Methylation Analyses Reveal Promoter Hypermethylation as a Rare Cause of “Second Hit” in Germline BRCA1-Associated Pancreatic Ductal Adenocarcinoma

Background and objectivePancreatic ductal adenocarcinoma (PDAC) is characterized by the occurrence of pathogenic variants in BRCA1/2 in 5-6% of patients. Biallelic loss of BRCA1/2 enriches for response to platinum agents and poly (ADP-ribose) polymerase 1 inhibitors. There is a dearth of evidence on the mechanism of inactivation of the wild-type BRCA1 allele in PDAC tumors with a germline BRCA1 (gBRCA1) pathogenic or likely pathogenic variant (P/LPV). Herein, we examine promotor hypermethylation as a "second hit" mechanism in patients with gBRCA1-PDAC.MethodsWe evaluated patients with PDAC who underwent Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) somatic and germline testing from an institutional database. DNA isolated from tumor tissue and matched normal peripheral blood were sequenced by MSK-IMPACT. In patients with gBRCA1-PDAC, we examined the somatic BRCA1 mutation status and promotor methylation status of the tumor BRCA1 allele via a methylation array analysis. In patients with sufficient remaining DNA, a second methylation analysis by pyrosequencing was performed.ResultsOf 1012 patients with PDAC, 19 (1.9%) were identified to harbor a gBRCA1 P/LPV. Fifteen patients underwent a methylation array and the mean percentage of BRCA1 promotor methylation was 3.62%. In seven patients in whom sufficient DNA was available, subsequent pyrosequencing confirmed an unmethylated BRCA1 promotor. Loss of heterozygosity was detected in 12 of 19 (63%, 95% confidence interval 38-84) patients, demonstrating loss of heterozygosity is the major molecular mechanism of BRCA1 inactivation in PDAC. Two (10.5%) cases had a somatic BRCA1 mutation.ConclusionsIn patients with gBRCA1-P/LPV-PDAC, loss of heterozygosity is the main inactivating mechanism of the wild-type BRCA1 allele in the tumor, and methylation of the BRCA1 promoter is a distinctly uncommon occurrence

Breast Cancer Family History and Contralateral Breast Cancer Risk in Young Women: An Update From the Women's Environmental Cancer and Radiation Epidemiology Study.

Purpose The Women's Environmental Cancer and Radiation Epidemiology (WECARE) study demonstrated the importance of breast cancer family history on contralateral breast cancer (CBC) risk, even for noncarriers of deleterious BRCA1/2 mutations. With the completion of WECARE II, updated risk estimates are reported. Additional analyses that exclude women negative for deleterious mutations in ATM, CHEK2*1100delC, and PALB2 were performed. Patients and Methods The WECARE Study is a population-based case-control study that compared 1,521 CBC cases with 2,212 individually matched unilateral breast cancer (UBC) controls. Participants were younger than age 55 years when diagnosed with a first invasive breast cancer between 1985 and 2008. Women were interviewed about breast cancer risk factors, including family history. A subset of women was screened for deleterious mutations in BRCA1/2, ATM, CHEK2*1100delC, and PALB2. Rate ratios (RRs) were estimated using multivariable conditional logistic regression. Cumulative absolute risks (ARs) were estimated by combining RRs from the WECARE Study and population-based SEER*Stat cancer incidence data. Results Women with any first-degree relative with breast cancer had a 10-year AR of 8.1% for CBC (95% CI, 6.7% to 9.8%). Risks also were increased if the relative was diagnosed at an age younger than 40 years (10-year AR, 13.5%; 95% CI, 8.8% to 20.8%) or with CBC (10-year AR, 14.1%; 95% CI, 9.5% to 20.7%). These risks are comparable with those seen in BRCA1/2 deleterious mutation carriers (10-year AR, 18.4%; 95% CI, 16.0% to 21.3%). In the subset of women who tested negative for deleterious mutations in BRCA1/2, ATM, CHEK2*1100delC, and PALB2, estimates were unchanged. Adjustment for known breast cancer single-nucleotide polymorphisms did not affect estimates. Conclusion Breast cancer family history confers a high CBC risk, even after excluding women with deleterious mutations. Clinicians are urged to use detailed family histories to guide treatment and future screening decisions for young women with breast cancer

Risk for contralateral breast cancer among carriers of the CHEK2*1100delC mutation in the WECARE Study

The protein encoded by the CHEK2 gene is involved in cellular repair of DNA damage. The truncating mutation, CHEK2*1100delC, seems to increase the risk for breast cancer. We investigated whether the CHEK2*1100delC mutation carrier status increases the risk for asynchronous contralateral breast cancer (CBC) and whether it interacts with radiation therapy (RT) or chemotherapy in regard to CBC risk. The germline mutation frequency was assessed in 708 women with CBC and 1395 women with unilateral breast cancer (UBC) in the Women's Environment, Cancer and Radiation Epidemiology (WECARE) Study whose first primary breast cancer was diagnosed before age 55 years and during 1985–1999. Seven women with CBC (1.0%) and 10 women with UBC (0.7%) were CHEK2*1100delC variant carriers (rate ratio (RR)=1.8, 95% confidence interval (CI)=0.6–5.4 for CBC vs UBC). Carriers who received RT for their first breast cancer, compared with non-carriers not treated with RT, had an RR of developing CBC of 2.6 (95% CI=0.8–8.7). We found no significant associations between the CHEK2*1100delC mutation and CBC overall or among those treated with RT. However, the sampling variability was such that modest increases in risk could not be excluded. Nonetheless, because this is a rare mutation, it is unlikely to explain a major fraction of CBC in the population

Meta-analysis of binary outcomes via generalized linear mixed models: a simulation study

Background: Systematic reviews and meta-analyses of binary outcomes are widespread in all areas of application. The odds ratio, in particular, is by far the most popular effect measure. However, the standard meta-analysis of odds ratios using a random-effects model has a number of potential problems. An attractive alternative approach for the meta-analysis of binary outcomes uses a class of generalized linear mixed models (GLMMs). GLMMs are believed to overcome the problems of the standard random-effects model because they use a correct binomial-normal likelihood. However, this belief is based on theoretical considerations, and no sufficient simulations have assessed the performance of GLMMs in meta-analysis. This gap may be due to the computational complexity of these models and the resulting considerable time requirements. Methods: The present study is the first to provide extensive simulations on the performance of four GLMM methods (models with fixed and random study effects and two conditional methods) for meta-analysis of odds ratios in comparison to the standard random effects model. Results: In our simulations, the hypergeometric-normal model provided less biased estimation of the heterogeneity variance than the standard random-effects meta-analysis using the restricted maximum likelihood (REML) estimation when the data were sparse, but the REML method performed similarly for the point estimation of the odds ratio, and better for the interval estimation. Conclusions: It is difficult to recommend the use of GLMMs in the practice of meta-analysis. The problem of finding uniformly good methods of the meta-analysis for binary outcomes is still open

Liana loads and their association with Bertholletia excelsa fruit and nut production, diameter growth and crown attributes

We investigated the association between lianas and Bertholletia excelsa (Brazil nut), a long-lived, emergent tree of significant ecological and economic importance in Amazonia. Our objectives were: (1) to determine the relationship between crown liana load and liana number, basal area, and origin in relation to the B. excelsa host; and (2) to determine the relationship between liana load and B. excelsa fruit and nut production, diameter growth, and crown form, position and area. One hundred and forty trees ([greater-than-or-equal]50 cm dbh) were selected with representatives of 10 diameter classes and four liana load categories. To quantify fruit and nut production, fruit counts and nut fresh weights per tree were measured in 2002 and 2003, and annual diameter growth was quantified using dendrometer bands. Trees with lianas produced significantly fewer fruits and had reduced nut fresh weights than liana-free trees. Trees with the most extensive liana loads (\u3e75% crown coverage) were 10.2 times more likely to have crown forms categorized as less than half-crowns or few branches than trees with reduced liana loads. No statistically significant relationship was found between liana load and tree diameter growth. Results suggest that liana cutting might increase B. excelsa fecundity and commercial nut yields

Risk factors for developing a new venous thromboembolism in ambulatory patients with non-hematologic malignancies and impact on survival for gastroesophageal malignancies

Background: Venous thromboembolism(VTE) is a significant, common comorbidity of cancer patients associated with increased mortality. We evaluated the incidence and risk factors for developing a new VTE in ambulatory cancer patients while they were receiving therapy for advanced cancer. We also examined the affect of developing a new VTE on survival for patients with gastroesophageal malignancies. Methods: All patients with non-hematologic malignancies who were treated using investigator-initiated therapeutic protocols at Memorial Sloan Kettering Cancer Center (MSKCC) from 2003 through to 2005 were identified for this cohort study. The occurrence of VTE was prospectively recorded in an actively managed clinical research database. Baseline laboratory parameters, treatment details and tumor type were correlated with VTE risk and patient survival. Results: 115 out of 2120 patients being treated for advanced malignancy developed a new VTE(12.8 VTEs/100 person-years). In multivariate analysis, a diagnosis of gastroesophageal cancer (hazard ratio (HR), 2.76 (1.41-5.38); P = 0.003), pancreatic cancer (HR, 2.26 (1.06-4.80); P = 0.05), use of white cell growth factors (HR 1.69(1.09-2.64); P = 0.02) and irinotecan therapy (HR, 1.89 (1.29-3.59); P = 0.05) were independently associated with VTE development. Hemoglobin > 10 g dL(-1) (HR, 0.52 (0.3-0.91); P = 0.02) and albumin >= 4 g dL(-1) (HR, 0.61 (0.39-0.94); P - 0.024) were associated with reduced VTE risk. The unadjusted HR for death among ambulatory gastroesophageal cancer patients with VTE is 0.89 (0.61-1.3), P = 0.53. After adjusting for confounding risk factors associated with survival, the HR for death associated with VTE is 0.78 (0.5-1.2), P = 0.25. Conclusion: Upper gastrointestinal malignancies are independently associated with the development of a new VTE, implicating tumor biology in VTE development. Even after adjusting for prognostic factors, we were unable to demonstrate an adverse impact on survival due to the new development of VTE amongst patients with active gastroesophageal malignancy receiving therapy

Pancreatic adenocarcinoma: insights into patterns of recurrence and disease behavior

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers with high metastatic potential. Clinical observations suggest that there is disease heterogeneity among patients with different sites of distant metastases, yielding distinct clinical outcomes. Herein, we investigate the impact of clinical and pathological parameters on recurrence patterns and compare survival outcomes for patients with a first site of recurrence in the liver versus lung from PDAC following original curative surgical resection. Methods Using the Memorial Sloan Kettering Cancer Center ICD billing codes and tumor registry database over a 10 years period (January 2004–December 2014), we identified PDAC patients who underwent resection and subsequently presented with either liver or lung recurrence. Time from relapse to death (TRD) was calculated from date of recurrence to date of death. Using the Kaplan-Meier method, TRD was estimated and compared by recurrence site using log-rank test. Results The median overall follow-up was 37.3 months among survivors in the entire cohort. Median TRD in this cohort was 10.7 months (95%CI: 8.9–14.6 months). Patients with first site of lung recurrence had a more favorable outcome compared to patients who recurred with liver metastasis as the first site of recurrence (median TRD of 15 versus 9 months respectively, P = 0.02). Moderate to poorly or poor differentiation was associated more often with liver than lung recurrence (40% vs 21% respectively, P = 0.047). A trend to increased lymph node metastasis in the lung recurrence cohort was observed. Conclusion PDAC patients who recur with a first site of lung metastasis have an improved clinical outcome compared to patients with first site of liver recurrence. Our data suggests there may be epidemiologic and pathologic determinants related to patterns of recurrence in PDAC

Dual energy computed tomography analysis in cancer patients: What factors affect iodine concentration in contrast enhanced studies?

Purpose: The aim of the study is to explore the patient's and scan's parameters that affect the iodine concentration in the abdomen using dual energy computed tomography (DECT) in an oncologic population. Method: This is a retrospective study with consecutive patients with different cancers who underwent a single-source DECT (ssDECT) examinations at our institution between years 2015 and 2017. On axial IODINE images, the radiologist manually drew a circular ROI along the inner contour of the aorta. Mean iodine concentration and ROI areas were recorded. Body mass index for every patient was recorded. Descriptive statistics were summarized for iodine concentration and patient/scan characteristics. Linear regression was used to examine associations between iodine concentration in aorta and studied characteristics. Statistical significance was set at a p value < 0.05. Results: The univariate analysis, showed a statistically significant association between iodine concentration within the aorta and the area of ROI (Estimated Coefficient β: −0.013), the rate of injection (Estimated Coefficient β: 2.09), the acquisition time (Estimated Coefficient β: −0.195). In multivariable analysis iodine concentration in the aorta increased with higher rate of injection (4 ml/sec), smaller ROI area and lower BMI. Conclusion: Our results showed how iodine concentration is highly dependent on some intrinsic and extrinsic parameters of the examination. These parameters should be taken into account since lower concentration of iodine decrease contrast-to-noise ratio, and in longitudinal follow up studies, they would affect iodine quantitive assessments in cancer patients with frequent chemotherapy-induced variations in BMI and cardiac function