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Stephen B Gruber

Publications and source records attributed to Stephen B Gruber.

At least 55 records · Page 3Linked to original sources
PubMed2004

EGF gene polymorphism and the risk of incident primary melanoma.

Overexpression of the epidermal growth factor (EGF) pathway has been implicated in melanoma pathogenesis, and a recent case-control study identified a single nucleotide polymorphism (G to A) in the EGF gene where the G allele was associated with increased EGF expression and an increased risk of melanoma. To further evaluate this association, we conducted a case-control analysis from the Genes, Environment, and Melanoma study at the University of Michigan site using two different study designs. Incident cases of histopathologically confirmed first primary melanoma that were diagnosed between January 1, 2000 and December 31, 2000 from the University of Michigan Melanoma Clinic (n = 330) were compared with the following two different sources of nonmelanoma controls: spouse/friend controls (n = 84) and healthy volunteer controls from a case-control study of psoriasis (n = 148). Using a second analytic design, comparisons between multiple primary melanoma cases (n = 62) and single primary melanoma cases (n = 330) were also evaluated to estimate odds ratios (ORs). Genotyping for the single nucleotide substitution (G to A) at position 61 in the 5' untranslated region of the EGF gene was performed from genomic DNA, and epidemiological risk factors were assessed through a telephone interview. When EGF genotypes were compared between incident primary melanoma cases and the nonmelanoma controls, the risk associated with the homozygous G/G genotype was not statistically significantly associated with an increased risk for incident primary melanoma compared with the homozygous A/A genotype [OR, 1.09; 95% confidence interval (CI); 0.65-1.85]. No strong associations with EGF G/G genotype were observed in comparisons of multiple primary and single primary melanoma cases (OR, 0.66; 95% CI; 0.25-1.73). Case subjects with tumors >/=3.5 mm compared with those <3.5 mm were not significantly associated with the G/G genotype (OR, 0.54; 95% CI; 0.12-2.35). Our data do not support a significant association between melanoma and the EGF 61*G allele or the homozygous G/G genotype. The EGF polymorphism is not a reproducible risk factor for melanoma or thick melanoma in our data. The two analytic approaches used in the study provide evidence against a strong association between EGF 61*G and melanoma and demonstrate the potential utility of case-case designs for evaluating the role of single nucleotide polymorphisms and cancer. Additional independent studies will be required to elucidate relationships between genetic variation in the EGF gene and risk of melanoma.

Alleles↗
PubMed2004

Risk perception and concern among brothers of men with prostate carcinoma.

BACKGROUND: It is important for clinicians, researchers, and others who shape public health policy to understand the demographic correlates and psychologic factors that drive health behaviors, such as screening for early detection of cancer, particularly among individuals at high risk for developing the disease. METHODS: One-hundred eleven men whose brothers were diagnosed with prostate carcinoma completed a computer-assisted telephone interview aimed to assess their perception of absolute risk and concern about developing prostate carcinoma over the next 10 years and across their lifetime. Comparisons were made between selected demographic, behavioral, family pedigree characteristics, and measures of perceived risk and concern. RESULTS: The majority of men perceived their personal risk of developing prostate carcinoma to be > or =50%. Men who at the time of the interview were younger than their affected brother were significantly more concerned about prostate carcinoma and perceived their risk to be higher than men who were older than their brother. Estimates of personal risk and concern were also uniformly higher among men with more than one first-degree relative affected with prostate carcinoma compared to men with only one affected first-degree relative. Risk perception and concern about an impending prostate carcinoma diagnosis were associated with the use of supplements marketed for prostate health. CONCLUSIONS: The findings indicated that birth order in relation to a brother diagnosed with prostate carcinoma is significantly associated with risk perception and concern in unaffected family members. These results highlight the need for further study of the familial dynamics and characteristics that drive health behaviors and stress importance of public health education to inform men of personal risk assessment as well as the risks and benefits of screening. These studies ultimately can contribute to the success of strategies for the primary prevention and early detection of cancer.

Adult↗
PubMed2004

BRCA1 and BRCA2 founder mutations and the risk of colorectal cancer.

BACKGROUND: Mutations in BRCA1 and/or BRCA2 (BRCA1/2) profoundly increase the risks of breast and ovarian cancers, but it is unclear whether mutations in these genes increase the risk of colorectal cancer. We investigated BRCA1/2 founder mutations and a family history of breast cancer as potential risk factors for colorectal cancer. METHODS: In the population-based Molecular Epidemiology of Colorectal Cancer study in northern Israel, 1422 case patients with incident colorectal cancer, diagnosed between March 31, 1998, and December 31, 2002, and 1566 control subjects without colorectal cancer were genotyped for the BRCA1 187delAG, BRCA1 5385insC, and BRCA2 6174delT founder mutations. Genotypes and interview data from all case patients and control subjects and from only those of Ashkenazi Jewish descent (1002 case patients and 1038 control subjects) were used to calculate odds ratios [ORs] from logistic regression. RESULTS: Twenty-four (2.4%) case patients and 20 (1.9%) control subjects carried one of the three mutations (OR = 1.24, 95% confidence interval [CI] = 0.68 to 2.26). A family history of breast cancer in a female relative was not associated with an increased risk of colorectal cancer, even after adjustment for the presence of a BRCA founder mutation (OR = 1.03, 95% CI = 0.75 to 1.41). CONCLUSIONS: Although weak associations cannot be excluded, Ashkenazi BRCA founder mutations do not confer a strongly elevated risk of colorectal cancer. Similarly, a family history of breast cancer does not appear to be a strong risk factor for colorectal cancer in this population.

Aged↗
PubMed2004

Staging workup, sentinel node biopsy, and follow-up tests for melanoma: update of current concepts.

OBJECTIVES: To clarify and update workup and follow-up strategies based on fundamental principles and current data, and to discuss new and current concepts regarding sentinel lymph node biopsy (SLNB), particularly in relation to the staging workup. DATA SOURCES: Studies conducted from 1995 to 2003 were identified by PubMed search. Additional searches included workup for reference lists of retrieved articles when applicable, and PubMed-related articles. STUDY SELECTION: Contemporary studies with good design, conclusions based on sound methods, and results pertaining to staging workup, SLNB, and follow-up tests were critically reviewed. DATA EXTRACTION: Data and conclusions based on the above studies were incorporated into a review. DATA SYNTHESIS: Routine tests have marginal to no efficacy and are not cost-efficient for detecting occult disease in asymptomatic patients with localized melanoma. The only staging test that has relatively high sensitivity and specificity and provides tissue diagnosis is SLNB; moreover, SLNB has revolutionized our understanding of lymphatic pathways. The concepts of interval nodes and unexpected lymphatic drainage pathways have been addressed by several recent reports. There are no data that demonstrate any significant difference in overall survival for detection of asymptomatic vs symptomatic stage IV melanoma. CONCLUSIONS: An initial workup is useful for staging and prognosis to identify occult disease, with potential outcome benefit if treated early; and, by detecting distant occult disease (stage IV), to obviate the need for an extensive surgical procedure and thereby avoid associated increased morbidity. The foundation for the workup and follow-up remains thorough history taking and a physical examination, combined with a low index of suspicion for symptom-directed tests.

Humans↗
PubMed2004

Familial aggregation of melanoma risks in a large population-based sample of melanoma cases.

OBJECTIVE: Melanoma has been shown in numerous studies to be associated with sun exposure, and with host phenotypic factors of genetic origin. In this study we use information from a large series of incident cases of melanoma from an international population-based study to examine the patterns of incidence of melanoma in the first-degree relatives of these cases. METHODS: A total of 2508 incident cases of melanoma provided information on basic demographic data and pigmentary characteristics, in addition to detailed information on family history of melanoma. These data were used to examine the incidence rates ratios of melanoma in the relatives of cases in relation to population rates, and also with respect to phenotypic characteristics of the probands that have been shown to be associated with melanoma: mole counts, hair color, eye color, and skin sensitivity to the sun. RESULTS: The incidence rates reflect the underlying patterns of incidence in the source populations, with generally higher rates in the Australian sample, low rates in Italy, and intermediate rates in the USA and Canada. Also, rates are higher in men than in women, except at very young ages. Phenotypic characteristics of the probands were only weakly associated with the observed rates in the relatives although there is a strong inverse association with age at diagnosis. Cumulative risk of melanoma rises to 6.9% (6.1%) at age 80 in male (female) first-degree relatives of cases, and to 10.8% (9.5%) in relatives of cases diagnosed before age 50. CONCLUSIONS: Relatives of cases diagnosed with melanoma are at considerable lifetime risk of the disease, especially if the case is diagnosed at a young age.

Adult↗
PubMed2004

Vulvar melanoma: a report of 20 cases and review of the literature.

BACKGROUND: Vulvar melanoma is the second most common vulvar malignancy and represents a significant women's health issue. OBJECTIVE: To report experience with 21 cases of vulvar melanoma in 20 patients and to review the literature about the condition. METHODS: Parameters retrospectively reviewed included age at diagnosis, family history of melanoma, location on the vulva, atypical nevi, Breslow depth, ulceration status, histologic pattern, presenting signs and symptoms, and the results of sentinel lymph node biopsy. Molecular characterization of the melanocortin type 1 receptor was performed in 1 patient. RESULTS: A family history of cutaneous melanoma was present in 15% of cases. The mean Breslow depth was 2.8 mm (range, 0.0-11.0 mm). Ten patients successfully underwent sentinel lymph node biopsy, results of which were positive in 2 (20%). Reported for the first time is that one patient had a germline mutation in the melanocortin type 1 receptor. CONCLUSION: Vulvar and cutaneous melanoma behave similarly despite their unique pathogeneses. Sentinel lymph node biopsy can be performed successfully for vulvar melanoma.

Adult↗
PubMed2004

Use of complementary and alternative medicine in men with family history of prostate cancer: a pilot study.

OBJECTIVES: To describe the use of complementary and alternative medicines (CAMs) among men with a family history of prostate cancer and to evaluate the relationship between selected sociodemographic and behavioral characteristics and the use of CAMs. METHODS: Unaffected brothers of men diagnosed with prostate cancer were asked to participate in a short computer-assisted telephone interview. The survey focused primarily on the use of different vitamins, herbal supplements, and medications, some of which are marketed for prostate health or prostate cancer prevention. RESULTS: A total of 111 men completed the survey, representing 66% of eligible study subjects. Of the 111 men, 61 (55%) reported currently taking some form of CAM, with 30% taking a vitamin or supplement purported to have prostate-specific benefits. The prevalence of CAM use generally increased with increasing age; however, men who were younger than their affected brother at the time of the diagnosis of prostate cancer were more likely to use CAMs than were older brothers. CONCLUSIONS: Most men with a family history of prostate cancer take vitamins and supplements, some of which are believed to prevent future cancer occurrence. The results of this study and others provide some insight into the determinants of potentially beneficial health behaviors in high-risk individuals.

Adenocarcinoma↗
PubMed2004

Relative frequency and morphology of cancers in STK11 mutation carriers.

BACKGROUND & AIMS: There is limited data on the spectrum and risk for cancer associated with germline serine/threonine protein kinase 11 (STK11) mutations that cause Peutz-Jeghers syndrome (PJS). METHODS: We analyzed the incidence of cancer in 240 individuals with PJS possessing germline mutations in STK11. RESULTS: Fifty-four cancers were found among carriers. Overall, the risk for developing cancer at ages 20, 30, 40, 50, 60, and 70 years was 1%, 3%, 19%, 32%, 63%, and 81%, respectively. Kaplan-Meier analysis showed similar cancer risks between missense and truncating mutation carriers (log-rank chi(2) = 2.48; P = 0.12). There was some evidence that mutations in exon 3 of STK11 were associated with a higher cancer risk than mutations within other regions of the gene. We found no difference in overall cancer risk between male and female carriers (log-rank chi(2) = 1.31; P = 0.25) or between familial and sporadic cases (log-rank chi(2) = 1.16, with 1 df; P = 0.28). The most common cancers represented were gastrointestinal in origin--gastroesophageal, small bowel, colorectal, and pancreatic--and the risk for these cancers at ages 30, 40, 50, and 60 years was 1%, 10%, 18%, and 42%, respectively. In women, the risk for breast cancer was substantially increased, being 32% by age 60 years. CONCLUSIONS: These results quantitatively show the spectrum of cancer risk associated with STK11 germline mutations in the context of PJS and provide a valuable reference for defining surveillance regimens.

AMP-Activated Protein Kinase Kinases↗
PubMed2004

Vulvar melanoma: review of diagnosis, staging, and therapy.

OBJECTIVES: To update, assimilate, and bridge the contemporary literature on vulvar and cutaneous melanoma regarding diagnosis, staging, and therapy to provide a useful clinical reference for managing and counseling for affected patients. MATERIALS AND METHODS: A computerized search for reports in the literature up to June 2003 was carried out using PubMed and MEDLINE databases. Multidisciplinary involvement was used in evaluating the available data and formulating conclusions. RESULTS: More than 300 reports were reviewed. Diagnosis, staging, and therapy aspects of vulvar melanoma are summarized. CONCLUSIONS: Vulvar melanoma represents a subtype of cutaneous melanoma, with similar prognostic and staging factors. The most recent American Joint Committee on Cancer staging system for cutaneous melanoma is applicable to vulvar melanoma. Sentinel lymph node biopsy is reliable for staging the regional lymph node basin for vulvar melanoma. Standardized documentation of clinical and histopathologic parameters is needed to standardize grouping of cases for future comparison studies.

Journal Article↗
PubMed2004

Endometrial cancer: socioeconomic status and racial/ethnic differences in stage at diagnosis, treatment, and survival.

OBJECTIVE: We evaluated the association between socioeconomic status and racial/ ethnic differences in endometrial cancer stage at diagnosis, treatment, and survival. METHODS: We conducted a population-based study among 3656 women. RESULTS: Multivariate analyses showed that either race/ethnicity or income, but not both, was associated with advanced-stage disease. Age, stage at diagnosis, and income were independent predictors of hysterectomy. African American ethnicity, increased age, aggressive histology, poor tumor grade, and advanced-stage disease were associated with increased risk for death; higher income and hysterectomy were associated with decreased risk for death. CONCLUSIONS: Lower income was associated with advanced-stage disease, lower likelihood of receiving a hysterectomy, and lower rates of survival. Earlier diagnosis and removal of barriers to optimal treatment among lower-socioeconomic status women will diminish racial/ethnic differences in endometrial cancer survival.

Black or African American↗
PubMed2003

Genetic anthropology of the colorectal cancer-susceptibility allele APC I1307K: evidence of genetic drift within the Ashkenazim.

The adenomatous polyposis coli (APC) I1307K allele is found in 6% of the Ashkenazi Jewish population and in 1%-2% of Sephardi Jews; it confers a relative risk of 1.5-2.0 for colorectal cancer (CRC) on all carriers. Within the Ashkenazim, the existence of numerous high-prevalence mutations, including I1307K, has sparked controversy over whether genetic drift or selection is the underlying cause. For the present population-based case-control study of CRC in Israel, we tested whether selection has operated at I1307K. We also estimated the age of the I1307K allele, to understand its origin in the context of the Jewish diasporas and subsequent founder events. We genotyped 83 matched pairs, in which one or both members of the pair carried I1307K, at three microsatellites and two SNPs. Haplotypes were statistically constructed using PHASE software. Single-marker age estimates for I1307K were calculated using the approach described by Risch et al. A common progenitor haplotype spanned across APC I1307K from the centromeric marker D5S135 to the telomeric marker D5S346 and was observed in individuals of Ashkenazi, Sephardi, and Arab descent. The ancestor of modern I1307K alleles existed 87.9-118 generations ago ( approximately 2,200-2,950 years ago). This age estimate indicates that I1307K existed at about the time of the beginning of the Jewish diaspora, explaining its presence in non-Ashkenazi populations. Our data do not indicate that selection operated at I1307K (D5S346, P=.114; D5S135, P=.373), providing compelling evidence that the high frequency of disease-susceptibility alleles in the Ashkenazim is due to genetic drift, not selection. This research underscores the importance of the migratory patterns of ancestral populations in the ethnic and geographic distribution of APC I1307K.

Adenomatous Polyposis Coli↗
PubMed2003

Cyclooxygenase 2 expression and molecular alterations in Peutz-Jeghers hamartomas and carcinomas.

PURPOSE: Peutz-Jeghers syndrome (PJS) is a hamartomatous polyposis disorder with a high cancer risk. Debate exists about the premalignant potential of hamartomas. Also, treatment options other than surveillance are not available. Therefore, molecular alterations in hamartomas and PJS carcinomas were studied. The objective was (a) to evaluate expression of cyclooxygenase (COX)-2 as target for chemopreventive treatment and (b) to define the neoplastic potential of hamartomas at the molecular level. EXPERIMENTAL DESIGN: Paraffin-embedded samples of 24 PJS hamartomas, including 2 hamartomas with dysplastic changes, and 11 PJS carcinomas were available. Slides were stained with antibodies against COX-2, beta-catenin, cyclin D1, p21(waf1/cip1), Ki-67, and p53. DNA was studied for loss of heterozygosity (LOH) at 19p (STK11), 5q (APC), and 17p (TP53); mutations in beta-catenin, APC, and K-RAS; and microsatellite instability. RESULTS: Moderate or strong epithelial COX-2 was present in 25% of hamartomas, including two hamartomas with dysplastic changes, and 64% of carcinomas. Several hamartomas showed focal nuclear beta-catenin (18%) and cyclin D1 overexpression (29%), both unrelated to dysplasia at histological examination. Disturbed topographical expression of Ki-67 in relation to p21(waf1/cip1) was focally present in 27% of hamartomas, including those with dysplastic changes. Most carcinomas showed nuclear beta-catenin (71%), cyclin D1 overexpression (71%), and aberrant Ki-67 staining (100%). There was LOH at 19p in 32% of hamartomas and 82% of carcinomas. p53 staining was present in four (36%) carcinomas, one of which showed LOH at 17p. No beta-catenin mutations were found. APC mutations were present in two carcinomas, but LOH at 5q was not found. Two carcinomas had K-RAS mutations, and one carcinoma had microsatellite instability. CONCLUSIONS: The presence of COX-2 expression in PJS carcinomas and dysplastic hamartomas provides a rationale for chemoprevention with nonsteroidal anti-inflammatory drugs or COX-2 inhibitors. Focal immunohistochemical changes, which may indicate a premalignant potential, were present in some nondysplastic PJS hamartomas. Molecular changes in carcinomas and dysplastic hamartomas in PJS are distinct from the usual adenoma-carcinoma sequence.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2003

R726L androgen receptor mutation is uncommon in prostate cancer families in the united states.

BACKGROUND: A mutation in the androgen receptor (AR) gene, namely AR R726L, was described in 2% of Finnish men with sporadic or familial prostate cancer and was associated with an approximately sixfold increased risk of prostate cancer. We set out to determine the incidence of this mutation in a sample of men with either early-onset and/or familial prostate cancer in the United States. METHODS: Five hundred forty-eight men with prostate cancer from 411 unrelated families participating in the University of Michigan Prostate Cancer Genetics Project (PCGP) were studied. Allele-specific oligonucleotide hybridization was used to detect the presence of the AR R726L mutation in germline DNA. RESULTS: None of the 548 prostate cancer patients studied, including 513 White, 29 African American, 3 Asian, and 3 Hispanic men, were found to carry the AR R726L allele. Therefore, the prevalence of this allele is significantly less than that observed among Finnish men with prostate cancer (Fisher's exact test, P = 0.002). CONCLUSIONS: The AR R726L allele does not account for a significant proportion of early-onset and/or familial prostate cancer in the United States.

Family Health↗
PubMed2003

Accurate molecular classification of human cancers based on gene expression using a simple classifier with a pathological tree-based framework.

Recent studies suggest accurate prediction of tissue of origin for human cancers can be achieved by applying sophisticated statistical learning procedures to gene expression data obtained from DNA microarrays. We have pursued the hypothesis that a more straightforward and equally accurate strategy for classifying human tumors is to use a simple algorithm that considers gene expression levels within a tree-based framework that encodes limited information about pathology and tissue ontogeny. By considering gene expression data within this framework, we found only a small number of genes were required to achieve a relatively high accuracy level in tumor classification. Using as few as 45 genes we were able to classify 157 of 190 human malignant tumors correctly, which is comparable to previous results obtained with sophisticated classifiers using thousands of genes. Our simple classifier accurately predicted the origin of metastatic tumors even when the classifier was trained using only primary tumors, and the classifier produced accurate predictions when trained and tested on expression data from different labs, and from different microarray platforms. Our findings suggest that accurate and robust cancer diagnosis from gene expression profiles can be achieved by mimicking the classification strategies routinely used by surgical pathologists.

Algorithms↗
PubMed2003

Prostate cancer early detection practices among men with a family history of disease.

OBJECTIVES: Genetic studies of familial prostate cancer, which is often asymptomatic until advanced stages, rely on correct designation of affection status. In this pilot study, we set out to determine the proportion of unaffected men whose families are participating in a study of hereditary prostate cancer who have been tested for prostate cancer with serum prostate-specific antigen (PSA) measurement and digital rectal examination (DRE). METHODS: Participants were identified from the University of Michigan Prostate Cancer Genetics Project, a family-based study of inherited prostate cancer susceptibility. Of the 141 eligible affected and unaffected sons of men with prostate cancer, 124 (88%) completed a mailed questionnaire regarding serum PSA testing and DRE history. RESULTS: Among unaffected men, 95% reported ever having had a PSA test, and 97% ever having had a DRE, with most initial tests occurring between the ages of 40 and 60 years. No significant difference in the mean age at first PSA test or DRE between the affected and unaffected men was observed. Affected men were significantly more likely than unaffected men to have a first PSA level greater than 2.5 ng/mL (P = 0.006), but not greater than 4.0 ng/mL (P = 0.614). CONCLUSIONS: Most men with a family history of prostate cancer are undergoing early detection testing. The differences in early detection testing practices do not appear to account for the difference in affection status among the sons of men with prostate cancer.

Adult↗
PubMed2003

Phenotype of microsatellite unstable colorectal carcinomas: Well-differentiated and focally mucinous tumors and the absence of dirty necrosis correlate with microsatellite instability.

The phenotypic markers of colorectal carcinomas with microsatellite instability have been widely studied and include mucinous or poor differentiation, prominent host response, a circumscribed growth pattern, histologic heterogeneity, and right-sided location. As part of a population-based case-control study of colorectal cancer in northern Israel, we reviewed the pathology and microsatellite status of 528 consecutively diagnosed colorectal cancers. Phenotypic analysis was performed by one pathologist (J.K.G.) and included assessment of grade, mucinous histology (>50%, or focal), histologic heterogeneity, growth pattern, necrosis, and host response. Microsatellite status was determined on microdissected portions of formalin-fixed, paraffin-embedded tissue using a panel of 5 NCI consensus primers. Fifty-two of 528 colorectal carcinomas were microsatellite unstable (9.85%). Multivariate analysis found that >2 tumor infiltrating lymphocytes per high power field (p <0.0001), the lack of dirty necrosis (p = 0.0054), a Crohn's-like host response (p = 0.0064), right-sided location (p = 0.032), well or poor differentiation (p = 0.037), and any mucinous differentiation (p = 0.039) were independent predictors of microsatellite instability. Tumor infiltrating lymphocytes were the single best histologic predictor of microsatellite instability. The absence of dirty necrosis and the presence of well-differentiated tumors and tumors with only focal mucinous differentiation were also important markers for microsatellite instability that have not been emphasized previously. The combination of >2 tumor infiltrating lymphocytes per high power field and/or any mucinous differentiation and/or the absence of dirty necrosis identified all MSI-H tumors in this study.

Adenocarcinoma↗