Publications by authors named "Linda S Cook"

125 Publications

Associations between Genetically Predicted Circulating Protein Concentrations and Endometrial Cancer Risk.

Cancers (Basel) 2021 Apr 26;13(9). Epub 2021 Apr 26.

Population Sciences in the Pacific Program, Cancer Epidemiology Division, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI 96813, USA.

Endometrial cancer (EC) is the leading female reproductive tract malignancy in developed countries. Currently, genome-wide association studies (GWAS) have identified 17 risk loci for EC. To identify novel EC-associated proteins, we used previously reported protein quantitative trait loci for 1434 plasma proteins as instruments to evaluate associations between genetically predicted circulating protein concentrations and EC risk. We studied 12,906 cases and 108,979 controls of European descent included in the Endometrial Cancer Association Consortium, the Epidemiology of Endometrial Cancer Consortium, and the UK Biobank. We observed associations between genetically predicted concentrations of nine proteins and EC risk at a false discovery rate of <0.05 (-values range from 1.14 × 10 to 3.04 × 10). Except for vascular cell adhesion protein 1, all other identified proteins were independent from known EC risk variants identified in EC GWAS. The respective odds ratios (95% confidence intervals) per one standard deviation increase in genetically predicted circulating protein concentrations were 1.21 (1.13, 1.30) for DNA repair protein RAD51 homolog 4, 1.27 (1.14, 1.42) for desmoglein-2, 1.14 (1.07, 1.22) for MHC class I polypeptide-related sequence B, 1.05 (1.02, 1.08) for histo-blood group ABO system transferase, 0.77 (0.68, 0.89) for intestinal-type alkaline phosphatase, 0.82 (0.74, 0.91) for carbohydrate sulfotransferase 15, 1.07 (1.03, 1.11) for D-glucuronyl C5-epimerase, and 1.07 (1.03, 1.10) for CD209 antigen. In conclusion, we identified nine potential EC-associated proteins. If validated by additional studies, our findings may contribute to understanding the pathogenesis of endometrial tumor development and identifying women at high risk of EC along with other EC risk factors and biomarkers.
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http://dx.doi.org/10.3390/cancers13092088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8123478PMC
April 2021

Southwest Harvest for Health: Adapting a mentored vegetable gardening intervention for cancer survivors in the southwest.

Contemp Clin Trials Commun 2021 Mar 11;21:100741. Epub 2021 Feb 11.

Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL, USA.

Few diet and physical activity evidence-based interventions have been routinely used in community settings to achieve population health outcomes. Adapting interventions to fit the implementation context is important to achieve the desired results. Harvest for Health is a home-based vegetable gardening intervention that pairs cancer survivors with certified Master Gardeners from the Cooperative Extension Service with the ultimate goal of increasing vegetable consumption and physical activity, and improving physical functioning and health-related quality-of-life. Harvest for Health has potential for widespread dissemination since Master Gardener Programs exist throughout the United States. However, state- and population-specific adaptations may be needed to improve intervention adoption by other Master Gardener Programs. Our primary objective was to adapt this evidence-informed intervention that was initially incepted in Alabama, for the drastically different climate and growing conditions of New Mexico using a recommended adaptation framework. Our secondary objective was to develop a study protocol to support a pilot test of the adapted intervention, Southwest Harvest for Health. The adaptation phase is a critical first step towards widespread dissemination, implementation, and scale-out of an evidence-based intervention. This paper describes the adaptation process and outcomes, and the resulting protocol for the ongoing pilot study that is currently following 30 cancer survivors and their paired Extension Master Gardener mentors.
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http://dx.doi.org/10.1016/j.conctc.2021.100741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896154PMC
March 2021

A Population-Based Feasibility Study of Occupation and Thoracic Malignancies in New Mexico.

Southwest J Pulm Crit Care 2021 13;22(1):23-25. Epub 2021 Aug 13.

UNM Comprehensive Cancer Center, University of New Mexico, MSC 07-4025, 1 UNM, Albuquerque, NM, 87131, USA.

Background: Occupational exposures in mining and oil/gas extraction are known risk factors for thoracic malignancies (TMs). Given the relatively high proportion of these industries in New Mexico (NM), we conducted a feasibility study of adult lifetime occupational history among TM cases. We hypothesized a higher proportion of occupational TM in NM relative to the estimated national average of 10-14%.

Methods: We identified incident TM cases through the population-based New Mexico Tumor Registry (NMTR), from 2017-2018. Cases completed a telephone interview. An adjudication panel reviewed case histories and classified cancers as probable, possible, or non-occupational related, taking into account the presence, duration, and latency of exposures. We characterized recruitment and describe job titles and exposures among those with occupational TMs. We also compared the distributions of industry between those with and without occupational TM.

Results: The NMTR identified 400 eligible TM cases, 290 of which were available to be recruited (n=285 lung/bronchial cancer; n=5 mesotheliomas). Of the latter, 60% refused and 18% were deceased, 9% had invalid addresses, 11% were unable to be reached by telephone, and 3% were too ill to participate. The 43 cases who completed an interview held 236 jobs. A total of 33% of cases were classified as probable occupational TM and 5% as possible occupational TM.

Conclusions: High rates of early mortality and refusals were significant barriers to study participation. Nonetheless, the proportion of probable occupational TMs greatly exceeded the estimated national average, highlighting the need for further study of occupational TM in the state.
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http://dx.doi.org/10.13175/swjpcc067-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891545PMC
August 2021

Cross-Cancer Genome-Wide Association Study of Endometrial Cancer and Epithelial Ovarian Cancer Identifies Genetic Risk Regions Associated with Risk of Both Cancers.

Cancer Epidemiol Biomarkers Prev 2021 01 3;30(1):217-228. Epub 2020 Nov 3.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.

Background: Accumulating evidence suggests a relationship between endometrial cancer and ovarian cancer. Independent genome-wide association studies (GWAS) for endometrial cancer and ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. We aimed to identify joint endometrial and ovarian cancer risk loci by performing a meta-analysis of GWAS summary statistics from these two cancers.

Methods: Using LDScore regression, we explored the genetic correlation between endometrial cancer and ovarian cancer. To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e., inverse-variance meta-analysis, colocalization, and M-values) and performed analyses stratified by subtype. Candidate target genes were then prioritized using functional genomic data.

Results: Genetic correlation analysis revealed significant genetic correlation between the two cancers ( = 0.43, = 2.66 × 10). We found seven loci associated with risk for both cancers ( < 2.4 × 10). In addition, four novel subgenome-wide regions at 7p22.2, 7q22.1, 9p12, and 11q13.3 were identified ( < 5 × 10). Promoter-associated HiChIP chromatin loops from immortalized endometrium and ovarian cell lines and expression quantitative trait loci data highlighted candidate target genes for further investigation.

Conclusions: Using cross-cancer GWAS meta-analysis, we have identified several joint endometrial and ovarian cancer risk loci and candidate target genes for future functional analysis.

Impact: Our research highlights the shared genetic relationship between endometrial cancer and ovarian cancer. Further studies in larger sample sets are required to confirm our findings.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0739DOI Listing
January 2021

Pregnancy outcomes and risk of endometrial cancer: A pooled analysis of individual participant data in the Epidemiology of Endometrial Cancer Consortium.

Int J Cancer 2021 May 17;148(9):2068-2078. Epub 2020 Nov 17.

Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy.

A full-term pregnancy is associated with reduced endometrial cancer risk; however, whether the effect of additional pregnancies is independent of age at last pregnancy is unknown. The associations between other pregnancy-related factors and endometrial cancer risk are less clear. We pooled individual participant data from 11 cohort and 19 case-control studies participating in the Epidemiology of Endometrial Cancer Consortium (E2C2) including 16 986 women with endometrial cancer and 39 538 control women. We used one- and two-stage meta-analytic approaches to estimate pooled odds ratios (ORs) for the association between exposures and endometrial cancer risk. Ever having a full-term pregnancy was associated with a 41% reduction in risk of endometrial cancer compared to never having a full-term pregnancy (OR = 0.59, 95% confidence interval [CI] 0.56-0.63). The risk reduction appeared the greatest for the first full-term pregnancy (OR = 0.78, 95% CI 0.72-0.84), with a further ~15% reduction per pregnancy up to eight pregnancies (OR = 0.20, 95% CI 0.14-0.28) that was independent of age at last full-term pregnancy. Incomplete pregnancy was also associated with decreased endometrial cancer risk (7%-9% reduction per pregnancy). Twin births appeared to have the same effect as singleton pregnancies. Our pooled analysis shows that, while the magnitude of the risk reduction is greater for a full-term pregnancy than an incomplete pregnancy, each additional pregnancy is associated with further reduction in endometrial cancer risk, independent of age at last full-term pregnancy. These results suggest that the very high progesterone level in the last trimester of pregnancy is not the sole explanation for the protective effect of pregnancy.
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http://dx.doi.org/10.1002/ijc.33360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969437PMC
May 2021

Determinants of Guideline-Discordant Breast Cancer Care.

Cancer Epidemiol Biomarkers Prev 2021 01 22;30(1):61-70. Epub 2020 Oct 22.

Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.

Background: Evidence-based breast cancer treatment guidelines recommend the most appropriate course of therapy based on tumor characteristics and extent of disease. Evaluating the multilevel factors associated with guideline discordance is critical to identifying strategies to eliminate breast cancer survival disparities.

Methods: We identified females diagnosed with a first primary, stage I-III breast cancer between the ages of 20-69 years of age from the population-based Seattle-Puget Sound Surveillance, Epidemiology, and End Results registry. Participants completed a survey about social support, utilization of patient support services, hypothesized barriers to care, and initiation of breast cancer treatment. We used logistic regression to estimate odds ratios and 95% confidence intervals (CI).

Results: Among 1,390 participants, 10% reported guideline-discordant care. In analyses adjusted for patient-level sociodemographic factors, individuals who did not have someone to go with them to appointments or drive them home (OR 1.96; 95% CI, 1.09-3.59) and those who had problems talking to their doctors or their staff (OR 2.03; 95% CI, 1.13-3.64) were more likely to be guideline discordant than those with social support or without such problems, respectively. Use of patient support services was associated with a 43% lower odds of guideline discordance (OR 0.57; 95% CI, 0.36-0.88).

Conclusions: Although guideline discordance in this cohort of early-stage breast cancer survivors diagnosed <70 years of age was low, instrumental social support, patient support services, and communication with doctors and their staff emerged as potential multilevel intervention targets for improving breast cancer care delivery.

Impact: This study supports extending the reach of interventions designed to improve guideline concordance.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855615PMC
January 2021

Prospective Cohort Study of Pre- and Postdiagnosis Physical Activity and Endometrial Cancer Survival.

J Clin Oncol 2020 12 7;38(34):4107-4117. Epub 2020 Oct 7.

Faculty of Kinesiology, Sport, and Recreation, University of Alberta, Edmonton, Alberta, Canada.

Purpose: The aim of this study was to evaluate associations between pre- and postdiagnosis physical activity and survival in survivors of endometrial cancer by physical activity domain, intensity, dose (metabolic-equivalent task [MET]-hours/week/year), and change from pre- to postdiagnosis.

Methods: We conducted a prospective cohort study in Alberta, Canada, of 425 women who were diagnosed with histologically confirmed invasive endometrial cancer between 2002 and 2006 and observed to 2019. The interviewer-administered Lifetime Total Physical Activity Questionnaire recorded prediagnosis (assessed at a median of 4.4 months after diagnosis) and postdiagnosis physical activity (assessed at a median of 3.4 years after diagnosis). Associations between physical activity and overall and disease-free survival were assessed using Cox proportional hazards models adjusted for age, stage, grade, treatments, body mass index, menopausal status, hormone therapy use, family history of cancer, and comorbidities.

Results: After a median follow-up of 14.5 years, there were 60 deaths, including 18 endometrial cancer deaths, and 80 disease-free survival events. Higher prediagnosis recreational physical activity was statistically significantly associated with improved disease-free survival (> 14 ≤ 8 MET-hours/week/year; hazard ratio [HR], 0.54; 95% CI, 0.30 to 0.96; = .04), but not overall survival (HR, 0.56; 95% CI, 0.29 to 1.07; = .06). Higher postdiagnosis recreational physical activity (> 13 ≤ 5 MET-hours/week/year) was strongly associated with both improved disease-free survival (HR, 0.33; 95% CI, 0.17 to 0.64; = .001) and overall survival (HR, 0.33; 95% CI, 0.15 to 0.75; = .007). Participants who maintained high recreational physical activity levels from pre- to postdiagnosis also had improved disease-free survival (HR, 0.35; 95% CI, 0.18 to 0.69) and overall survival (HR, 0.43; 95% CI, 0.20 to 0.94) compared with those who maintained low physical activity levels.

Conclusion: Recreational physical activity, especially postdiagnosis, is associated with improved survival in survivors of endometrial cancer.
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http://dx.doi.org/10.1200/JCO.20.01336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768343PMC
December 2020

Mendelian randomization analyses suggest a role for cholesterol in the development of endometrial cancer.

Int J Cancer 2021 01 7;148(2):307-319. Epub 2020 Aug 7.

Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, Georgia, USA.

Blood lipids have been associated with the development of a range of cancers, including breast, lung and colorectal cancer. For endometrial cancer, observational studies have reported inconsistent associations between blood lipids and cancer risk. To reduce biases from unmeasured confounding, we performed a bidirectional, two-sample Mendelian randomization analysis to investigate the relationship between levels of three blood lipids (low-density lipoprotein [LDL] and high-density lipoprotein [HDL] cholesterol, and triglycerides) and endometrial cancer risk. Genetic variants associated with each of these blood lipid levels (P < 5 × 10 ) were identified as instrumental variables, and assessed using genome-wide association study data from the Endometrial Cancer Association Consortium (12 906 cases and 108 979 controls) and the Global Lipids Genetic Consortium (n = 188 578). Mendelian randomization analyses found genetically raised LDL cholesterol levels to be associated with lower risks of endometrial cancer of all histologies combined, and of endometrioid and non-endometrioid subtypes. Conversely, higher genetically predicted HDL cholesterol levels were associated with increased risk of non-endometrioid endometrial cancer. After accounting for the potential confounding role of obesity (as measured by genetic variants associated with body mass index), the association between genetically predicted increased LDL cholesterol levels and lower endometrial cancer risk remained significant, especially for non-endometrioid endometrial cancer. There was no evidence to support a role for triglycerides in endometrial cancer development. Our study supports a role for LDL and HDL cholesterol in the development of non-endometrioid endometrial cancer. Further studies are required to understand the mechanisms underlying these findings.
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http://dx.doi.org/10.1002/ijc.33206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757859PMC
January 2021

New Mexico Female Miners Have Lower Odds for COPD than Their Male Counterparts.

COPD 2020 10 24;17(5):509-514. Epub 2020 Aug 24.

Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM, USA.

Chronic obstructive pulmonary disease (COPD) is a significant cause of morbidity among miners. There is an increasing number of women in the mining industry and the differences in their risk for COPD compared to men miners are not understood. Our objective is to compare the odds for COPD between male and female miners. Using cross-sectional data from the ning ust in the nited tates (MiDUS) Cohort, that included New Mexico miners between 1989 and 2018, we compared the odds for airflow obstruction or chronic bronchitis between women and men. There were 299 women in this diverse cohort of 7,464 miners. Compared to men, female miners reported lower cumulative smoking but higher prevalence of current smoking. Multivariable analysis showed that women miners had significantly lower odds for having airflow obstruction (OR 0.40; 95% CI (0.26, 0.6)) and chronic bronchitis (OR 0.31, 95% CI (0.19, 0.53)) than men. Future studies need to determine whether this sex difference is explained by residual confounders or true biological difference.
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http://dx.doi.org/10.1080/15412555.2020.1804847DOI Listing
October 2020

Refined cut-off for TP53 immunohistochemistry improves prediction of TP53 mutation status in ovarian mucinous tumors: implications for outcome analyses.

Mod Pathol 2021 01 28;34(1):194-206. Epub 2020 Jul 28.

Centre for Cancer Research, The Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW, Australia.

TP53 mutations are implicated in the progression of mucinous borderline tumors (MBOT) to mucinous ovarian carcinomas (MOC). Optimized immunohistochemistry (IHC) for TP53 has been established as a proxy for the TP53 mutation status in other ovarian tumor types. We aimed to confirm the ability of TP53 IHC to predict TP53 mutation status in ovarian mucinous tumors and to evaluate the association of TP53 mutation status with survival among patients with MBOT and MOC. Tumor tissue from an initial cohort of 113 women with MBOT/MOC was stained with optimized IHC for TP53 using tissue microarrays (75.2%) or full sections (24.8%) and interpreted using established criteria as normal or abnormal (overexpression, complete absence, or cytoplasmic). Cases were considered concordant if abnormal IHC staining predicted deleterious TP53 mutations. Discordant tissue microarray cases were re-evaluated on full sections and interpretational criteria were refined. The initial cohort was expanded to a total of 165 MBOT and 424 MOC for the examination of the association of survival with TP53 mutation status, assessed either by TP53 IHC and/or sequencing. Initially, 82/113 (72.6%) cases were concordant using the established criteria. Refined criteria for overexpression to account for intratumoral heterogeneity and terminal differentiation improved concordance to 93.8% (106/113). In the expanded cohort, 19.4% (32/165) of MBOT showed evidence for TP53 mutation and this was associated with a higher risk of recurrence, disease-specific death, and all-cause mortality (overall survival: HR = 4.6, 95% CI 1.5-14.3, p = 0.0087). Within MOC, 61.1% (259/424) harbored a TP53 mutation, but this was not associated with survival (overall survival, p = 0.77). TP53 IHC is an accurate proxy for TP53 mutation status with refined interpretation criteria accounting for intratumoral heterogeneity and terminal differentiation in ovarian mucinous tumors. TP53 mutation status is an important biomarker to identify MBOT with a higher risk of mortality.
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http://dx.doi.org/10.1038/s41379-020-0618-9DOI Listing
January 2021

Prospective cohort study of metabolic syndrome and endometrial cancer survival.

Gynecol Oncol 2020 09 27;158(3):727-733. Epub 2020 Jun 27.

Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Department of Cancer Epidemiology and Prevention Research, CancerControl Alberta, Alberta Health Services, Calgary, Alberta, Canada; Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada. Electronic address:

Objective: Comorbidities are known to increase endometrial cancer risk, but the separate and combined impact of these risk factors on endometrial cancer survival remains unclear. This study aimed to determine the associations between metabolic syndrome and its components with disease-free survival, overall survival, endometrial cancer-specific survival and recurrence among endometrial cancer survivors.

Methods: Cases from a population-based case-control study who were diagnosed with primary endometrial cancer between 2002 and 2006 in Alberta, Canada were followed until death or March 20, 2019. Baseline in-person interviews, direct anthropometric measurements and fasting blood samples were used to assess metabolic syndrome (presence of ≥3 of the following: waist circumference ≥ 88 cm, fasting blood glucose ≥100 mg/dL, triglycerides ≥150 mg/dL, high-density lipoprotein cholesterol <50 mg/dL and self-reported hypertension). Cox proportional hazards regression and Fine and Gray competing risk models were used to estimate multivariate-adjusted hazard ratios (95% CI) for these associations.

Results: Among 540 endometrial cancer survivors, 325 had metabolic syndrome at diagnosis and 132 had a recurrence and/or died during the median 14.2 years of follow-up (range: 0.3-16.5 years). In multivariable analyses, being diagnosed with metabolic syndrome (HR = 1.98, 95% CI = 1.07-3.67) and having an elevated waist circumference (≥88 cm; HR = 2.12, 95% CI = 1.18-3.80; HR = 1.21, 95% CI = 1.07-1.36) were associated with worse overall survival. Additionally, increasing waist circumference (per 5 cm) was also associated worse with disease-free survival (HR = 1.11, 95% CI = 1.00-1.24).

Conclusion: The metabolic syndrome, in particular central adiposity, were associated with worse overall and disease-free survival in endometrial cancer survivors.
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http://dx.doi.org/10.1016/j.ygyno.2020.06.488DOI Listing
September 2020

Clinical and pathological associations of PTEN expression in ovarian cancer: a multicentre study from the Ovarian Tumour Tissue Analysis Consortium.

Br J Cancer 2020 09 18;123(5):793-802. Epub 2020 Jun 18.

Department of Oncology, Strangeways Research Laboratory, University of Cambridge, Cambridge, England.

Background: PTEN loss is a putative driver in histotypes of ovarian cancer (high-grade serous (HGSOC), endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous (LGSOC)). We aimed to characterise PTEN expression as a biomarker in epithelial ovarian cancer in a large population-based study.

Methods: Tumours from 5400 patients from a multicentre observational, prospective cohort study of the Ovarian Tumour Tissue Analysis Consortium were used to evaluate associations between immunohistochemical PTEN patterns and overall survival time, age, stage, grade, residual tumour, CD8+ tumour-infiltrating lymphocytes (TIL) counts, expression of oestrogen receptor (ER), progesterone receptor (PR) and androgen receptor (AR) by means of Cox proportional hazard models and generalised Cochran-Mantel-Haenszel tests.

Results: Downregulation of cytoplasmic PTEN expression was most frequent in ENOC (most frequently in younger patients; p value = 0.0001) and CCOC and was associated with longer overall survival in HGSOC (hazard ratio: 0.78, 95% CI: 0.65-0.94, p value = 0.022). PTEN expression was associated with ER, PR and AR expression (p values: 0.0008, 0.062 and 0.0002, respectively) in HGSOC and with lower CD8 counts in CCOC (p value < 0.0001). Heterogeneous expression of PTEN was more prevalent in advanced HGSOC (p value = 0.019) and associated with higher CD8 counts (p value = 0.0016).

Conclusions: PTEN loss is a frequent driver in ovarian carcinoma associating distinctly with expression of hormonal receptors and CD8+ TIL counts in HGSOC and CCOC histotypes.
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http://dx.doi.org/10.1038/s41416-020-0900-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463007PMC
September 2020

Combined CCNE1 high-level amplification and overexpression is associated with unfavourable outcome in tubo-ovarian high-grade serous carcinoma.

J Pathol Clin Res 2020 10 11;6(4):252-262. Epub 2020 May 11.

Department of Pathology and Laboratory Medicine, University of Calgary, Foothills Medical Center, Calgary, AB, Canada.

CCNE1 amplification is a recurrent alteration associated with unfavourable outcome in tubo-ovarian high-grade serous carcinoma (HGSC). We aimed to investigate whether immunohistochemistry (IHC) can be used to identify CCNE1 amplification status and to validate whether CCNE1 high-level amplification and overexpression are prognostic in HGSC. A testing set of 528 HGSC samples stained with two optimised IHC assays (clones EP126 and HE12) was subjected to digital image analysis and visual scoring. DNA and RNA chromogenic in situ hybridisation for CCNE1 were performed. IHC cut-off was determined by receiver operating characteristics (ROC). Survival analyses (endpoint ovarian cancer specific survival) were performed and validated in an independent validation set of 764 HGSC. Finally, combined amplification/expression status was evaluated in cases with complete data (n = 1114). CCNE1 high-level amplification was present in 11.2% of patients in the testing set and 10.2% in the combined cohort. The optimal cut-off for IHC to predict CCNE1 high-level amplification was 60% positive tumour cells with at least 5% strong staining cells (sensitivity 81.6%, specificity 77.4%). CCNE1 high-level amplification and overexpression were associated with survival in the testing and validation set. Combined CCNE1 high-level amplification and overexpression was present in 8.3% of patients, mutually exclusive to germline BRCA1/2 mutation and significantly associated with a higher risk of death in multivariate analysis adjusted for age, stage and cohort (hazard ratio = 1.78, 95 CI% 1.38-2.26, p < 0.0001). CCNE1 high-level amplification combined with overexpression identifies patients with a sufficiently poor prognosis that treatment alternatives are urgently needed. Given that this combination is mutually exclusive to BRCA1/2 germline mutations, a predictive marker for PARP inhibition, CCNE1 high-level amplification combined with overexpression may serve as a negative predictive test for sensitivity to PARP inhibitors.
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http://dx.doi.org/10.1002/cjp2.168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578325PMC
October 2020

Case-control study of endogenous sex steroid hormones and risk of endometrial cancer.

Cancer Causes Control 2020 Feb 21;31(2):161-171. Epub 2019 Dec 21.

Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.

Background: Epidemiologic evidence regarding the role of endogenous sex hormones in endometrial cancer etiology remains inconsistent. The objective of this study was to investigate if circulating levels of endogenous estrone, estradiol, sex hormone binding globulin (SHBG), testosterone, and androstenedione are associated with endometrial cancer risk.

Methods: We conducted a population-based case-control study of 522 incident endometrial cancer cases and 976 population controls, in Alberta, Canada from 2002 to 2006. Study participants completed in-person interviews and provided fasting blood samples. Sex hormone levels were determined by enzyme-linked immunosorbent assays.

Results: Higher levels of androstenedione were associated with increased endometrial cancer risk (OR 1.44, 95% CI 1.04-2.02). Endometrial cancer risk in pre- and peri-menopausal women was reduced for the highest versus lowest quartiles of estrone (OR 0.44, 95% CI 0.22-0.88) and estradiol (OR 0.30, 95% CI 0.14-0.65), but in post-menopausal women, the endometrial cancer risk was increased for the highest versus lowest quartile of androstenedione (OR 1.82, 95% CI 1.25-2.65). In addition, endometrial cancer risk in normal/underweight women was decreased for the highest versus lowest quartile of serum SHBG (OR 0.39, 95% CI 0.19-0.84).

Conclusions: Overall, positive associations were found for androstenedione concentrations, while sub-group analyses revealed = inverse associations with estrogens and SHBG. Results of this study provide empirical evidence for the role of circulating sex hormones in endometrial cancer etiology and highlight the importance of modifiable factors that contribute to changes in sex hormone concentration levels.
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http://dx.doi.org/10.1007/s10552-019-01260-5DOI Listing
February 2020

Relationship between Diabetes and Diabetes Medications and Risk of Different Molecular Subtypes of Breast Cancer.

Cancer Epidemiol Biomarkers Prev 2019 11 8;28(11):1802-1808. Epub 2019 Aug 8.

Department of Epidemiology, University of Washington, Seattle, Washington.

Background: Type II diabetes and certain diabetes treatments have been observed to impact breast cancer risk. However, their associations with different breast cancer molecular subtype defined by estrogen receptor (ER)/progesterone receptor (PR)/HER2 status are unclear.

Methods: We conducted a retrospective multi-center population-based case-case study consisting of 4,557 breast cancer cases to evaluate the impact of type II diabetes and diabetes medications on the risk of different breast cancer molecular subtypes [ER/HER2, ER/HER2, triple negative (ER/PR/HER2), and HER2 overexpressing (H2E, ER/PR/HER2)]. Using ER/HER2 cases as the reference group, we estimated ORs and corresponding 95% confidence intervals (CI) for each subtype using polytomous logistic regression.

Results: Compared with those without a diabetes history, women with type II diabetes had a 38% (95% CI, 1.01-1.89) increased odds of triple-negative breast cancer (TNBC). Current and longer term recent metformin use (13-24 months of treatment within the 24-month period prior to breast cancer diagnosis) was associated with elevated odds of TNBC (OR = 1.54; 95% CI, 1.07-2.22 and OR = 1.80; 95% CI, 1.13-2.85, respectively).

Conclusions: The odds of having a triple-negative rather than ER/HER2 breast cancer is greater for women with type II diabetes, and particularly for those who were users of metformin. This finding is supported by some preclinical data suggesting that diabetes may be more strongly associated with risk of triple-negative disease.

Impact: Our study provides novel evidence regarding potential differential effects of type II diabetes and metformin use on risk of different molecular subtypes of breast cancer.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-0291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825551PMC
November 2019

Dual Actions of Ketorolac in Metastatic Ovarian Cancer.

Cancers (Basel) 2019 Jul 24;11(8). Epub 2019 Jul 24.

Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.

Cytoreductive surgery and chemotherapy are cornerstones of ovarian cancer treatment, yet disease recurrence remains a significant clinical issue. Surgery can release cancer cells into the circulation, suppress anti-tumor immunity, and induce inflammatory responses that support the growth of residual disease. Intervention within the peri-operative window is an under-explored opportunity to mitigate these consequences of surgery and influence the course of metastatic disease to improve patient outcomes. One drug associated with improved survival in cancer patients is ketorolac. Ketorolac is a chiral molecule administered as a 1:1 racemic mixture of the S- and R-enantiomers. The S-enantiomer is considered the active component for its FDA indication in pain management with selective activity against cyclooxygenase (COX) enzymes. The R-enantiomer has a previously unrecognized activity as an inhibitor of Rac1 (Ras-related C3 botulinum toxin substrate) and Cdc42 (cell division control protein 42) GTPases. Therefore, ketorolac differs from other non-steroidal anti-inflammatory drugs (NSAIDs) by functioning as two distinct pharmacologic entities due to the independent actions of each enantiomer. In this review, we summarize evidence supporting the benefits of ketorolac administration for ovarian cancer patients. We also discuss how simultaneous inhibition of these two distinct classes of targets, COX enzymes and Rac1/Cdc42, by S-ketorolac and R-ketorolac respectively, could each contribute to anti-cancer activity.
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http://dx.doi.org/10.3390/cancers11081049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721416PMC
July 2019

A combination of the immunohistochemical markers CK7 and SATB2 is highly sensitive and specific for distinguishing primary ovarian mucinous tumors from colorectal and appendiceal metastases.

Mod Pathol 2019 12 25;32(12):1834-1846. Epub 2019 Jun 25.

Department of Obstetrics and Gynecology, Sahlgrenska Cancer Center, Inst Clinical Scienses, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.

Primary ovarian mucinous tumors can be difficult to distinguish from metastatic gastrointestinal neoplasms by histology alone. The expected immunoprofile of a suspected metastatic lower gastrointestinal tumor is CK7/CK20/CDX2/PAX8. This study assesses the addition of a novel marker SATB2, to improve the diagnostic algorithm. A test cohort included 155 ovarian mucinous tumors (105 carcinomas and 50 borderline tumors) and 230 primary lower gastrointestinal neoplasms (123 colorectal adenocarcinomas and 107 appendiceal neoplasms). All cases were assessed for SATB2, PAX8 CK7, CK20, and CDX2 expression on tissue microarrays. Expression was scored in a 3-tier system as absent, focal (1-50% of tumor cells) and diffuse ( >50% of tumor cells) and then categorized into either absent/present or nondiffuse/diffuse. SATB2 and PAX8 expression was further evaluated in ovarian tumors from an international cohort of 2876 patients (expansion cohort, including 159 mucinous carcinomas and 46 borderline mucinous tumors). The highest accuracy of an individual marker in distinguishing lower gastrointestinal from ovarian mucinous tumors was CK7 (91.7%, nondiffuse/diffuse cut-off) followed by SATB2 (88.8%, present/absent cut-off). The most effective combination was CK7 and SATB2 with accuracy of 95.3% using the 3-tier interpretation, absent/focal/diffuse. This combination outperformed the standard clinical set of CK7, CK20 and CDX2 (87.5%). Re-evaluation of outlier cases confirmed ovarian origin for all but one case. The accuracy of SATB2 was confirmed in the expansion cohort (91.5%). SATB2 expression was also detected in 15% of ovarian endometrioid carcinoma but less than 5% of other ovarian histotypes. A simple two marker combination of CK7 and SATB2 can distinguish lower gastrointestinal from ovarian primary mucinous tumors with greater than 95% accuracy. PAX8 and CDX2 have value as second-line markers. The utility of CK20 in this setting is low and this warrants replacement of this marker with SATB2 in clinical practice.
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http://dx.doi.org/10.1038/s41379-019-0302-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8207534PMC
December 2019

Recent Use of Oral Contraceptives and Risk of Luminal B, Triple-Negative, and HER2-Overexpressing Breast Cancer.

Horm Cancer 2019 06 15;10(2-3):71-76. Epub 2019 Apr 15.

Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N., M4-C308, Seattle, WA, 98109, USA.

Oral contraceptive use is a well-established risk factor for breast cancer and is common among reproductive-aged women in the USA. Its relationship with less common, more aggressive, molecular subtypes is less clear. A population-based case-case analysis was conducted comparing three less common molecular subtypes to luminal A breast cancer among 1701 premenopausal cases aged 21-49 diagnosed with a first primary invasive breast cancer between 2004 and 2015. Medical record reviews and structured interviewer-administered questionnaires were used to collect data on oral contraceptive use. Multinomial logistic regression was used to estimate odds ratios (OR) and corresponding 95% confidence intervals (95% CI) for recency of oral contraceptive use for each subtype of breast cancer. Current use of oral contraceptives and use within 5 years before diagnosis was associated with lower odds of H2E tumors compared with luminal A tumors [OR = 0.5, 95% CI: 0.3, 0.9 and OR = 0.5, 95% CI: 0.4, 0.8, respectively] with increasing duration associated with decreasing odds (p for trend < 0.05). Oral contraceptive use was not associated with risks of TN or luminal B breast cancer. Oral contraceptive use may be more strongly positively associated with risks of luminal A, luminal B, and TN breast cancer than with risk of H2E tumors. These findings contribute to the etiological understanding of different molecular subtypes of breast cancer.
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http://dx.doi.org/10.1007/s12672-019-00362-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6550997PMC
June 2019

Among All Miners, Coal Miners Demonstrate a Disproportionately High Prevalence of Obstructive Spirometric Abnormality and Chronic Bronchitis.

J Occup Environ Med 2019 04;61(4):328-334

University of New Mexico School of Medicine, Albuquerque (Dr Sood, Mrs Shore, Dr Myers, Dr Assad, Dr Cook); and Miners' Colfax Medical Center, Raton (Dr Sood, Mr Pollard), New Mexico.

Objective: To compare the prevalence of chronic obstructive pulmonary disease (COPD) between miners extracting coal versus other minerals.

Methods: The study population was based on New Mexico miners, mostly Hispanic and American Indian, attending a rural community-based mobile screening clinic program between 1989 and 2014. We compared self-reported symptoms, lung diseases, and spirometric patterns between 1353 coal miners and 4140 non-coal miners.

Results: Obstruction was the most common abnormal spirometric pattern among all miners (16.9%). Coal miners were more likely to demonstrate an obstructive pattern and report chronic bronchitis symptoms than non-coal miners (adjusted odds ratio [OR] = 1.24, 95% confidence interval [CI]: 1.03, 1.48; and OR = 1.47, 95% CI: 1.24, 1.75, respectively). These associations remained significant among never smoking miners.

Conclusions: The prevention and management of COPD among coal miners deserves greater emphasis by rural health care delivery systems.
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http://dx.doi.org/10.1097/JOM.0000000000001547DOI Listing
April 2019

Greater Odds for Angina in Uranium Miners Than Nonuranium Miners in New Mexico.

J Occup Environ Med 2019 01;61(1):1-7

Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico (Drs al Rashida, Wang, Myers, Boyce, Kocher, Assad, Cook, Sood); Division of Cardiovascular Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas (Dr al Rashida); and Black Lung Program, Miners' Colfax Medical Center, Raton, New Mexico (Moreno, Karr, Dr Sood).

Objective: The aim of this study was to test the hypothesis that uranium miners in New Mexico (NM) have a greater prevalence of cardiovascular disease than miners who extracted the nonuranium ore.

Methods: NM-based current and former uranium miners were compared with nonuranium miners by using cross-sectional standardized questionnaire data from the Mining Dust in the United States (MiDUS) study from 1989 to 2016.

Results: Of the 7215 eligible miners, most were men (96.3%). Uranium miners (n = 3151, 43.7%) were older and diabetic, but less likely to currently smoke or use snuff (P ≤ 0.001 for all). After adjustment for covariates, uranium miners were more likely to report angina (odds ratio 1.51, 95% confidence interval 1.23 to 1.85) than nonuranium miners.

Conclusion: Our data suggest that along with screening for pulmonary diseases, uranium industry workers should be screened for cardiovascular diseases.
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http://dx.doi.org/10.1097/JOM.0000000000001482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6541557PMC
January 2019

Genetic Data from Nearly 63,000 Women of European Descent Predicts DNA Methylation Biomarkers and Epithelial Ovarian Cancer Risk.

Cancer Res 2019 02 17;79(3):505-517. Epub 2018 Dec 17.

The Center for Bioinformatics and Functional Genomics at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.

DNA methylation is instrumental for gene regulation. Global changes in the epigenetic landscape have been recognized as a hallmark of cancer. However, the role of DNA methylation in epithelial ovarian cancer (EOC) remains unclear. In this study, high-density genetic and DNA methylation data in white blood cells from the Framingham Heart Study ( = 1,595) were used to build genetic models to predict DNA methylation levels. These prediction models were then applied to the summary statistics of a genome-wide association study (GWAS) of ovarian cancer including 22,406 EOC cases and 40,941 controls to investigate genetically predicted DNA methylation levels in association with EOC risk. Among 62,938 CpG sites investigated, genetically predicted methylation levels at 89 CpG were significantly associated with EOC risk at a Bonferroni-corrected threshold of < 7.94 × 10. Of them, 87 were located at GWAS-identified EOC susceptibility regions and two resided in a genomic region not previously reported to be associated with EOC risk. Integrative analyses of genetic, methylation, and gene expression data identified consistent directions of associations across 12 CpG, five genes, and EOC risk, suggesting that methylation at these 12 CpG may influence EOC risk by regulating expression of these five genes, namely , and . We identified novel DNA methylation markers associated with EOC risk and propose that methylation at multiple CpG may affect EOC risk via regulation of gene expression. SIGNIFICANCE: Identification of novel DNA methylation markers associated with EOC risk suggests that methylation at multiple CpG may affect EOC risk through regulation of gene expression.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-2726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6359948PMC
February 2019

Post-1971 Era Uranium Workers in New Mexico Have Significant Lung Disease Burden.

Ann Am Thorac Soc 2019 04;16(4):515-518

1 University of New Mexico Health Sciences Center School of Medicine Albuquerque, New Mexico and.

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http://dx.doi.org/10.1513/AnnalsATS.201805-309RLDOI Listing
April 2019

A comprehensive gene-environment interaction analysis in Ovarian Cancer using genome-wide significant common variants.

Int J Cancer 2019 05 20;144(9):2192-2205. Epub 2019 Jan 20.

Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.

As a follow-up to genome-wide association analysis of common variants associated with ovarian carcinoma (cancer), our study considers seven well-known ovarian cancer risk factors and their interactions with 28 genome-wide significant common genetic variants. The interaction analyses were based on data from 9971 ovarian cancer cases and 15,566 controls from 17 case-control studies. Likelihood ratio and Wald tests for multiplicative interaction and for relative excess risk due to additive interaction were used. The top multiplicative interaction was noted between oral contraceptive pill (OCP) use (ever vs. never) and rs13255292 (p value = 3.48 × 10 ). Among women with the TT genotype for this variant, the odds ratio for OCP use was 0.53 (95% CI = 0.46-0.60) compared to 0.71 (95%CI = 0.66-0.77) for women with the CC genotype. When stratified by duration of OCP use, women with 1-5 years of OCP use exhibited differential protective benefit across genotypes. However, no interaction on either the multiplicative or additive scale was found to be statistically significant after multiple testing correction. The results suggest that OCP use may offer increased benefit for women who are carriers of the T allele in rs13255292. On the other hand, for women carrying the C allele in this variant, longer (5+ years) use of OCP may reduce the impact of carrying the risk allele of this SNP. Replication of this finding is needed. The study presents a comprehensive analytic framework for conducting gene-environment analysis in ovarian cancer.
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http://dx.doi.org/10.1002/ijc.32029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6399057PMC
May 2019

rs495139 in the TYMS-ENOSF1 Region and Risk of Ovarian Carcinoma of Mucinous Histology.

Int J Mol Sci 2018 Aug 21;19(9). Epub 2018 Aug 21.

Department of Gynecology, Jena University Hospital-Friedrich Schiller University, Jena 07743, Germany.

Thymidylate synthase (TYMS) is a crucial enzyme for DNA synthesis. TYMS expression is regulated by its antisense mRNA, ENOSF1. Disrupted regulation may promote uncontrolled DNA synthesis and tumor growth. We sought to replicate our previously reported association between rs495139 in the 3' gene region and increased risk of mucinous ovarian carcinoma (MOC) in an independent sample. Genotypes from 24,351 controls to 15,000 women with invasive OC, including 665 MOC, were available. We estimated per-allele odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression, and meta-analysis when combining these data with our previous report. The association between rs495139 and MOC was not significant in the independent sample (OR = 1.09; 95% CI = 0.97⁻1.22; = 0.15; N = 665 cases). Meta-analysis suggested a weak association (OR = 1.13; 95% CI = 1.03⁻1.24; = 0.01; N = 1019 cases). No significant association with risk of other OC histologic types was observed ( = 0.05 for tumor heterogeneity). In expression quantitative trait locus (eQTL) analysis, the rs495139 allele was positively associated with ENOSF1 mRNA expression in normal tissues of the gastrointestinal system, particularly esophageal mucosa ( = 0.51, = 1.7 × 10), and nonsignificantly in five MOC tumors. The association results, along with inconclusive tumor eQTL findings, suggest that a true effect of rs495139 might be small.
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http://dx.doi.org/10.3390/ijms19092473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6163881PMC
August 2018

Identification of nine new susceptibility loci for endometrial cancer.

Nat Commun 2018 08 9;9(1):3166. Epub 2018 Aug 9.

Department of Obstetrics and Gynecology, University Hospitals KU Leuven, University of Leuven, Division of Gynecologic Oncology, Leuven, 3000, Belgium.

Endometrial cancer is the most commonly diagnosed cancer of the female reproductive tract in developed countries. Through genome-wide association studies (GWAS), we have previously identified eight risk loci for endometrial cancer. Here, we present an expanded meta-analysis of 12,906 endometrial cancer cases and 108,979 controls (including new genotype data for 5624 cases) and identify nine novel genome-wide significant loci, including a locus on 12q24.12 previously identified by meta-GWAS of endometrial and colorectal cancer. At five loci, expression quantitative trait locus (eQTL) analyses identify candidate causal genes; risk alleles at two of these loci associate with decreased expression of genes, which encode negative regulators of oncogenic signal transduction proteins (SH2B3 (12q24.12) and NF1 (17q11.2)). In summary, this study has doubled the number of known endometrial cancer risk loci and revealed candidate causal genes for future study.
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http://dx.doi.org/10.1038/s41467-018-05427-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6085317PMC
August 2018

Association of p16 expression with prognosis varies across ovarian carcinoma histotypes: an Ovarian Tumor Tissue Analysis consortium study.

J Pathol Clin Res 2018 10 21;4(4):250-261. Epub 2018 Sep 21.

Cancer Control and Population Sciences, Duke Cancer Institute, Durham, NC, USA.

We aimed to validate the prognostic association of p16 expression in ovarian high-grade serous carcinomas (HGSC) and to explore it in other ovarian carcinoma histotypes. p16 protein expression was assessed by clinical-grade immunohistochemistry in 6525 ovarian carcinomas including 4334 HGSC using tissue microarrays from 24 studies participating in the Ovarian Tumor Tissue Analysis consortium. p16 expression patterns were interpreted as abnormal (either overexpression referred to as block expression or absence) or normal (heterogeneous). CDKN2A (which encodes p16) mRNA expression was also analyzed in a subset (n = 2280) mostly representing HGSC (n = 2010). Association of p16 expression with overall survival (OS) was determined within histotypes as was CDKN2A expression for HGSC only. p16 block expression was most frequent in HGSC (56%) but neither protein nor mRNA expression was associated with OS. However, relative to heterogeneous expression, block expression was associated with shorter OS in endometriosis-associated carcinomas, clear cell [hazard ratio (HR): 2.02, 95% confidence (CI) 1.47-2.77, p < 0.001] and endometrioid (HR: 1.88, 95% CI 1.30-2.75, p = 0.004), while absence was associated with shorter OS in low-grade serous carcinomas (HR: 2.95, 95% CI 1.61-5.38, p = 0.001). Absence was most frequent in mucinous carcinoma (50%), and was not associated with OS in this histotype. The prognostic value of p16 expression is histotype-specific and pattern dependent. We provide definitive evidence against an association of p16 expression with survival in ovarian HGSC as previously suggested. Block expression of p16 in clear cell and endometrioid carcinoma should be further validated as a prognostic marker, and absence in low-grade serous carcinoma justifies CDK4 inhibition.
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http://dx.doi.org/10.1002/cjp2.109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6174617PMC
October 2018

Variants in genes encoding small GTPases and association with epithelial ovarian cancer susceptibility.

PLoS One 2018 6;13(7):e0197561. Epub 2018 Jul 6.

Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.

Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality in American women. Normal ovarian physiology is intricately connected to small GTP binding proteins of the Ras superfamily (Ras, Rho, Rab, Arf, and Ran) which govern processes such as signal transduction, cell proliferation, cell motility, and vesicle transport. We hypothesized that common germline variation in genes encoding small GTPases is associated with EOC risk. We investigated 322 variants in 88 small GTPase genes in germline DNA of 18,736 EOC patients and 26,138 controls of European ancestry using a custom genotype array and logistic regression fitting log-additive models. Functional annotation was used to identify biofeatures and expression quantitative trait loci that intersect with risk variants. One variant, ARHGEF10L (Rho guanine nucleotide exchange factor 10 like) rs2256787, was associated with increased endometrioid EOC risk (OR = 1.33, p = 4.46 x 10-6). Other variants of interest included another in ARHGEF10L, rs10788679, which was associated with invasive serous EOC risk (OR = 1.07, p = 0.00026) and two variants in AKAP6 (A-kinase anchoring protein 6) which were associated with risk of invasive EOC (rs1955513, OR = 0.90, p = 0.00033; rs927062, OR = 0.94, p = 0.00059). Functional annotation revealed that the two ARHGEF10L variants were located in super-enhancer regions and that AKAP6 rs927062 was associated with expression of GTPase gene ARHGAP5 (Rho GTPase activating protein 5). Inherited variants in ARHGEF10L and AKAP6, with potential transcriptional regulatory function and association with EOC risk, warrant investigation in independent EOC study populations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0197561PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6034790PMC
December 2018

Ovarian Carcinoma Histotype: Strengths and Limitations of Integrating Morphology With Immunohistochemical Predictions.

Int J Gynecol Pathol 2019 Jul;38(4):353-362

Departments of Pathology and Laboratory Medicine (M.K., S.L.) Community Health Sciences (L.S.C.), University of Calgary Department of Cancer Epidemiology and Prevention Research, Alberta Health Services-Cancer Control Alberta (X.G., L.S.C.), Calgary, Alberta Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver; and Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby (A.B.-W.) Department of Pathology and Laboratory Medicine, University of British Columbia (C.B.G.) Cancer Control Research, BC Cancer Research Centre (N.D.L.), Vancouver, British Columbia, Canada Department of Internal Medicine, Division of Epidemiology, Biostatistics and Preventive Medicine, UNM Comprehensive Cancer Center, University of New Mexico, Albuquerque, New Mexico (L.L., L.S.C.).

Ovarian carcinoma histotypes are critical for research and patient management and currently assigned by a combination of histomorphology +/- ancillary immunohistochemistry (IHC). We aimed to validate the previously described IHC algorithm (Calculator of Ovarian carcinoma Subtype/histotype Probability version 3, COSPv3) in an independent population-based cohort, and to identify problem areas for IHC predictions. Histotype was abstracted from cancer registries for eligible ovarian carcinoma cases diagnosed from 2002 to 2011 in Alberta and British Columbia, Canada. Slides were reviewed according to World Health Organization 2014 criteria, tissue microarrays were stained with and scored for the 8 COSPv3 IHC markers, and COSPv3 histotype predictions were calculated. Discordant cases for review and COSPv3 prediction were arbitrated by integrating morphology with IHC results. The integrated histotype (N=880) was then used to identify areas of inferior COSPv3 performance. Review histotype and integrated histotype demonstrated 93% agreement suggesting that IHC information revises expert review in up to 7% of cases. There was also 93% agreement between COSPv3 prediction and integrated histotype. COSPv3 errors predominated in 4 areas: endometrioid carcinoma (EC) versus clear cell (N=23), EC versus low-grade serous (N=15), EC versus high-grade serous (N=11), and high-grade versus low-grade serous (N=6). Most problems were related to Napsin A-negative clear cell, WT1-positive EC, and p53 IHC wild-type high-grade serous carcinomas. Although 93% of COSPv3 prediction accuracy was validated, some histotyping required integration of morphology with ancillary test results. Awareness of these limitations will avoid overreliance on IHC and misclassification of histotypes for research and clinical management.
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http://dx.doi.org/10.1097/PGP.0000000000000530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6291360PMC
July 2019

Alcohol, smoking, and risk of Her2-overexpressing and triple-negative breast cancer relative to estrogen receptor-positive breast cancer.

Int J Cancer 2018 10 26;143(8):1849-1857. Epub 2018 Jul 26.

Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA.

Epidemiological evidence is limited on how alcohol consumption and smoking are associated with risk of different subtypes of breast cancer, such as triple-negative (TN) and human epidermal growth factor receptor 2-overexpressing (H2E) breast cancers, which may have different etiologies from more common luminal (estrogen receptor [ER+]) breast cancers. In this population-based case-case study, we evaluated the association between alcohol, smoking, and risk of H2E and TN breast cancer, compared with ER+ breast cancers, among women aged 20-69 years. Using polytomous regression, associations between alcohol consumption, smoking, and breast cancer risk were evaluated in 909 ER+, 1,290 TN, and 489 H2E breast cancer patients, with ER+ breast cancer patients as the reference group. Current alcohol consumption at diagnosis was associated with a lower risk of H2E breast cancer (odds ratio = 0.74, 95% confidence interval: 0.58-0.92) relative to ER+ cancers. No difference in association was observed by menopausal status. No association between alcohol consumption and TN breast cancer relative to ER+ breast cancer was observed. Women who smoked did not have an altered risk of TN or H2E breast cancer, relative to ER+ cancer. Our results suggest that alcohol is associated with lower risk of H2E breast cancer relative to ER+ breast cancer. This study adds to the body of epidemiologic evidence that breast cancer etiology differs by breast cancer subtype.
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http://dx.doi.org/10.1002/ijc.31575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6158121PMC
October 2018

Adult height is associated with increased risk of ovarian cancer: a Mendelian randomisation study.

Br J Cancer 2018 04 20;118(8):1123-1129. Epub 2018 Mar 20.

Radiation Oncology Research Unit, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625, Hannover, Germany.

Background: Observational studies suggest greater height is associated with increased ovarian cancer risk, but cannot exclude bias and/or confounding as explanations for this. Mendelian randomisation (MR) can provide evidence which may be less prone to bias.

Methods: We pooled data from 39 Ovarian Cancer Association Consortium studies (16,395 cases; 23,003 controls). We applied two-stage predictor-substitution MR, using a weighted genetic risk score combining 609 single-nucleotide polymorphisms. Study-specific odds ratios (OR) and 95% confidence intervals (CI) for the association between genetically predicted height and risk were pooled using random-effects meta-analysis.

Results: Greater genetically predicted height was associated with increased ovarian cancer risk overall (pooled-OR (pOR) = 1.06; 95% CI: 1.01-1.11 per 5 cm increase in height), and separately for invasive (pOR = 1.06; 95% CI: 1.01-1.11) and borderline (pOR = 1.15; 95% CI: 1.02-1.29) tumours.

Conclusions: Women with a genetic propensity to being taller have increased risk of ovarian cancer. This suggests genes influencing height are involved in pathways promoting ovarian carcinogenesis.
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http://dx.doi.org/10.1038/s41416-018-0011-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5931085PMC
April 2018
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