Adult body mass index and risk of ovarian cancer by subtype: a Mendelian randomization study

Abstract (repost)

 on behalf of the Ovarian Cancer Association Consortium

• Accepted April 7, 2016.

 

Background: Observational studies have reported a positive association between body mass index (BMI) and ovarian cancer risk. However, questions remain as to whether this represents a causal effect, or holds for all histological subtypes. The lack of association observed for serous cancers may, for instance, be due to disease-associated weight loss. Mendelian randomization (MR) uses genetic markers as proxies for risk factors to overcome limitations of observational studies. We used MR to elucidate the relationship between BMI and ovarian cancer, hypothesizing that genetically predicted BMI would be associated with increased risk of non-high grade serous ovarian cancers (non-HGSC) but not HGSC. 

Methods: We pooled data from 39 studies (14 047 cases, 23 003 controls) in the Ovarian Cancer Association Consortium. We constructed a weighted genetic risk score (GRS, partial F-statistic = 172), summing alleles at 87 single nucleotide polymorphisms previously associated with BMI, weighting by their published strength of association with BMI. Applying two-stage predictor-substitution MR, we used logistic regression to estimate study-specific odds ratios (OR) and 95% confidence intervals (CI) for the association between genetically predicted BMI and risk, and pooled these using random-effects meta-analysis. 

Results: Higher genetically predicted BMI was associated with increased risk of non-HGSC (pooled OR = 1.29 per 5 units BMI) but not HGSC (pooled OR = 1.06). Secondary analyses stratified by behaviour/subtype suggested that, consistent with observational data, the association was strongest for low-grade/borderline serous cancers (OR = 1.93). 

Conclusions: Our data suggest that higher BMI increases risk of non-HGSC, but not the more common and aggressive HGSC subtype, confirming the observational evidence.

Commentary: Mendelian randomization study of adiposity-related traits and risk of breast, ovarian, prostate, lung and colorectal cancer

open access - Commentary

Introduction

In this volume of the IJE, Gao and colleagues explore the causal effect of adiposity on several cancers using two-sample Mendelian randomization (MR), and find some evidence that greater adult body mass index (BMI) causally reduces the risk of breast cancer while increasing ovarian, lung and colorectal cancer.¹ The authors conclude that the study provides ‘…additional understanding of the complex relationship between adiposity and cancer risks’....

 

 As this is the denominator of the MR ratio estimate, it means that the estimated effect of WHR adjusted for BMI for female cancers (breast and ovarian) may be exaggerated and those for prostate cancers underestimated.

But this study does illustrate some of the pitfalls of using summary GWAS data (Genome Wide Association Study)  and methods that might be used to limit these.

 Beyond Mendelian randomization—what can we learn from genetic epidemiology?

What strikes me in watching (and participating in) the development of GWAS and MR over the past decade is how slow those of us largely working in epidemiology, including in intervention research, have been to do what we all know is good science. Our genetic colleagues have led the way in ensuring replication in large collaborations where ‘team science’ is appreciated and for the large part appropriately rewarded. Those developing MR as a method have from the start been very open about its limitations and have worked at developing methods to test and limit sources of bias.^2,3,9 It is notable, for example, that Gao et al. comment on the ‘strong’ assumptions of MR, but rarely do we see such statements about the equally strong, and untestable, assumptions of conventional multivariable regression analyses. Now genetic epidemiologists have shown us how to provide complete open-access summary data, and it is likely that over the coming decade important and impactful use will be made of these data.⁴
 

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2. Introduction
3. (One-sample) Mendelian randomization
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Mendelian randomization study of adiposity-related traits and risk of breast, ovarian, prostate, lung and colorectal cancer

Wiki: Background: the problem of spurious findings in observational epidemiology

An important focus of observational epidemiology is the identification of modifiable causes of common diseases that are of public health interest. In order to have firm evidence that a recommended public health intervention will have the desired beneficial effect, the observed association between the particular risk factor and disease must imply that the risk factor actually causes the disease.
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abstract:
Mendelian randomization study of adiposity-related traits and risk of breast, ovarian, prostate, lung and colorectal cancer

 on behalf of: the Colorectal Transdisciplinary Study (CORECT); Discovery, Biology and Risk of Inherited Variants in Breast Cancer (DRIVE); Elucidating Loci Involved in Prostate Cancer Susceptibility (ELLIPSE); Follow-up of Ovarian Cancer Genetic Association and Interaction Studies (FOCI); and Transdisciplinary Research in Cancer of the Lung (TRICL)

Background: Adiposity traits have been associated with risk of many cancers in observational studies, but whether these associations are causal is unclear. Mendelian randomization (MR) uses genetic predictors of risk factors as instrumental variables to eliminate reverse causation and reduce confounding bias. We performed MR analyses to assess the possible causal relationship of birthweight, childhood and adult body mass index (BMI), and waist-hip ratio (WHR) on the risks of breast, ovarian, prostate, colorectal and lung cancers. 

Methods: We tested the association between genetic risk scores and each trait using summary statistics from published genome-wide association studies (GWAS) and from 51 537 cancer cases and 61 600 controls in the Genetic Associations and Mechanisms in Oncology (GAME-ON) Consortium. 

Results: We found an inverse association between the genetic score for childhood BMI and risk of breast cancer [odds ratio (OR) = 0.71 per standard deviation (s.d.) increase in childhood BMI; 95% confidence interval (CI): 0.60, 0.80; P = 6.5 × 10^-5). We also found the genetic score for adult BMI to be inversely associated with breast cancer risk (OR = 0.66 per s.d. increase in BMI; 95% CI: 0.57, 0.77; P = 2.5 × 10^-7), and positively associated with ovarian cancer (OR = 1.35; 95% CI: 1.05, 1.72; P = 0.017), lung cancer (OR = 1.27; 95% CI: 1.09, 1.49; P = 2.9 × 10^-3) and colorectal cancer (OR = 1.39; 95% CI: 1.06, 1.82, P = 0.016). The inverse association between genetically predicted adult BMI and breast cancer risk remained even after adjusting for directional pleiotropy via MR-Egger regression. 

Conclusions: Findings from this study provide additional understandings of the complex relationship between adiposity and cancer risks. Our results for breast and lung cancer are particularly interesting, given previous reports of effect heterogeneity by menopausal status and smoking status.

Group-Based Trajectory Modeling of Fear of Disease Recurrence Among Women Recently Diagnosed with Gyn Cancers

abstract:
Group-Based Trajectory Modeling of Fear of Disease Recurrence Among Women Recently Diagnosed with Gynecological Cancers - Manne - Psycho-Oncology

Objective

Fear of cancer recurrence is an important clinical phenomenon and is associated with decrements in life domains. The study goals were to characterize patterns of global fear of recurrence (FOR) and four domains of fear (health, role, womanhood, and death worry) over time in women who were diagnosed with gynecological cancer and to identify demographic, medical, and psychological predictors of FOR.

Method

One hundred eighteen women participating in the Usual Care arm of a randomized trial completed the Concerns about Recurrence scale as well as measures of depressive symptoms, cancer-specific distress, coping, coping efficacy, and social network responses at four time points. The majority of the sample was diagnosed with stage 3 ovarian cancer.

Results

Group-based trajectory modeling identified subgroups of women with high-stable (49.1%), high-decreasing (25.3%), and low-stable (25.5%) trajectories for global FOR. For role worries, three similar group trajectories were identified. For health worries, modeling identified subgroups with high-decreasing (19.1%) and low-increasing (80.9%) trajectories. For womanhood worries, modeling identified subgroups with high-increasing (15.7%) and low-decreasing (84.2%) trajectories. Young age, metastatic cancer, depression, cancer distress, holding back, and lower coping efficacy were associated with the high-stable global FOR and at least one domain of FOR.

Conclusion

Almost half of the women recently diagnosed with gynecological cancer evidence persistently elevated FOR over the six month period post-diagnosis. Psychological interventions to reduce FOR may be more effective if they focus on teaching patients coping skills, as well as greater comfort expressing cancer-specific concerns to others.

Preservation of gonadal function in women undergoing chemotherapy: A review of the potential role for gonadotropin-releasing hormone agonists

abstract:
Preservation of gonadal function in women undergoing chemotherapy: A review of the potential role for gonadotropin-releasing hormone agonists - American Journal of Obstetrics & Gynecology

 A cancer diagnosis in women of reproductive age has unique medical and psychosocial ramifications, especially with treatments known to cause gonadal toxicity. For patients undergoing chemotherapy, a multidisciplinary team approach is essential to ensure that the patients’ reproductive wishes are addressed. Currently embryo and oocyte cryopreservation are the standard of care for those who wish to preserve their fertility. The use of gonadotropin releasing hormone agonists (GnRHa) has been a source of debate with numerous studies investigating the efficacy on both fertility and ovarian function preservation. This review will evaluate the current literature on the use of GnRHa for preservation of gonadal function. Assisted reproductive technology is excellent for preservation of fertility but will not protect gonadal function. Protection of gonadal function is critical for the broader issues of health and quality of life as a result of a hypogonadal state. At this moment, GnRHa are the only drug class available to protect gonadal function.

The Balance between Cancer and the Immune System Challenges the Therapeutic Specificity of Targeting Nuclear Factor-κB Signaling for Cancer Treatment

abstract:
Molecular Pathways: The Balance between Cancer and the Immune System Challenges the Therapeutic Specificity of Targeting Nuclear Factor-κB Signaling for Cancer Treatment | Clincal Cancer Research
 

The Nuclear Factor-κB (NF-κB) signaling pathway is a complex network linking extracellular stimuli to cell survival and proliferation. Cytoplasmic signaling to activate NF-kB can occur as part of the DNA damage response or in response to a large variety of activators including viruses, inflammation, and cell death. NF-κB transcription factors play a fundamental role in tumorigenesis and are implicated in the origination and propagation of both hematologic and solid tumor types, including melanoma, breast, prostate, ovarian, pancreatic, colon, lung, and thyroid cancers. On the other hand, NF-kB signaling is key to immune function, and is likely necessary for anti-tumor immunity. This presents a dilemma when designing therapeutic approaches to target NF-kB. There is growing interest in identifying novel modulators to inhibit NF-κB activity since impeding different steps of the NF-κB pathway has potential to slow tumor growth, progression, and resistance to chemotherapy. Despite significant advances in our understanding of this pathway, our ability to effectively clinically block key targets for cancer therapy remains limited due to on-target effects in normal tissues. Tumor specificity is critical to developing therapeutic strategies targeting this anti-apoptotic signaling pathway in order to maintain anti-tumor immune surveillance when applying such therapy to patients.

AARP - Supplement Pills That Promise Too Much

Drug, Vitamin and Supplement Claims Unregulated - AARP

 

Dietary Supplements Are A $36 Billion Business

medical news - Interview


MedicalResearch.com: Is there anything else you would like to add?

Response: Dietary supplements can interact with prescription drugs. Be sure to tell your health care provider if you are taking or considering taking a supplement in conjunction with prescribed medications.

Citation:
Article in July/August 2016 AARP Bulletin: http://www.aarp.org/health/drugs-supplements/info-2016/drug-vitamin-supplement-claims.html

Early Postmenopausal Transdermal 17 -Estradiol Therapy and Amyloid- Deposition

open access

Neuroimaging for the current study was conducted
from December 2012 through July 2014 and
included the subsample of women who were enrolled
in KEEPS at the Mayo Clinic, to investigate the
effects of the KEEPS hormone treatments on A
deposition three years after the end of the trial.....

Background: It remains controversial whether hormone therapy in recently postmenopausal women modifies the risk of
Alzheimer’s disease (AD).

Estrogen Patch in Newly Postmenopausal Women May Reduce Alzheimer’s Risk

Interview

 Response: If confirmed in a larger group of KEEPS participants, this finding has the potential to change the concepts for preventive interventions that drive the Alzheimer’s disease field today, and may have a significant impact on women making the decision to use hormone therapy in the early postmenopausal years.
MedicalResearch.com: Thank you for your contribution to the MedicalResearch.com community.
Citation:
Early Postmenopausal Transdermal 17β-Estradiol Therapy and Amyloid-β Deposition, DOI: 10.3233/JAD-160258,
http://content.iospress.com/articles/journal-of-alzheimers-disease/jad160258

Cancer Prevention Campaign Stopped After Massive Critique - social media

Cancer Prevention Campaign Stopped After Massive Critique


Last April, the Swedish cancer association Cancerfonden launched its “30 Dagar–30 Nej” (“30 Days–30 No’s”) campaign to encourage Swedes to adopt a healthier lifestyle to prevent cancer. But the campaign has been halted after facing heavy criticism on social media for its perceived blaming of those affected by the disease and for implying individuals can “say no” to cancer. In response, Cancerfonden suspended the campaign after just a week and will reconsider how to communicate the roles of lifestyle and behavior in cancer prevention.

Cancer Clinical Trials Ideas - NCI - submit ideas deadline Aug 30th

Cancer Clinical Trials Ideas

NCI is redesigning the way patients and oncologists learn about and find information about cancer clinical trials.

How can we make cancer clinical trials information more accessible to you? Submit your ideas by August 30.

Determinants of Patient-Oncologist Prognostic Discordance in Advanced Cancer

open access

 Results  Among the 236 patients (mean [SD] age, 64.5 [11.4] years; 54% female), 161 patient-oncologist survival prognosis ratings (68%; 95% CI, 62%-75%) were discordant.

Importance  Patients with advanced cancer often report expectations for survival that differ from their oncologists’ expectations. Whether patients know that their survival expectations differ from those of their oncologists remains unknown. This distinction is important because knowingly expressing differences of opinion is important for shared decision making, whereas patients not knowing that their understanding differs from that of their treating physician is a potential marker of inadequate communication.
Objective  To describe the prevalence, distribution, and proportion of prognostic discordance that is due to patients’ knowingly vs unknowingly expressing an opinion that differs from that of their oncologist.....

Key Points

• Question When patients with advanced cancer report beliefs about their survival prognosis that differ from the expectations of their oncologists, how often do they know that their beliefs differ?
• Findings In this cross-sectional analysis of 236 patients and 38 oncologists, 68% of patients held opinions about their survival prognosis that differed from their oncologist and only 1 in 10 discordant patients knew that their opinions differed.
• Meaning In this study, patient-oncologist discordance about survival prognosis was common and usually due to patients’ inaccurate understanding of their oncologists’ expectations.

Gynecologic Oncology, July 2016 (Index)

Gynecologic Oncology, July 2016

Endometriosis and risks for ovarian, endometrial and breast cancers: A nationwide cohort study

abstract

Highlights

• •The risks for ovarian-, endometrial and breast cancer among 45,790 women with endometriosis were studied.
• •We found an increased risk for endometrioid- and clear-cell ovarian cancer in women with endometriosis.
• •We observed that endometriosis was associated with an excess risk for endometrial cancer, primarily type 1.
• •The risk for breast cancer was only increased in women where endometriosis was first diagnosed at ≥50 years of age.

Canadian researchers who commit scientific fraud are protected by privacy laws (media)

Toronto Star

Science Minister Kristy Duncan and Health Minister Jane Philpott, who oversee the agencies, both declined to comment and referred the Star to the joint statement provided by the agency presidents.

open access: Psychological stress, adverse life events and breast cancer incidence (included ovarian cancer)

open access:
Psychological stress, adverse life events and breast cancer incidence: a cohort investigation in 106,000 women in the United Kingdom | Breast Cancer Research | Full Text

Upsetting life events like bereavement 'not linked to cancer' finds Breast Cancer Now Generations Study

media

 The finding comes from the Breast Cancer Now Generations Study, which looked into the causes of breast cancer, following more than 113,000 British women for 40 years.

• Stress or an upsetting life event is unlikely to increase the risk of breast cancer, a study has found.

• Women with the disease often think it was caused by stress - but researchers found no link between the two. 

• And going through a difficult period such as a bereavement or divorce does not increase the odds.

Low-Grade Serous Carcinoma of the Ovary (Cancer Network)

open access

 Introduction

The World Health Organization classification system of ovarian cancer, published in 2014 by Kurman et al, eliminated the older practice of grading serous tumors on a continuum (grade 1, 2, or 3) and instead differentiates low-grade serous and high-grade serous ovarian cancers as two distinct diseases.[1] In general, tumors previously classified as grade 1, and most of those classified as grade 2 according to the old system, are now classified as low-grade serous ovarian cancers (LGSOCs). Those tumors previously classified as grade 3 are now considered high-grade serous ovarian cancers (HGSOCs)....

 KEY POINTS

• Low-grade serous ovarian cancer is a rare disease, accounting for < 10% of ovarian cancer cases.
• Initial treatment consists of surgical staging and adjuvant chemotherapy.
• Recurrent disease is relatively chemoresistant;
  hormonal therapies, as well as bevacizumab and MEK inhibitors, have shown some promising results.

Increased risk of non-cutaneous malignancy after diagnosis of non-melanoma skin cancer may be due to sun avoidance

Letter

 An analysis of second non-cutaneous malignancy in the Woman's Health Initiative after diagnosis of non-melanoma skin cancer (NMSC) found significantly higher rates for any, breast, colon, and lung cancer, leukemia, melanoma, and non-Hodgkin's lymphoma after adjustment for various risk-modifying factors.¹ Non-significant increases were found for endometrial and ovarian cancer. Participant information was collected at baseline (1993-1998) and three years, with follow up through August 2014. No explanation was given for the associations found.

EPIC - European Prospective Investigation into Cancer and Nutrition

EPIC