Tuya Pal

Long-Term Ovarian Cancer Survival Associated With Mutation in BRCA1 or BRCA2

BACKGROUND Studies have suggested that the 5-year survival of women with ovarian cancer and a BRCA1 or BRCA2 mutation is better than expected. We sought to evaluate the impact of carrying a BRCA1 or BRCA2 mutation on long-term survival of women after a diagnosis of invasive ovarian cancer. METHODS One thousand six hundred twenty-six unselected women diagnosed with invasive ovarian cancer in Ontario, Canada, or in Tampa, Florida, between 1995 and 2004 were followed for a mean of 6.9 years (range = 0.3 to 15.7 years). Mutation screening for BRCA1 and BRCA2 revealed mutations in 218 women (13.4%). Left-truncated survival analysis was conducted to estimate ovarian cancer-specific survival at various time points after diagnosis for women with and without mutations. RESULTS In the 3-year period after diagnosis, the presence of a BRCA1 or BRCA2 mutation was associated with a better prognosis (adjusted hazard ratio = 0.68, 95% confidence interval [CI] = 0.48 to 0.98; P = .03), but at 10 years after diagnosis, the hazard ratio was 1.00 (95% CI = 0.83 to 1.22; P = .90). Among women with serous ovarian cancers, 27.4% of women who were BRCA1 mutation carriers, 27.7% of women who were BRCA2 carriers, and 27.1% of women who were noncarriers were alive at 12 years past diagnosis. CONCLUSION For women with invasive ovarian cancer, the short-term survival advantage of carrying a BRCA1 or BRCA2 mutation does not lead to a long-term survival benefit.

Systematic Review and Meta-analysis of Ovarian Cancers: Estimation of Microsatellite-High Frequency and Characterization of Mismatch Repair Deficient Tumor Histology

Purpose: A meta-analytic approach was used to estimate the frequency of: (a) microsatellite instability-high (MSI-H) phenotype in unselected ovarian cancers and (b) various histologic subtypes of mismatch repair (MMR)-deficient epithelial ovarian cancers. Methods: A systematic search of the Medline electronic database was conducted to identify articles published between January 1, 1966, and December 31, 2007, that examined MMR deficiency in ovarian cancers. Data were extracted on the study population, sample size, MSI-H frequency, and histology of MMR-deficient ovarian tumors. Results: The pooled proportion of MSI-H ovarian cancers was 0.12 [95% confidence interval (CI), 0.08-0.17] from 18 studies with 977 cases. The proportion of histologic subtypes in the pooled analysis from 15 studies with 159 cases was serous at 0.32 (95% CI, 0.20-0.44), mucinous at 0.19 (95% CI, 0.12-0.27), endometrioid at 0.29 (95% CI, 0.22-0.36), clear cell at 0.18 (95% CI, 0.09-0.28), and mixed at 0.24 (95% CI, 0.07-0.47). There was significant heterogeneity between studies. Conclusions: The frequency of the MSI-H phenotype in unselected ovarian cancers approximates 12%. MMR-deficient ovarian cancers also seem to be characterized by an overrepresentation of nonserous histologic subtypes. Knowledge of histologic subtype may aid clinicians in identifying the relatively large proportion of ovarian cancers due to MMR defects; such knowledge has potential implications for medical management.

Panel‐based testing for inherited colorectal cancer: a descriptive study of clinical testing performed by a US laboratory

Next‐generation sequencing enables testing for multiple genes simultaneously (‘panel‐based testing’) as opposed to sequential testing for one inherited condition at a time (‘syndrome‐based testing’). This study presents results from patients who underwent hereditary colorectal cancer (CRC) panel‐based testing (‘ColoNext™’). De‐identified data from a clinical testing laboratory were used to calculate (1) frequencies for patient demographic, clinical, and family history variables and (2) rates of pathogenic mutations and variants of uncertain significance (VUS). The proportion of individuals with a pathogenic mutation who met national syndrome‐based testing criteria was also determined. Of 586 patients, a pathogenic mutation was identified in 10.4%, while 20.1% had at least one VUS. After removing eight patients with CHEK2 mutations and 11 MUTYH heterozygotes, the percentage of patients with ‘actionable’ mutations that would clearly alter cancer screening recommendations per national guidelines decreased to 7.2%. Of 42 patients with an ‘actionable’ result, 30 (71%) clearly met established syndrome‐based testing guidelines. This descriptive study is among the first to report on a large clinical series of patients undergoing panel‐based testing for inherited CRC. Results are discussed in the context of benefits and concerns that have been raised about panel‐based testing implementation.

Estrogen Bioactivation, Genetic Polymorphisms, and Ovarian Cancer

Recent experimental evidence has shown that catechol estrogens can be activated through metabolism to form depurinating DNA adducts and thereby initiate cancer. Limited data are available regarding this pathway in epithelial ovarian cancer. We conducted a case-control study of 503 incident epithelial ovarian cancer cases at the Mayo Clinic in Rochester, MN, and Jacksonville, FL, and a 48-county region in North Carolina. Six hundred nine cancer-free controls were frequency matched to the cases on age, race, and residence. After an interview to obtain data on risk factors, a sample of blood was collected for DNA isolation. Subjects were genotyped for seven common single nucleotide polymorphisms in four genes involved in catechol estrogen formation (CYP1A1 and CYP1B1) or conjugation (COMT and SULT1A1). Data were analyzed using logistic regression, stratified by race, and with adjustment for design factors and potential confounders. None of the individual genotypes were significantly associated with ovarian cancer risk. However, an oligogenic model that considered the joint effects of the four candidate genes provided evidence for an association between combinations of these genes and ovarian cancer status (P = 0.015). Although preliminary, this study provides some support for the hypothesis that low-penetrance susceptibility alleles may influence risk of epithelial ovarian cancer.

A review of the clinical relevance of mismatch-repair deficiency in ovarian cancer.

Ovarian cancer ranks fifth in both cancer incidence and mortality among women in the United States. Defects in the mismatch‐repair (MMR) pathway that arise through genetic and/or epigenetic mechanisms may be important etiologically in a reasonable proportion of ovarian cancers. Genetic mechanisms of MMR dysfunction include germline and somatic mutations in the MMR proteins. Germline mutations cause hereditary nonpolyposis colorectal cancer (HNPCC), which is the third most common cause of inherited ovarian cancer after BRCA1 and BRCA2 mutations. An epigenetic mechanism known to cause inactivation of the MMR system is promoter hypermethylation of 1 of the MMR genes, mutL homolog 1 (MLH1). Various laboratory methods, in addition to clinical and histopathologic criteria, can be used to identify MMR‐deficient ovarian cancers. Such methods include microsatellite instability analysis, immunohistochemistry, MLH1 promoter hypermethylation testing, and germline mutation analysis. In this review, the authors describe the existing literature regarding the molecular, clinical, and histologic characteristics of MMR‐deficient ovarian cancers along with the possible effect on survival and treatment response. By further defining the profile of MMR‐deficient ovarian cancers and their associated etiologic mechanisms, there may be a greater potential to distinguish between those of hereditary and sporadic etiology. The ability to make such distinctions may be of diagnostic, prognostic, and therapeutic utility. Cancer 2008.

Bilateral Oophorectomy and Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers.

Background: Whether oophorectomy reduces breast cancer risk among BRCA mutation carriers is a matter of debate. We undertook a prospective analysis of bilateral oophorectomy and breast cancer risk in BRCA mutation carriers. Methods: Subjects had no history of cancer, had both breasts intact, and had information on oophorectomy status (n = 3722). Women were followed until breast cancer diagnosis, prophylactic bilateral mastectomy, or death. A Cox regression model was used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of breast cancer associated with oophorectomy (coded as a time-dependent variable). All statistical tests were two-sided. Results: Over a mean follow-up of 5.6 years, 350 new breast cancers were diagnosed. Among women with a BRCA1 or BRCA2 mutation, oophorectomy was not associated with breast cancer risk compared with women who did not undergo an oophorectomy. The age-adjusted hazard ratio associated with oophorectomy was 0.96 (95% CI = 0.73 to 1.26, P = .76) for BRCA1 and was 0.65 (95% CI = 0.37 to 1.16, P = .14) for BRCA2 mutation carriers. In stratified analyses, the effect of oophorectomy was statistically significant for breast cancer in BRCA2 mutation carriers diagnosed prior to age 50 years (age-adjusted HR = 0.18, 95% CI = 0.05 to 0.63, P = .007). Oophorectomy was not associated with risk of breast cancer prior to age 50 years among BRCA1 mutation carriers (age-adjusted HR = 0.79, 95% CI = 0.55 to 1.13, P = .51). Conclusions: Findings from this large prospective study support a role of oophorectomy for the prevention of premenopausal breast cancer in BRCA2, but not BRCA1 mutation carriers. These findings warrant further evaluation.

Do MSH6 mutations contribute to double primary cancers of the colorectum and endometrium

Mismatch repair (MMR) gene mutations cause hereditary nonpolyposis colorectal cancer (HNPCC), a common form of familial colorectal cancer. Among MMR genes, germline MSH6 mutations are often observed in HNPCC-like families with an increased frequency of endometrial cancer. We have previously shown that a proportion of women affected with double primary cancers of the colorectum and endometrium carry germline MSH2 or MLH1 mutations and, thus, belong to HNPCC families. In this study, we have investigated the specific contribution of MSH6 defects to such double primary patients. By sequence analysis of the entire coding region of MSH6, three putative missense mutations were identified in patients with atypical family histories that do not meet HNPCC criteria. Moreover, one of these mutations, a novel substitution Arg901His, was found in a patient previously shown to carry a truncating germline MLH1 mutation. Thus, MSH6 mutations are likely to contribute to the etiology of double primary cancers of the colorectum and endometrium.

Fertility in women with BRCA mutations: a case-control study

OBJECTIVE To investigate whether or not fertility is reduced in women carrying mutations in the BRCA genes (BRCA1 and BRCA2), compared with noncarrier family members. DESIGN Matched case-control study. SETTING Academic. PATIENT(S) A total of 2,254 BRCA carriers and 764 noncarrier controls who were from the same families as the carriers, but tested negative for the BRCA mutation. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) History of fertility problems (yes/no) and prior use of fertility medications (yes/no) in cases and controls, obtained through administered questionnaire. RESULT(S) There was no difference in mean parity between carriers (1.9) and noncarriers (1.9). CONCLUSION(S) This study, which is the first epidemiologic study to specifically investigate the effect of carrying a BRCA mutation on parity and fertility, suggests that there is likely little or no effect of the BRCA gene mutation on fertility. To our knowledge previous epidemiologic studies have not investigated the effect of carrying a BRCA mutation on parity or fertility. However, we expect that if fertility differences exist, they would be toward the limits of reproductive life, thus larger studies with age-stratified analyses are needed to definitively answer this question.

Comparing universal Lynch syndrome tumor-screening programs to evaluate associations between implementation strategies and patient follow-through.

Purpose:Universal tumor screening (UTS) for all colorectal cancer patients can improve the identification of Lynch syndrome, the most common cause of hereditary colorectal cancer. This multiple-case study explored how variability in UTS procedures influenced patient follow-through (PF) with germ-line testing after a screen-positive result.Methods:Data were obtained through Web-based surveys and telephone interviews with institutional informants. Institutions were categorized as Low-PF (≤10% underwent germ-line testing), Medium-PF (11–40%), or High-PF (>40%). To identify implementation procedures (i.e., conditions) unique to High-PF institutions, qualitative comparative analysis was performed.Results:Twenty-one informants from 15 institutions completed surveys and/or interviews. Conditions present among all five High-PF institutions included the following: (i) disclosure of screen-positive results to patients by genetic counselors; and (ii) genetic counselors either facilitate physician referrals to genetics professionals or eliminate the need for referrals. Although both of these High-PF conditions were present among two Medium-PF institutions, automatic reflex testing was lacking and difficulty contacting screen-positive patients was a barrier. The three remaining Medium-PF and five Low-PF institutions lacked the conditions found in High-PF institutions.Conclusion:Methods for streamlining UTS procedures, incorporating a high level of involvement of genetic counselors in tracking and communication of results and in reducing barriers to patient contact, are reviewed within a broader discussion on maximizing the effectiveness and public health impact of UTS.Genet Med 16 10, 773–782.

Frequency of mutations in mismatch repair genes in a population-based study of women with ovarian cancer.

Background:Mutations in genes for hereditary non-polyposis colorectal cancer (HNPCC) in ovarian cancer patients remains poorly defined. We sought to estimate the frequency and characteristics of HNPCC gene mutations in a population-based sample of women with epithelial ovarian cancer.Methods:The analysis included 1893 women with epithelial ovarian cancer ascertained from three population-based studies. Full-germline DNA sequencing of the coding regions was performed on three HNPCC genes, MLH1, MSH2 and MSH6. Collection of demographic, clinical and family history information was attempted in all women.Results:Nine clearly pathogenic mutations were identified, including five in MSH6, two each in MLH1 and MSH2. In addition, 28 unique predicted pathogenic missense variants were identified in 55 patients. Pathogenic mutation carriers had an earlier mean age at diagnosis of ovarian cancer, overrepresentation of cancers with non-serous histologies and a higher number of relatives with HNPCC-related cancers.Conclusions:Our findings suggest that fewer than 1% of women with ovarian cancer harbour a germline mutation in the HNPCC genes, with overrepresentation of MSH6 mutations. This represents a lower-range estimate due to the large number of predicted pathogenic variants in which pathogenicity could not definitively be determined. Identification of mismatch repair gene mutations has the potential to impact screening and treatment decisions in these women.