Characteristics of the Menstrual Cycle After Discontinuation of Oral Contraceptives

Background: Menstrual cycle function may continue to be altered after discontinuation of oral contraceptives (OC). Few studies have been published on the effects of recent OC use on menstrual cycle parameters; none have examined characteristics of the menstrual flow or the quality of cervical mucus. The purpose of this retrospective matched cohort study is to assess biomarkers of the menstrual cycle after discontinuation of OCs. Methods: Among a sample of women who daily recorded observations of menstrual cycle biomarkers, 70 women who had recently discontinued OCs were randomly matched by age and parity with 70 women who had not used OCs for at least 1 year. Outcomes investigated included overall cycle length, length of the luteal phase, estimated day of ovulation, duration of menstrual flow, menstrual intensity, and mucus score. Differences between recent OC users and controls were assessed using random effects modeling. Results: Recent OC users had statistically significantly lower scores for mucus quality for cycles 1 and 2. Additionally, OC users had a later estimated day of ovulation that was statistically significant in cycle 2 and a decreased intensity of menstrual flow that was significant in the first four cycles (difference = −0.48 days). In random effects modeling, all these parameters were significantly different for the first six cycles combined. Conclusions: Menstrual cycle biomarkers are altered for at least two cycles after discontinuation of OCs, and this may help explain the temporary decrease in fecundity associated with recent OC use

The search for predictive patterns in ovarian cancer: Proteomics meets bioinformatics

AbstractProteomic patterns in serum that discriminate between malignant and benign ovaries may provide a powerful tool for screening in high risk women

Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers

Peer reviewedPublisher PD

Communicating genetic test results within the family: Is it lost in translation? A survey of relatives in the randomized six-step study

Genetic testing for cancer susceptibility genes is increasingly being integrated into medical care. Test results help inform risks of the individual being tested as well as family members who could benefit from knowing the results. The responsibility for informing relatives of genetic test results falls on the proband, the first family member being tested. However, there are several challenges associated with sharing genetic test results within families including incomplete understanding of test results, emotional distance among family members, and poor communication skills. In this paper we describe the communication process between probands randomized to receive BRCA1/2 genetic test results in an enhanced versus a standard of care counseling session, and their first degree relatives with whom they shared results. We contacted 561 first degree relatives of probands who had undergone BRCA1/2 genetic testing to measure their level of understanding of the test results, their difficulty and distress upon hearing the results, the impact of the test results on their risk perception, and their intention to pursue genetic counseling/testing. 82.1 % of relatives correctly reported the test results of their proband. Distress upon hearing the test result was highest for those relatives whose proband received informative test results. Relatives reported a decrease in cancer risk perception after hearing the test results, regardless of the type of result. Intention to pursue counseling/testing was low, even among those relatives whose proband received informative test results. Male relatives were less likely to be informed of test results and more likely to forget hearing them. These results suggest ways to improve the communication process within families

Breast cancer risk prediction using a polygenic risk score in the familial setting: a prospective study from the Breast Cancer Family Registry and kConFab.

PURPOSE: This study examined the utility of sets of single-nucleotide polymorphisms (SNPs) in familial but non-BRCA-associated breast cancer (BC). METHODS: We derived a polygenic risk score (PRS) based on 24 known BC risk SNPs for 4,365 women from the Breast Cancer Family Registry and Kathleen Cuningham Consortium Foundation for Research into Familial Breast Cancer familial BC cohorts. We compared scores for women based on cancer status at baseline; 2,599 women unaffected at enrollment were followed-up for an average of 7.4 years. Cox proportional hazards regression was used to analyze the association of PRS with BC risk. The BOADICEA risk prediction algorithm was used to measure risk based on family history alone. RESULTS: The mean PRS at baseline was 2.25 (SD, 0.35) for affected women and was 2.17 (SD, 0.35) for unaffected women from combined cohorts (P < 10-6). During follow-up, 205 BC cases occurred. The hazard ratios for continuous PRS (per SD) and upper versus lower quintiles were 1.38 (95% confidence interval: 1.22-1.56) and 3.18 (95% confidence interval: 1.84-5.23) respectively. Based on their PRS-based predicted risk, management for up to 23% of women could be altered. CONCLUSION: Including BC-associated SNPs in risk assessment can provide more accurate risk prediction than family history alone and can influence recommendations for cancer screening and prevention modalities for high-risk women.Genet Med 19 1, 30-35.National Institutes of HealthThis is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/gim.2016.4

New resources for the Drosophila 4th chromosome : FRT101F enabled mitotic clones and Bloom syndrome helicase enabled meiotic recombination

Genes on the long arm of the Drosophila melanogaster 4th chromosome are difficult to study because the chromosome lacks mitotic and meiotic recombination. Without recombination numerous standard methods of genetic analysis are impossible. Here, we report new resources for the 4th. For mitotic recombination, we generated a chromosome with an FRT very near the centromere in 101F and a derivative that carries FRT101F with a distal ubiquitously expressed GAL80 transgene. This pair of chromosomes enables both unmarked and MARCM clones. For meiotic recombination, we demonstrate that a Bloom syndrome helicase and recombination defective double mutant genotype can create recombinant 4th chromosomes via female meiosis. All strains will be available to the community via the Bloomington Drosophila Stock Center. Additional resources for studies of the 4th are in preparation and will also be made available. The goal of the 4th Chromosome Resource Project is to accelerate the genetic analysis of protein-coding genes on the 4th, including the 44 genes with no demonstrated function. Studies of these previously inaccessible but largely conserved genes will close longstanding gaps in our knowledge of metazoan development and physiology.Peer reviewe

Establishing a Target Exposure for Once-Daily Intravenous Busulfan Given with Fludarabine and Thymoglobulin before Allogeneic Transplantation

AbstractA combination of fludarabine (Flu) and daily i.v. busulfan (Bu) is well tolerated and effective in patients undergoing allogeneic hematopoietic stem cell transplantation. Although there is some evidence that Bu exposures exceeding 6000 μM/min may lead to excessive toxicity, there is little information on the effect of exposures below this level on outcomes. We studied Bu exposure, as measured by area under the concentration-time curve (AUC), in 158 patients with various hematologic malignancies in an attempt to identify an optimal range for targeted therapy. The preparative chemotherapy regimen comprised Flu 50 mg/m2 on days -6 to -2 and i.v. Bu 3.2 mg/kg on days -5 to -2 inclusive. Graft-versus-host disease (GVHD) prophylaxis included methotrexate, cyclosporin A, and antithymocyte globulin. Patients with Bu exposures below the median AUC of 4439 μM/min were at increased risk for acute GVHD grade II-IV (hazard ratio [HR], 2.30; 95% confidence interval [CI], 1.19 to 4.49; P = .014). Those in the highest and lowest Bu exposure quartiles (daily AUC <3814 μM/min and >4993 μM/min) had an increased risk of nonrelapse mortality (subdistribution HR, 3.32; 95% CI, 1.46 to 7.54; P = .004), as well as worse disease-free survival (HR, 1.81; 95% CI, 1.09 to 2.99; P = .021) and overall survival (HR, 1.94; 95% CI, 1.12 to 3.37; P = .018). Bu exposures between 4440 and 4993 μM/min were accompanied by the lowest risk of both nonrelapse mortality and acute GVHD

Food Frequency Questionnaires and Overnight Urines Are Valid Indicators of Daidzein and Genistein Intake in U.S. Women Relative to Multiple 24-h Urine Samples

Data regarding convenient, valid methods for measuring U.S. isoflavone intake are limited. We evaluated a soy food questionnaire (SFQ), the Willett food frequency questionnaire (FFQ), and overnight urine samples relative to excretion in 24-h urine samples. We also described intake among women in a high-risk program for breast or ovarian cancer. Between April 2002 and June 2003, 451 women aged 30 to 50 yr with a family history of breast or ovarian cancer completed the SFQ and FFQ. Of them, 27 provided four 24-h and overnight urine specimens. In these women, 24-h sample measures were correlated with SFQ estimates of daidzein (Spearman r = .48) and genistein (r = .54) intake, moderately correlated with the Willett FFQ (daidzein r = .38, genistein r = .33), and strongly correlated with overnight urine excretion (daidzein r = .84, genistein r = 0.93). Among all 451 SFQ respondents, mean (median) daidzein and genistein intakes were 2.8 (0.24) and 3.9 (0.30) mg/day. Primary sources of both were soymilk, soy nuts, and tofu.We conclude that targeted soy food questionnaires, comprehensive FFQs, and multiple overnight urines are all reasonable options for assessing isoflavone intake in epidemiologic studies

Strong signature of natural selection within an FHIT intron implicated in prostate cancer risk

Previously, a candidate gene linkage approach on brother pairs affected with prostate cancer identified a locus of prostate cancer susceptibility at D3S1234 within the fragile histidine triad gene (FHIT), a tumor suppressor that induces apoptosis. Subsequent association tests on 16 SNPs spanning approximately 381 kb surrounding D3S1234 in Americans of European descent revealed significant evidence of association for a single SNP within intron 5 of FHIT. In the current study, resequencing and genotyping within a 28.5 kb region surrounding this SNP further delineated the association with prostate cancer risk to a 15 kb region. Multiple SNPs in sequences under evolutionary constraint within intron 5 of FHIT defined several related haplotypes with an increased risk of prostate cancer in European-Americans. Strong associations were detected for a risk haplotype defined by SNPs 138543, 142413, and 152494 in all cases (Pearson's χ2 = 12.34, df 1, P = 0.00045) and for the homozygous risk haplotype defined by SNPs 144716, 142413, and 148444 in cases that shared 2 alleles identical by descent with their affected brothers (Pearson's χ2 = 11.50, df 1, P = 0.00070). In addition to highly conserved sequences encompassing SNPs 148444 and 152413, population studies revealed strong signatures of natural selection for a 1 kb window covering the SNP 144716 in two human populations, the European American (π = 0.0072, Tajima's D= 3.31, 14 SNPs) and the Japanese (π = 0.0049, Fay & Wu's H = 8.05, 14 SNPs), as well as in chimpanzees (Fay & Wu's H = 8.62, 12 SNPs). These results strongly support the involvement of the FHIT intronic region in an increased risk of prostate cancer. © 2008 Ding et al

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer.

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM -/- patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors