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Biomedical subjects

T S Frank

Publications and source records attributed to T S Frank.

At least 19 recordsLinked to original sources
PubMed2001

Efficacy of bilateral prophylactic mastectomy in BRCA1 and BRCA2 gene mutation carriers.

BACKGROUND: In women with a family history of breast cancer, bilateral prophylactic mastectomy is associated with a decreased risk of subsequent breast cancer of approximately 90%. We examined the association between bilateral prophylactic mastectomy and breast cancer risk in women at high risk for breast cancer who also had mutations in BRCA1 and BRCA2 genes. METHODS: We obtained blood samples from 176 of the 214 high-risk women who participated in our previous retrospective cohort study of bilateral prophylactic mastectomy. We used conformation-sensitive gel electrophoresis and direct sequence analysis of the blood specimens to identify women with mutations in BRCA1 and BRCA2. The carriers' probabilities of developing breast cancer were estimated from two different penetrance models. RESULTS: We identified 26 women with an alteration in BRCA1 or BRCA2. Eighteen of the mutations were considered to be deleterious and eight to be of uncertain clinical significance. None of the 26 women has developed breast cancer after a median of 13.4 years of follow-up (range, 5.8-28.5 years). Three of the 214 women are known to have developed a breast cancer after prophylactic mastectomy. For two of these women, BRCA1 and BRCA2 screening was negative, and no blood specimen was available for the third. Estimations of the effectiveness of prophylactic mastectomy were performed, considering this woman as both a mutation carrier and a noncarrier. These calculations predicted that six to nine breast cancers should have developed among the mutation carriers, which translates into a risk reduction, after bilateral prophylactic mastectomy, of 89.5%-100% (95% confidence interval = 41.4% to 100%). CONCLUSIONS: Prophylactic mastectomy is associated with a substantial reduction in the incidence of subsequent breast cancer not only in women identified as being at high risk on the basis of a family history of breast cancer but also in known BRCA1 or BRCA2 mutation carriers.

Breast Neoplasms↗
PubMed2001

Identifying and managing hereditary risk of breast and ovarian cancer.

In the past, all women with a family history of breast or ovarian cancer were considered to be at increased risk of cancer themselves. The discovery of BRCA1 and BRCA2 demonstrated that susceptibility to breast and ovarian cancer can be inherited by women as a single-gene autosomal dominant disorder. For such women, evaluation of family history is an important screening tool to identify the possibility of hereditary cancer risk but only genetic testing can provide definitive, individualized risk assessment. Women who have inherited mutations in BRCA1 or BRCA2 now have several medical management options to address their increased risk of cancer. A well-educated community of health care providers and patients can use hereditary risk assessment, including genetic testing, to improve health care.

Age Factors↗
PubMed2001

Interpreting epidemiological research: blinded comparison of methods used to estimate the prevalence of inherited mutations in BRCA1.

While sequence analysis is considered by many to be the most sensitive method of detecting unknown mutations in large genes such as BRCA1, most published estimates of the prevalence of mutations in this gene have been derived from studies that have used other methods of gene analysis. In order to determine the relative sensitivity of techniques that are widely used in research on BRCA1, a set of blinded samples containing 58 distinct mutations were analysed by four separate laboratories. Each used one of the following methods: single strand conformational polymorphism analysis (SSCP), conformation sensitive gel electrophoresis (CSGE), two dimensional gene scanning (TDGS), and denaturing high performance liquid chromatography (DHPLC). Only the laboratory using DHPLC correctly identified each of the mutations. The laboratory using TDGS correctly identified 91% of the mutations but produced three apparent false positive results. The laboratories using SSCP and CSGE detected abnormal migration for 72% and 76% of the mutations, respectively, but subsequently confirmed and reported only 65% and 60% of mutations, respectively. False negatives therefore resulted not only from failure of the techniques to distinguish wild type from mutant, but also from failure to confirm the mutation by sequence analysis as well as from human errors leading to misreporting of results. These findings characterise sources of error in commonly used methods of mutation detection that should be addressed by laboratories using these methods. Based upon sources of error identified in this comparison, it is likely that mutations in BRCA1 and BRCA2 are more prevalent than some studies have previously reported. The findings of this comparison provide a basis for interpreting studies of mutations in susceptibility genes across many inherited cancer syndromes.

Chromatography, High Pressure Liquid↗
PubMed2001

Hereditary cancer syndromes.

OBJECTIVE: To summarize the biological basis, clinical implications, identification, and medical management of syndromes associated with increased risk of common adult cancers. DATA SOURCES: Recent studies and data available from molecular and clinical analysis of genes responsible for autosomal-dominant inheritance of cancer risk. DATA SYNTHESIS: Several hereditary cancer syndromes have been identified for which there are increasingly effective diagnostic and management options. Specific hereditary susceptibility syndromes have been characterized that increase the risk of malignancies of the breast, ovary, colon, endometrium, and endocrine organs. Following a summary of the biological basis of hereditary cancer risk in adults, the identification of such syndromes by clinical and laboratory means is reviewed. Finally, management options for individuals with these syndromes are summarized. CONCLUSIONS: Advances in gene discovery have allowed the diagnosis of recently characterized hereditary cancer syndromes to enhance medical management for individuals with inherited susceptibility to common cancers.

Adenomatous Polyposis Coli↗
PubMed2000

Incidence of BRCA1/2 germ line alterations in a high risk cohort participating in a phase II chemoprevention trial.

It is unknown what proportion of women at high risk for breast cancer, entering phase II chemoprevention trials, have BRCA1/2 alterations, and whether their initial biomarker patterns or response to preventive interventions will differ between carriers and non-carriers. As part of a 6-month phase II chemoprevention trial of diflouromethlyornithine (DFMO), high-risk subjects (family history, prior precancerous breast disease or prior breast cancer), who had random peri-areolar fine needle evidence of epithelial hyperplasia with or without atypia, were offered genetic counselling and testing at the completion of their study participation. 97% of the 119 women eligible for testing underwent BRCA1/2 gene sequencing, 3 declined. 26 (22%) of the 116 women had an alteration in BRCA1/2. Known deleterious mutations were present in 3 (3%), uncertain significance mutations in 19 (16%), and probable polymorphisms in 6 (5%). There does not appear to be a difference in initial biomarker distribution between participants with and without germ line alterations.

Adult↗
PubMed2000

The predictive value of BRCA1 and BRCA2 mutation testing.

Genetic testing for mutations in BRCA1 and BRCA2, two genes predisposing to breast and ovarian cancers, is available to women with a relevant family history. The aim of this study was to estimate the positive and negative predictive value of clinical sequence analysis of these genes. A reference graph showing positive and negative predictive values over a range of pre-test risk was derived, taking into account the sensitivity and specificity of a full-sequence analysis test. High positive and negative predictive values were found for women with pre-test risk between 4% and 40%, a range of risk commonly seen in clinical testing. The predictive value of full sequence and single-site analysis of BRCA1 and BRCA2, therefore, compares favorably with other diagnostic medical tests. Our results provide a numerical estimate of the predictive value of BRCA testing, and as such, provide a valuable tool to healthcare providers and families as they interpret BRCA1 and BRCA2 test results.

BRCA1 Protein↗
PubMed1999

Comparison of alterations of chromosome 17 in carcinoma of the ovary and of the breast.

Breast and ovarian carcinomas share a region of allelic loss on chromosome 17q25, suggesting that these tumours may arise by similar molecular pathways. We analysed paraffin-embedded tissues from 84 sporadic ovarian carcinomas and 42 sporadic infiltrating ductal carcinomas of the breast for abnormalities on chromosome 17. Loss of heterozygosity (LOH) of at least one informative marker on 17q was identified in 49 of 82 (60%) ovarian carcinomas, as against only 6 of 40 (15%) informative breast carcinomas (P<0.0001). In ovarian carcinoma, LOH was most commonly observed for GH on 17q23 (56%), and was also frequently observed at 17q21 (46%). In contrast, LOH of D17S 1330/CTT16 on 17q25 was observed in only 19% of ovarian tumours. LOH in breast carcinomas was most frequently observed at 17q21 (16%), less frequently at 17q23 (7%) and not identified at all at 17q25 in any breast cancers. Immunohistochemical analysis demonstrated overexpression of the p53 gene product in 38 of 84 (45%) ovarian carcinomas, as against 10 of 42 (24%) breast carcinomas (P = 0.0195). p53 immunoreactivity was significantly associated with LOH in ovarian and breast cancers. Immunohistochemical expression of HER2/neu was observed in 6 of 84 (7%) ovarian and 3 of 42 (7%) breast carcinomas. There was no relationship between HER2/neu immunoreactivity and LOH. Although sporadic carcinomas of breast and ovary share some regions of allelic loss on chromosome 17q, differences in other alterations on this chromosome suggest divergent pathways of tumour development.

Breast Neoplasms↗
PubMed1999

Comparison of mutations of Ki-RAS and p53 immunoreactivity in borderline and malignant epithelial ovarian tumors.

Ovarian tumors of low malignant potential ("borderline tumors") have been proposed variably to represent a distinctive type of malignancy, precursors of frank ovarian malignancy, or a nonmalignant process. We analyzed 81 malignant and 39 borderline ovarian tumors for p53 immunoreactivity and alterations in codon 12 of Ki-RAS in order to correlate these alterations with tumor and cell type. Diffuse p53 immunoreactivity was significantly more prevalent among malignant (36 of 81, 44%) than among borderline (3 of 39, 8%) tumors and was particularly prevalent among serous invasive carcinomas (16 of 26, 62%). Conversely, mutations in codon 12 of Ki-RAS were significantly more prevalent in borderline (16 of 39, 41%) than in malignant (9 of 81, 11%) ovarian tumors and were most prevalent among mucinous tumors. This preliminary molecular analysis suggests that serous borderline tumors have some molecular features usually associated with malignancy but are unlikely to represent a precursor of invasive serous carcinoma. In contrast, mucinous borderline tumors may represent a precursor or variant of mucinous carcinoma of the ovary.

Adenocarcinoma, Mucinous↗
PubMed1999

Hereditary susceptibility to breast cancer: significance of age of onset in family history and contribution of BRCA1 and BRCA2.

OBJECTIVE: To correlate mutations in BRCA1 and BRCA2 with family history of breast cancer in a first-degree relative for women diagnosed with breast cancer before age 45 who do not have a personal or family history of ovarian cancer. METHODS: Family history for women with breast cancer diagnosed before age 45 was provided by ordering physicians via a test requisition form designed for this purpose. Gene analysis was performed by dye primer sequencing for the entire coding regions of BRCA1 and BRCA2. Because a personal and family history of ovarian cancer are known to be significantly associated with mutations, women with either were excluded from analysis. RESULTS: Overall, deleterious mutations in BRCA1 or BRCA2 were identified in 85 of 440 women (19%) with breast cancer under 45. Mutations were identified in 73 of 276 women (26%) with a first degree family history of breast cancer compared to 12 of 164 without (7%) (P < .0001). When results were analyzed by the age of diagnosis in first degree relatives, mutations were identified in 56 of 185 women (30%) with at least one first degree relative with breast cancer diagnosed before age 50 compared with 17 of 91 women (19%), where the first degree family history of breast cancer was at or over age 50 (P = .042). CONCLUSION: Among women with breast cancer diagnosed before age 45, a first-degree relative diagnosed with the disease under age 50 is an indicator of a mutation in BRCA1 or BRCA2 even in the absence of a family history of ovarian cancer. Therefore, women diagnosed with early-onset breast cancer should be asked about the age of onset in any first-degree relative diagnosed with the disease, as well as about any family history of ovarian cancer. Mutations in BRCA2 account for a substantial proportion of hereditary breast cancer. Therefore, studies that are limited to BRCA1 or that do not analyze by age of onset of breast cancer in relatives may underestimate the contribution of mutations in BRCA1 and BRCA2 to women with early onset breast cancer.

Adult↗
PubMed1999

Laboratory determination of hereditary susceptibility to breast and ovarian cancer.

Inherited mutations in the genes BRCA1 and BRCA2 are associated with a significantly increased risk of breast cancer, particularly before the age of 50 years, as well as an increased risk of ovarian cancer. Patients with early-onset breast cancer or ovarian cancer at any age with a family history of either disease are at higher risk of carrying a mutation in BRCA1 or BRCA2. Laboratory analysis of these genes can determine whether a patient has inherited an increased risk of breast and ovarian cancer. In the absence of a mutation that has been previously identified in a family member, most tests for hereditary breast-ovarian cancer risk analyze the entire coding sequences of BRCA1 and BRCA2. The gene sequencing process itself can be automated, but the data must be interpreted by an individual with training in molecular diagnostics. Management options generally available to individuals with hereditary susceptibility to breast and ovarian cancer include heightened surveillance, prophylactic surgery, and chemoprevention. The use of genetic techniques to identify women with increased risk of cancer demonstrates the application of recent advances in the understanding of the genetic basis of malignancy to laboratory medicine and clinical care.

Adult↗
PubMed1998

Comparative analysis of histologic homologues of endometrial and ovarian carcinoma.

We compared molecular alterations in histologically homologous ovarian and uterine carcinomas, including the prevalence of allelic loss of markers on 17q (within and distal to the familial breast-ovarian cancer gene BRCA1), mutations of codon 12 of Ki-ras and immunohistochemical expression of the p53 and c-erbB2 gene products in endometrioid and papillary serous carcinomas occurring in the uterus and ovary. A total of 86 uterine and 28 ovarian endometrioid carcinomas, as well as 8 uterine and 26 ovarian papillary serous carcinomas, were evaluated. The prevalence of p53 gene product immunoreactivity was similar in papillary serous carcinomas occurring in the uterus (6 of 8, 75%) and ovary (16 of 26, 62%). Allelic loss on 17q also was seen in similarly high proportions of uterine (3 of 7, 43%) and ovarian (16 of 25, 64%) papillary serous carcinomas. In contrast, expression of the p53 gene product was seen in significantly more endometrioid tumors of the ovary (14 of 28, 50%) than in those occurring in the uterus (4 of 86, 5%) (p < 0.0001). Allelic loss on 17q also was present in significantly more ovarian (19 or 27, 70% than in uterine (2 of 72, 3%) endometrioid carcinomas (p < 0.0001). Immunohistochemical expression of c-erbB2 and mutations of codon 12 of Ki-ras were present in a minority of carcinomas. Endometrioid tumors of the ovary and endometrium, although histologically similar, may arise from different genetic events, whereas uterine papillary serous carcinoma shares with its ovarian counterpart several molecular alterations that may account for its aggressive clinical behavior.

Carcinoma↗
PubMed1998

Sequence analysis of BRCA1 and BRCA2: correlation of mutations with family history and ovarian cancer risk.

PURPOSE: Previous studies of mutations in BRCA1 or BRCA2 have used detection methods that may underestimate the actual frequency of mutations and have analyzed women using heterogeneous criteria for risk of hereditary cancer. PATIENTS AND METHODS: A total of 238 women with breast cancer before age 50 or ovarian cancer at any age and at least one first- or second-degree relative with either diagnosis underwent sequence analysis of BRCA1 followed by analysis of BRCA2 (except for 27 women who declined analysis of BRCA2 after a deleterious mutation was discovered in BRCA1). Results were correlated with personal and family history of malignancy. RESULTS: Deleterious mutations were identified in 94 (39%) women, including 59 of 117 (50%) from families with ovarian cancer and 35 of 121 (29%) from families without ovarian cancer. Mutations were identified in 14 of 70 (20%) women with just one other relative who developed breast cancer before age 50. In women with breast cancer, mutations in BRCA1 and BRCA2 were associated with a 10-fold increased risk of subsequent ovarian carcinoma (P = .005). CONCLUSION: Because mutations in BRCA1 and BRCA2 in women with breast cancer are associated with an increased risk of ovarian cancer, analysis of these genes should be considered for women diagnosed with breast cancer who have a high probability of carrying a mutation according to the statistical model developed with these data.

Adult↗
PubMed1998

Analysis of human papillomavirus infection and molecular alterations in adenocarcinoma of the cervix.

Although molecular alterations involved in the development of squamous cell carcinoma of the cervix have been extensively described, these genetic changes have not been as well characterized in the development of cervical adenocarcinoma. Twenty-seven paraffin-embedded adenocarcinomas of the cervix, including three cases of adenoma malignum, were analyzed for molecular alterations associated with other gynecologic malignancies. The presence of human papillomavirus (HPV) was assessed by polymerase chain reaction (PCR) using internally nested consensus primers. HPV types were identified by restriction endonuclease digestion of the PCR products, using DNA sequencing to confirm each digestion pattern. The presence of HPV was correlated with immunohistochemical expression of the p53 gene product, the presence of mutations in codon 12 of Ki-ras, and allelic deletion of markers associated with the development of other gynecologic carcinomas. HPV was identified in 16 (59%) of 27 cases, including type 18 in 7 tumors, type 16 in 7 tumors, and type 45 in 2 tumors. HPV types 16 and 45 were always identified in adjacent uninvolved cervical epithelium, but HPV type 18 was absent from the adjacent non-neoplastic epithelium in four of the seven positive cases. HPV was not identified in any of three cases of adenoma malignum. Diffuse immunohistochemical staining of the p53 gene product was present in only one (HPV-negative) tumor. A mutation in codon 12 of Ki-ras was observed in one endocervical adenocarcinoma (with an endometrioid pattern). Loss of heterozygosity was identified only for a marker on chromosome 6p in one mucinous endocervical carcinoma. Most endocervical adenocarcinomas lack molecular alterations characteristic of other histologically similar gynecologic malignancies, as well as those described in cervical squamous cell carcinomas.

Adenocarcinoma↗