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Biomedical subjects

Mark H Greene

Publications and source records attributed to Mark H Greene.

At least 19 recordsLinked to original sources
PubMed2006

Evolution of the colored eco-genetic relationship map (CEGRM) for assessing social functioning in women in hereditary breast-ovarian (HBOC) families.

The CEGRM was initially conceived as a simple, concise, visual representation of the social interaction domains of information, tangible services and emotional exchanges (Kenen, R., & Peters, J. (2001). J Genet Counsel, 10, 289-309). A blend of the genetic pedigree, genogram, and ecomap, the CEGRM was developed to facilitate contemporary genetic counseling goals. An exploratory pilot study of 20 subjects showed that it was feasible, comfortable and efficiently accomplished, and that the process was useful both for assessment and as an intervention with study participants (Peters, J. A., Kenen, R., Giusti, R., Loud, J., Weissman, N., & Greene, M. H. (2004). Am J Med Genet Part A, 130A, 258-264). Subsequently, we have extended the CEGRM to 150 women from hereditary breast/ovarian cancer (HBOC) families; three different investigators have successfully administered this tool. The preliminary findings from the exploratory study were confirmed in the larger sample. Engaging in the interactive, insight-promoting CEGRM process provides a novel tool for assessing the social context of genetic testing, and helping high-risk women better understand and integrate genetic information into their personal and family identities, health beliefs, and decisions.

Breast Neoplasms↗
PubMed2006

Family history of breast cancer as a risk factor for ovarian cancer in a prospective study.

BACKGROUND: A family history of breast cancer has been associated with increased ovarian cancer risk. However, few studies have assessed risk according to characteristics that suggest an inherited cancer susceptibility disorder, such as earlier-than-usual age at cancer diagnosis, family members with double primary cancers of different types, multiple relatives with cancer, and cancer in both members of paired organs. METHODS: Ovarian cancer risk was assessed according to a detailed breast cancer family history among 49,975 participants in the Breast Cancer Detection Demonstration Project Breast Cancer Defection Demenstration Project (BCDDP) Follow-up Study (1979-1998). In all, 362 incident ovarian cancers were identified during follow-up and rate ratios (RRs) were calculated by Poisson regression. RESULTS.: Breast cancer in a first- or second-degree relative was associated with increased risk of ovarian cancer (RR = 1.4; 95% confidence interval [CI] = 1.1-1.7). Having 2 or more affected first-degree relatives was associated with increased risk (RR = 1.8; 95% CI = 1.1-2.8), especially for women diagnosed with ovarian cancer before age 60 (RR = 4.2; 95% CI = 1.9-9.2) or with a personal history of breast cancer (RR = 3.7; 95% CI 1.8-7.7). Risk was also particularly high for women with 2 or more first-degree relatives with breast cancer and at least 1 affected relative diagnosed before age 50 (RR = 2.6; 95% CI = 1.4-4.8) or with bilateral breast cancer (RR = 4.2; 95% CI = 1.7-10). CONCLUSIONS: A detailed breast cancer family history as well as an individual's age and personal history of breast cancer are useful for identifying women at elevated genetic risk of ovarian cancer.

Age Factors↗
PubMed2006

Genome-wide linkage screen for testicular germ cell tumour susceptibility loci.

A family history of disease is a strong risk factor for testicular germ cell tumour (TGCT). In order to identify the location of putative TGCT susceptibility gene(s) we conducted a linkage search in 237 pedigrees with two or more cases of TGCT. One hundred and seventy-nine pedigrees were evaluated genome-wide with an average inter-marker distance of 10 cM. An additional 58 pedigrees were used to more intensively investigate several genomic regions of interest. Genetic linkage analysis was performed with the ALLEGRO software using two model-based parametric analyses and a non-parametric analysis. Six genomic regions on chromosomes 2p23, 3p12, 3q26, 12p13-q21, 18q21-q23 and Xq27 showed heterogeneity LOD (HLOD) scores of greater than 1, with a maximum HLOD of 1.94 at 3q26. Genome-wide simulation studies indicate that the observed number of HLOD peaks greater than one does not differ significantly from that expected by chance. A TGCT locus at Xq27 has been previously reported. Of the 237 pedigrees examined in this study, 66 were previously unstudied at Xq27, no evidence for linkage to this region was observed in this new pedigree set. Overall, the results indicate that no single major locus can account for the majority of the familial aggregation of TGCT, and suggests that multiple susceptibility loci with weak effects contribute to the disease.

Chromosome Mapping↗
PubMed2006

Cancer survivorship--genetic susceptibility and second primary cancers: research strategies and recommendations.

Cancer survivors constitute 3.5% of the United States population, but second primary malignancies among this high-risk group now account for 16% of all cancer incidence. Although few data currently exist regarding the molecular mechanisms for second primary cancers and other late outcomes after cancer treatment, the careful measurement and documentation of potentially carcinogenic treatments (chemotherapy and radiotherapy) provide a unique platform for in vivo research on gene-environment interactions in human carcinogenesis. We review research priorities identified during a National Cancer Institute (NCI)-sponsored workshop entitled "Cancer Survivorship--Genetic Susceptibility and Second Primary Cancers." These priorities include 1) development of a national research infrastructure for studies of cancer survivorship; 2) creation of a coordinated system for biospecimen collection; 3) development of new technology, bioinformatics, and biomarkers; 4) design of new epidemiologic methods; and 5) development of evidence-based clinical practice guidelines. Many of the infrastructure resources and design strategies that would facilitate research in this area also provide a foundation for the study of other important nonneoplastic late effects of treatment and psychosocial concerns among cancer survivors. These research areas warrant high priority to promote NCI's goal of eliminating pain and suffering related to cancer.

Antineoplastic Agents↗
PubMed2006

Ovarian cancer screening in women with a family history of breast or ovarian cancer.

OBJECTIVE: To evaluate positive predictive values of CA 125 or transvaginal ultrasonography screening for ovarian cancer according to family history of breast or ovarian cancer. METHODS: In the screening arm of a randomized controlled trial of screening compared with usual care, 28,460 women with family history data received baseline and annual CA 125 and transvaginal ultrasonography examinations. We analyzed CA 125 and transvaginal ultrasonography results from the first four rounds of screening. We classified women as average (n=22,687), moderate (n=2,572), or high (n=2,163) risk based on family history, or high risk due to a personal history of breast cancer (n=1,038). Cancers were identified by active follow-up of women with abnormal screening results and annual questionnaires. We calculated positive predictive values for screening combinations. RESULTS: Similar proportions (4.8-5.0%) of women in each group had abnormal screening results. Higher-risk women were more likely than lower-risk women to undergo biopsy after a positive screen. Screening identified 43 invasive ovarian cancers. The positive predictive values for abnormal screening results were 0.7% in average-risk, 1.3% in moderate-risk, and 1.6% in high-risk groups; one ovarian cancer occurred among the breast cancer survivors. The positive predictive values for postbaseline abnormal screening results were also higher in the higher-risk groups. The positive predictive values did not significantly differ across risk groups. CONCLUSION: Probabilities of abnormal annual CA 125 and transvaginal ultrasonography screens were similar across groups based on family history of breast or ovarian cancer. However, ovarian cancer was more likely to be diagnosed after an abnormal screening result among women at higher family history-based risk than among women at lower risk. LEVEL OF EVIDENCE: I.

Aged↗
PubMed2006

Familial testicular cancer: interest in genetic testing among high-risk family members.

PURPOSE: This study is part of an ongoing National Cancer Institute multidisciplinary, etiologically-focused, cross-sectional study of Familial Testicular Cancer (FTC). The current report targets interest in clinical genetic testing for susceptibility to FTC. METHODS: Demographics, knowledge, health beliefs, and psychological and social factors were evaluated as covariates related to interest in genetic testing. RESULTS: The majority (66%) of 229 participants (64 affected men, 66 unaffected men, and 99 women) from 47 multiple-case FTC families expressed interest in having a genetic test within 6 months, should such a test become available. Interest was similar among the three subgroups mentioned above. Worries about insurance discrimination based on genetic test results were associated with a significantly lower interest in testing. Alternatively, participants were more likely to be interested in genetic testing if they were younger and had higher levels of family support, a physician's recommendation supporting testing, cancer distress, and a need for information to inform the health care of their children. CONCLUSIONS: This study reveals social and relationship factors that FTC survivors and their relatives considered important when contemplating the use of new genetic technologies. This is the first study describing hypothetical interest in genetic testing for familial testicular cancer.

Adolescent↗
PubMed2006

The AIB1 polyglutamine repeat does not modify breast cancer risk in BRCA1 and BRCA2 mutation carriers.

This is by far the largest study of its kind to date, and further suggests that AIB1 does not play a substantial role in modifying the phenotype of BRCA1 and BRCA2 carriers. The AIB1 gene encodes the AIB1/SRC-3 steroid hormone receptor coactivator, and amplification of the gene and/or protein occurs in breast and ovarian tumors. A CAG/CAA repeat length polymorphism encodes a stretch of 17 to 29 glutamines in the HR-interacting carboxyl-terminal region of the protein which is somatically unstable in tumor tissues and cell lines. There is conflicting evidence regarding the role of this polymorphism as a modifier of breast cancer risk in BRCA1 and BRCA2 carriers. To further evaluate the evidence for an association between AIB1 glutamine repeat length and breast cancer risk in BRCA1 and BRCA2 mutation carriers, we have genotyped this polymorphism in 1,090 BRCA1 and 661 BRCA2 mutation carriers from Australia, Europe, and North America. There was no evidence for an increased risk associated with AIB1 glutamine repeat length. Given the large sample size, with more than adequate power to detect previously reported effects, we conclude that the AIB1 glutamine repeat does not substantially modify risk of breast cancer in BRCA1 and BRCA2 mutation carriers.

Acetyltransferases↗
PubMed2005

Prophylactic oophorectomy reduces breast cancer penetrance during prospective, long-term follow-up of BRCA1 mutation carriers.

PURPOSE: Breast cancer penetrance estimates in BRCA1 mutation carriers have varied from 40% to 85%; this heterogeneity has been attributed to variations in risk among different study populations. No study has taken oophorectomy status into account in estimating penetrance. Because prophylactic oophorectomy reduces breast cancer risk by approximately 50%, we hypothesized that population differences in oophorectomy prevalence might significantly influence breast cancer penetrance estimates. METHODS: Females from multiple-case breast/ovarian cancer families that segregate deleterious BRCA1 mutations were observed prospectively for breast cancer incidence and oophorectomy. RESULTS: Within this cohort, 33 cases of breast cancer developed in 98 women with deleterious BRCA1 mutations during follow-up, yielding an estimated cumulative lifetime breast cancer risk of 80%. This estimate increased to 94% when the study participants were censored at the time of oophorectomy. Six of the 33 mutation-positive women who underwent oophorectomy during follow-up developed breast cancer, compared with 27 of 65 mutation carriers with intact ovaries (hazard ratio = 0.38; 95% CI, 0.15 to 0.97). Estimates of absolute breast cancer risk demonstrated that the protective effect of oophorectomy was strongest among women who were premenopausal at the time of surgery. When surgical status was ignored, the strong protective effect of oophorectomy, coupled with the high prevalence of the procedure in these families, led to a significantly lower estimate of the breast cancer penetrance in BRCA1 mutation carriers. CONCLUSION: Differing rates of oophorectomy likely represent an underappreciated basis for a portion of the heterogeneity in estimated breast cancer penetrance described in BRCA mutation carriers, particularly mutation carriers from extensively affected, multiple-case families.

Adult↗
PubMed2005

The Y deletion gr/gr and susceptibility to testicular germ cell tumor.

Testicular germ cell tumor (TGCT) is the most common cancer in young men. Despite a considerable familial component to TGCT risk, no genetic change that confers increased risk has been substantiated to date. The human Y chromosome carries a number of genes specifically involved in male germ cell development, and deletion of the AZFc region at Yq11 is the most common known genetic cause of infertility. Recently, a 1.6-Mb deletion of the Y chromosome that removes part of the AZFc region--known as the "gr/gr" deletion--has been associated with infertility. In epidemiological studies, male infertility has shown an association with TGCT that is out of proportion with what can be explained by tumor effects. Thus, we hypothesized that the gr/gr deletion may be associated with TGCT. Using logistic modeling, we analyzed this deletion in a large series of TGCT cases with and without a family history of TGCT. The gr/gr deletion was present in 3.0% (13/431) of TGCT cases with a family history, 2% (28/1,376) of TGCT cases without a family history, and 1.3% (33/2,599) of unaffected males. Presence of the gr/gr deletion was associated with a twofold increased risk of TGCT (adjusted odds ratio [aOR] 2.1; 95% confidence interval [CI] 1.3-3.6; P = .005) and a threefold increased risk of TGCT among patients with a positive family history (aOR 3.2; 95% CI 1.5-6.7; P = .0027). The gr/gr deletion was more strongly associated with seminoma (aOR 3.0; 95% CI 1.6-5.4; P = .0004) than with nonseminoma TGCT (aOR 1.5; 95% CI 0.72-3.0; P = .29). These data indicate that the Y microdeletion gr/gr is a rare, low-penetrance allele that confers susceptibility to TGCT.

Alleles↗
PubMed2005

Ovarian cancer screening in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial: findings from the initial screen of a randomized trial.

OBJECTIVE: Ovarian cancer screening with transvaginal ultrasound (TVU) and CA-125 was evaluated in the Prostate, Lung, Colorectal and Ovarian (PLCO) Trial. STUDY DESIGN: This was a randomized controlled trial of screening versus usual care. Baseline screening results are reported. RESULTS: Of 39,115 women randomized to receive screening, 28,816 received at least 1 test. Abnormal TVU was found in 1338 (4.7%), and abnormal CA-125 in 402 (1.4%). Twenty-nine neoplasms were identified (26 ovarian, 2 fallopian, and 1 primary peritoneal neoplasm). Nine were tumors of low malignant potential and 20 were invasive. The positive predictive value for invasive cancer was 3.7% for an abnormal CA-125, 1.0% for an abnormal TVU, and 23.5% if both tests were abnormal. CONCLUSION: The effect of screening on ovarian cancer mortality in the PLCO cohort has yet to be evaluated and will require longer follow-up. Screening identified both early- and late-stage neoplasms, and the predictive value of both tests was relatively low.

Aged↗
PubMed2004

Exploratory study of the feasibility and utility of the colored eco-genetic relationship map (CEGRM) in women at high genetic risk of developing breast cancer.

We report here the results of an exploratory feasibility study of the colored eco-genetic relationship map (CEGRM), a novel, recently-developed psychosocial assessment tool, which incorporates features of the genetic pedigree, family systems genogram, and ecomap. The CEGRM presents a simple, concise, visual representation of the social interaction domains of information, services, and emotional support through the application of color-coded symbols to the genetic pedigree. The interactive process of completing the CEGRM was designed to facilitate contemporary genetic counseling goals of: (a) understanding the client in the context of her/his social milieu; (b) bolstering client self-awareness and insight; (c) fostering active client participation and mutuality in the counseling interaction; (d) eliciting illuminating social narratives; and (e) addressing outstanding emotional issues. Twenty women participating in a breast imaging study of women from families with BRCA1/2 mutations completed and evaluated various aspects of the CEGRM. We found that efficient construction of the CEGRM was feasible, and that compliance was excellent. Participants developed insights into their social milieu through observing the visual pattern of relationships illustrated by the CEGRM. The process of co-constructing the CEGRM fostered the participant's active involvement in the session, marked by mutuality and increased empathy. In this clinical research context, the participants felt free to share poignant stories about their friends and families. Further studies are planned to refine the CEGRM and to examine its utility in cancer genetics research.

Adult↗
PubMed2004

BRCA1 and sex ratio.

Two recent papers suggest distorted sex and transmission ratios associated with BRCA1 mutations. If real, these would provide novel insights into the normal biological function of this gene and have implications for genetic epidemiologic methods used to estimate penetrance. We addressed these observations in two settings: offspring of 283 mutation carriers and 471 mutation negative subjects from BRCA1/2 mutation-positive families with multiple cases of breast and ovarian cancer (NCI families); and relatives of 115 BRCA1/2 mutation carriers from the Washington Ashkenazi Study (WAS). The male:female ratio was below one in both BRCA1 (0.85, 95% CI 0.7-1.1 in NCI families; 0.90, 95% CI 0.6-1.4 in WAS) and BRCA2 families (0.77, 95% CI 0.5-1.3 and 0.80, 95% CI 0.5-1.2, in the NCI and WAS study groups, respectively). None of the sex ratios deviated significantly from one, and there was no significant difference between BRCA1 and BRCA2 families. The reduced sex ratio was due largely to the offspring of males, a distortion that is probably an artifact of ascertainment biases. Among adult daughters without breast or ovarian cancer born to mutation carriers, as expected, fewer than 50% were mutation carriers (39% in BRCA1 families and 44% in BRCA2 families). It is difficult, due to ascertainment biases, to draw firm conclusions regarding sex ratios in studies of a sex-limited phenotype. Nonetheless, these observations do not support the idea that BRCA1 mutation carriers have a lower ratio of male offspring than BRCA2 mutation carriers.

Breast Neoplasms↗
PubMed2004

Preneoplastic changes in ovarian tissues.

OBJECTIVE: To test whether histologically normal epithelium within ovarian inclusion cysts and stroma exhibit changes in nuclear chromatin pattern that indicate the presence of occult ovarian lesions. STUDY DESIGN: Ovaries were collected from 10 low-risk women,from 7 high-risk women and from 3 women with ovarian cancer. Histologic sections were cut at 5 microm and hematoxylin and eosin stained. High-resolution images were recorded from the epithelium lining inclusion cysts and from the underlying stroma of ovaries from these 20 subjects. A total of 2860 epithelial nuclei and 3610 stromal nuclei were recorded. Karyometric features and nuclear abnormality were computed. Discriminant analyses and unsupervised learning algorithms defined deviations from normal that were designated "above threshold" and used to compute average nuclear abnormality of a second nuclear phenotype. RESULTS: Histologically normal epithelium from inclusion cysts of ovaries harboring a malignant lesion was shown to exhibit changes in the nuclear chromatin pattern that were statistically significant using quantitative image analysis procedures. Similar changes were seen in the inclusion cyst epithelia of high-risk ovaries. A subpopulation of cells representing a new phenotype was detected in the underlying stroma of women harboring a malignant ovarian lesion and in women at high risk of ovarian cancer. CONCLUSION: The karyometric changes observed in the epithelia lining inclusion cysts and in the underlying stroma of ovaries either with ovarian cancer or at high risk of ovarian cancer suggest the presence of preneoplastic changes in histologically normal tissue.

Cell Nucleus↗
PubMed2003

Mutational analysis of the BRCA1-interacting genes ZNF350/ZBRK1 and BRIP1/BACH1 among BRCA1 and BRCA2-negative probands from breast-ovarian cancer families and among early-onset breast cancer cases and reference individuals.

Two potential breast cancer susceptibility genes, encoding the BRCA1-interacting proteins ZNF350 (or ZBRK1) and BRIP1 (or BACH1), have been identified in yeast two-hybrid screens. We sequenced these genes in probands from 21 families with potentially inherited breast/ovarian cancer, all of which were negative for BRCA1/BRCA2 mutations. Families had at least one case of male breast cancer, two cases of ovarian cancer, or three or more cases of breast and ovarian cancer. In addition, 58 early-onset (before age 35) breast cancer cases and 30 reference individuals were analyzed. Of 17 variants detected in ZBRK1, a missense mutation Val524Ile was identified in the proband of one high-risk family, but no other family members were available for testing. Of 25 variants identified in BRIP1, in addition to four common silent or missense mutations, we identified Gln540Leu, a non-conservative amino acid change, in a single familial proband with inflammatory breast cancer, but this mutation was not present in her three relatives with breast cancer. Haplotype analysis suggests that all ZBRK1 SNPs fall within a single block with two SNPs capturing 92% of the haplotype diversity, while the BRIP1 SNPs fall in two blocks, with five SNPs capturing 89% of the haplotype diversity. Based on sequencing of ZBRK1 and BRIP1 in 21 BRCA1/2-negative probands from inherited breast/ovarian cancer families, it appears unlikely that mutations in these genes account for a significant fraction of inherited breast cancer. Further analysis in unselected cases will be required to know whether the identified variants play a role in genetic predisposition to breast cancer in the general population. Hum Mutat 22:121-128, 2003. Published 2003 Wiley-Liss, Inc.

BRCA1 Protein↗