinomas, sarcomas, including osteosarcomas (OS), have been reported to display TA and ALT in more balanced proportions and, thus, present an opportunity to examine the impact of different TMMs on clinical tumor behavior. We studied OS samples from 62 patients for molecular evidence of TA and ALT. Kaplan-Meier analysis demonstrated that the absence of both TA and ALT (in 18%) was more strongly associated with improved survival (P = 0.05) than were stage (P = 0.16) or chemotherapy response (P = 0.18) in this group of patients with OS. Subsets of OS cases with either TA or ALT did not differ significantly from each other in clinical outcome. There were no significant associations of presence, absence, or type of TMM with patient age, stage, or chemotherapy response. Thus, the absence of a detectable TMM may identify a favorable clinical subset of OS patients. Our study also suggests that the likelihood of detecting correlations between TMMs and clinical outcome in studies of certain other tumor types might be improved if, in addition to TA, ALT is included in future analyses. Finally, we note that OS cases with a TA-/ALT+ phenotype seem to be as clinically aggressive as TA+ cases in terms of stage and clinical outcome.

Adult↗

PubMed2003

Age-adjusted International Prognostic Index predicts autologous stem cell transplantation outcome for patients with relapsed or primary refractory diffuse large B-cell lymphoma.

Second-line chemotherapy followed by high-dose therapy (HDT) with autologous stem cell transplantation (ASCT) cures less than half of the patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Prognostic models capable of predicting outcome are essential. In 3 sequential clinical trials, conducted from January 1993 to August 2000, we treated 150 patients with relapsed or primary refractory DLBCL with ifosfamide, carboplatin, and etoposide (ICE) chemotherapy followed by HDT/ASCT for patients with chemosensitive disease. We evaluated the age-adjusted International Prognostic Index at the initiation of second-line therapy (sAAIPI) as a predictor of progression-free survival (PFS) and overall survival (OS). At a median follow-up of 4 years, the PFS and OS are 28% and 34% by intention to treat and 39% and 45% for only those patients with chemosensitive disease. Three risk groups with different PFS and OS were identified by the sAAIPI: low risk (0 factors), 70% and 74%; intermediate risk (1 factor), 39% and 49%; and high risk (2 or 3 factors), 16% and 18% (P <.001 for both PFS and OS). The sAAIPI also predicts the PFS and OS for patients with ICEchemosensitive disease: low risk, 69% and 83%; intermediate risk, 46% and 55%; and high risk, 25% and 26% (P <.001 PFS and OS). The sAAIPI predicts outcome for patients with relapsed or primary refractory DLBCL in both intent-to-treat and chemosensitive populations. This powerful prognostic instrument should be used to evaluate new treatment approaches and to compare results of different regimens.

Adolescent↗

PubMed2003

A statistical perspective on gene expression data analysis.

Rapid advances in biotechnology have resulted in an increasing interest in the use of oligonucleotide and spotted cDNA gene expression microarrays for medical research. These arrays are being widely used to understand the underlying genetic structure of various diseases, with the ultimate goal to provide better diagnosis, prevention and cure. This technology allows for measurement of expression levels from several thousands of genes simultaneously, thus resulting in an enormous amount of data. The role of the statistician is critical to the successful design of gene expression studies, and the analysis and interpretation of the resulting voluminous data. This paper discusses hypotheses common to gene expression studies, and describes some of the statistical methods suitable for addressing these hypotheses. S-plus and SAS codes to perform the statistical methods are provided. Gene expression data from an unpublished oncologic study is used to illustrate these methods.

Cluster Analysis↗

PubMed2003

Optimal two-stage genotyping in population-based association studies.

We propose a cost-effective two-stage approach to investigate gene-disease associations when testing a large number of candidate markers using a case-control design. Under this approach, all the markers are genotyped and tested at stage 1 using a subset of affected cases and unaffected controls, and the most promising markers are genotyped on the remaining individuals and tested using all the individuals at stage 2. The sample size at stage 1 is chosen such that the power to detect the true markers of association is 1-beta(1) at significance level alpha(1). The most promising markers are tested at significance level alpha(2) at stage 2. In contrast, a one-stage approach would evaluate and test all the markers on all the cases and controls to identify the markers significantly associated with the disease. The goal is to determine the two-stage parameters (alpha(1), beta(1), alpha(2)) that minimize the cost of the study such that the desired overall significance is alpha and the desired power is close to 1-beta, the power of the one-stage approach. We provide analytic formulae to estimate the two-stage parameters. The properties of the two-stage approach are evaluated under various parametric configurations and compared with those of the corresponding one-stage approach. The optimal two-stage procedure does not depend on the signal of the markers associated with the study. Further, when there is a large number of markers, the optimal procedure is not substantially influenced by the total number of markers associated with the disease. The results show that, compared to a one-stage approach, a two-stage procedure typically halves the cost of the study.

Case-Control Studies↗

PubMed2003

BRCA1 and BRCA2 germline mutations in lymphoma patients.

Mutations in the BRCA1 and BRCA2 tumor suppressor genes are associated with an increased risk for breast and ovarian cancers as well as other types of malignancies. The observation of a germline BRCA1 mutation in an index case with a lymphoid neoplasm in the setting of a family history of breast cancer prompted us to explore the role of BRCA germline mutations as lymphoma susceptibility alleles. A panel of 286 DNA samples from Jewish lymphoma patients was analyzed for the three most frequent BRCA1 and BRCA2 germline mutations in those of Ashkenazi Jewish heritage, and compared to a cohort of 5010 DNA samples from healthy controls. Of the 286 cases, 2 patients carried a germline BRCA mutation; both were diagnosed at an early age with an intermediate grade non-Hodgkin's lymphoma. This data indicate that germline BRCA mutations are not associated with an increased risk for lymphoid malignancies.

Adult↗

PubMed2002

Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation.

BACKGROUND: Risk-reducing salpingo-oophorectomy is often considered by carriers of BRCA mutations who have completed childbearing. However, there are limited data supporting the efficacy of this approach. We prospectively compared the effect of risk-reducing salpingo-oophorectomy with that of surveillance for ovarian cancer on the incidence of subsequent breast cancer and BRCA-related gynecologic cancers in women with BRCA mutations. METHODS: All women with BRCA1 or BRCA2 mutations identified during a six-year period were offered enrollment in a prospective follow-up study. A total of 170 women 35 years of age or older who had not undergone bilateral oophorectomy chose to undergo either surveillance for ovarian cancer or risk-reducing salpingo-oophorectomy. Follow-up involved an annual questionnaire, telephone contact, and reviews of medical records. The time to cancer in the two groups was compared by Kaplan-Meier analysis and a Cox proportional-hazards model. RESULTS: During a mean follow-up of 24.2 months, breast cancer was diagnosed in 3 of the 98 women who chose risk-reducing salpingo-oophorectomy and peritoneal cancer was diagnosed in 1 woman in this group. Among the 72 women who chose surveillance, breast cancer was diagnosed in 8, ovarian cancer in 4, and peritoneal cancer in 1. The time to breast cancer or BRCA-related gynecologic cancer was longer in the salpingo-oophorectomy group, with a hazard ratio for subsequent breast cancer or BRCA-related gynecologic cancer of 0.25 (95 percent confidence interval, 0.08 to 0.74). CONCLUSIONS: Salpingo-oophorectomy in carriers of BRCA mutations can decrease the risk of breast cancer and BRCA-related gynecologic cancer.

Actuarial Analysis↗

PubMed2002

Two-stage designs for gene-disease association studies.

The goal of this article is to describe a two-stage design that maximizes the power to detect gene-disease associations when the principal design constraint is the total cost, represented by the total number of gene evaluations rather than the total number of individuals. In the first stage, all genes of interest are evaluated on a subset of individuals. The most promising genes are then evaluated on additional subjects in the second stage. This will eliminate wastage of resources on genes unlikely to be associated with disease based on the results of the first stage. We consider the case where the genes are correlated and the case where the genes are independent. Using simulation results, it is shown that, as a general guideline when the genes are independent or when the correlation is small, utilizing 75% of the resources in stage 1 to screen all the markers and evaluating the most promising 10% of the markers with the remaining resources provides near-optimal power for a broad range of parametric configurations. This translates to screening all the markers on approximately one quarter of the required sample size in stage 1.

Breast Neoplasms↗

PubMed2002

Ovarian cancer risk in Ashkenazi Jewish carriers of BRCA1 and BRCA2 mutations.

PURPOSE: Several studies to date have reported ovarian cancer risk due to inherited BRCA1 and BRCA2 mutations using familial data or population-based series of probands. Familial aggregation associated with both of these methods may result in a substantial ascertainment bias. To address this, we have used a case-control design that does not involve familial aggregation to estimate the lifetime penetrance of ovarian cancer due to BRCA1 and BRCA2 mutations. EXPERIMENTAL DESIGN: A total of 382 ovarian cancer cases self-identified as being Jewish with no prior diagnosis of breast cancer were derived from two hospital-based series. In the first series, all 197 invasive epithelial ovarian cancer cases self-identified as Jewish and without a prior history of breast cancer, diagnosed and treated at Memorial Sloan-Kettering Cancer Center between 1986 and 2000, were identified. In the second series, 185 Jewish invasive epithelial ovarian cancer patients without prior breast cancer were identified in a study conducted at 11 centers in North America and Israel from 1995 to 1996. Controls were 3434 Jewish women without any prior history of breast or ovarian cancer from a large study of genotyped volunteers of Jewish origin in the Washington, D. C. area recruited by investigators at the National Cancer Institute. The cases and controls were genotyped for three Ashkenazi Jewish founder mutations, namely 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2. The lifetime penetrances were estimated using the odds ratios, mutation prevalence in the controls, and ovarian cancer incidence rates in the general American population obtained from the Surveillance, Epidemiology and End Results database adjusted for the incidence of ovarian cancer following breast cancer. RESULTS: Mutations were identified in 147 cases and 62 controls. The estimated penetrances at age 70 years were 37% (95% confidence interval, 25-71%) for a BRCA1 mutation and 21% (95% CI, 13-41%) for a BRCA2 mutation. CONCLUSIONS: The lifetime penetrances of BRCA1 mutations are lower than estimates obtained using familial data with multiple affected members but larger than estimates from some population-based proband series. The lifetime penetrance estimate of a BRCA2 mutation is in the range reported by some of the studies based on familial data. These results could have implications for clinical counseling, surgical interventions, and screening recommendations in women carrying these founder mutations.

Adult↗

PubMed2002

Rare variants of ATM and risk for Hodgkin's disease and radiation-associated breast cancers.

PURPOSE: In this study, we first sought to evaluate whether individuals heterozygous for ATM mutations may have an increased susceptibility to radiation-induced breast cancer (BC) after treatment for Hodgkin's disease (HD). We next sought to determine the frequency of ATM variants in patients with Hodgkin's lymphoma, regardless of coexisting BC, compared with healthy volunteers. EXPERIMENTAL DESIGN: Full sequence analysis of ATM was performed on cDNA from peripheral blood lymphocytes from 37 cases of BC after therapeutic radiation therapy for HD and 27 comparison cases with HD and no BC treated during the same time period. The frequency of ATM variants was analyzed in the total group of 64 cases of HD and compared to allele frequencies in 128 ethnically matched controls from the same geographical region. RESULTS: No protein-truncating ATM mutations were observed in cases with HD with or without BC. Missense mutations were more frequent in the cohort with HD compared with patients with BC following HD (P = 0.02). The median time from HD to the development of BC was 18 years in patients with ATM variants compared with 16 years in those with no ATM variants (P = 0.04). Multiple ATM variants, including one homozygous mutation, were observed in 9 HD cases. CONCLUSIONS: Heterozygous protein-truncating or missense mutations of ATM were not associated with increased radiation-associated risk of BC after HD. The observation of multiple germ-line mutations and a homozygote suggests that rare ATM variants may constitute cancer-susceptibility alleles in a subset of cases.

Adolescent↗