Basics of qualitative research: Grounded theory procedures and techniques

Over the past decade, comprehensive sequencing efforts have revealed the genomic landscapes of common forms of human cancer. For most cancer types, this landscape consists of a small number of “mountains” (genes altered in a high percentage of tumors) and a much larger number of “hills” (genes altered infrequently). To date, these studies have revealed ~140 genes that, when altered by intragenic mutations, can promote or “drive” tumorigenesis. A typical tumor contains two to eight of these “driver gene” mutations; the remaining mutations are passengers that confer no selective growth advantage. Driver genes can be classified into 12 signaling pathways that regulate three core cellular processes: cell fate, cell survival, and genome maintenance. A better understanding of these pathways is one of the most pressing needs in basic cancer research. Even now, however, our knowledge of cancer genomes is sufficient to guide the development of more effective approaches for reducing cancer morbidity and mortality.

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Cancer Genome Landscapes

The detection of psychiatric illness by questionnaire

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Narrative Methods for the Human Sciences

Metastasis, the dissemination and growth of neoplastic cells in an organ distinct from that in which they originated, is the most common cause of death in cancer patients. This is particularly true for pancreatic cancers, where most patients are diagnosed with metastatic disease and few show a sustained response to chemotherapy or radiation therapy. Whether the dismal prognosis of patients with pancreatic cancer compared to patients with other types of cancer is a result of late diagnosis or early dissemination of disease to distant organs is not known. Here we rely on data generated by sequencing the genomes of seven pancreatic cancer metastases to evaluate the clonal relationships among primary and metastatic cancers. We find that clonal populations that give rise to distant metastases are represented within the primary carcinoma, but these clones are genetically evolved from the original parental, non-metastatic clone. Thus, genetic heterogeneity of metastases reflects that within the primary carcinoma. A quantitative analysis of the timing of the genetic evolution of pancreatic cancer was performed, indicating at least a decade between the occurrence of the initiating mutation and the birth of the parental, non-metastatic founder cell. At least five more years are required for the acquisition of metastatic ability and patients die an average of two years thereafter. These data provide novel insights into the genetic features underlying pancreatic cancer progression and define a broad time window of opportunity for early detection to prevent deaths from metastatic disease.

SF-010-4 Distant metastasis occurs late during the genetic evolution of pancreatic cancer

The article by Sadetzki and colleagues in this issue of Cancer showcases the impact of a horrendous event—the Holocaust—on subsequent health, decades after the occurrence. This study not only brings to light additional effects of the Holocaust in the Jewish population, but it brings to mind similarities in cancer development and extreme populationlevel tragedies. We highlight 2 additional examples of calamities—country-wide famines and population-level discrimination—as examples of this phenomenon to add evidence to the causal pathway identified by Sadetzki et al. First, however, important factors to consider are the “event” itself: Is it a constant event (eg, discrimination) or episodic/defined in time (eg, a famine)? The time point at which the event occurred in the life course is also important; for example, events may occur early in life, late in life, or continuously. The type of event is also important: Does it have a physical nature, such as a famine, or an emotional factor, such as discrimination, or both, as occurred in the Holocaust? The focus of the event is also important: Did it impact the entire population, as in a famine, or did it emphasize a specific group, as the Jews during the Holocaust? Finally, was the duration episodic (eg, a few months or years) or continuous (over a lifetime)? Individuals can be impacted differently by the same event because of many of these factors as well as genetic “heartiness.” Cancer is a dynamic process that increasingly is thought to be linked to the life-course; that is, exposures to carcinogens during 1 stage of life may influence cancer risk at a subsequent stage. One area that has been extensively studied in animal models is calorie deprivation. In general, such studies indicate that animals who experience caloric restrictions live longer and have fewer diseases than animals fed higher calorie diets. There also is some evidence that this is true in humans. Patients with eating disorders that involve calorie restriction have a reduced risk of subsequent breast cancer. Ecologic studies note that individuals who live in countries where fewer calories are consumed have lower death rates from cancer and other chronic diseases. Exposures during the life course, however, may be caused not only by the choices that individuals make but also by external factors. War and its consequences are such external factors. Unlike animal studies and some limited human research, war provides examples of real-life situations that can be examined for later consequences. World War II is an example of a time when exposures around caloric intake varied by country. In Europe, countries occupied by Germany included Norway and the Netherlands, and both have examined dietary intake with subsequent cancer outcomes. In Norway, which was occupied by Germany from 1940 to 1945, food restrictions were enacted early in the occupation. A 2002 analysis of Norwegian women who lived in food-producing areas compared with nonfood-producing areas during World War II demonstrated decreased incidence of breast cancer among women who lived in the nonfood areas, lending some credence to the suggestion that caloric restriction is protective against some cancers. The Dutch experience indicates the obverse. In a short but severe famine that lasted approximately 8 months (from September 1944 to April 1945), the Dutch faced a cut in daily adult food rations from 1500 kilocalories to 700 kilocalories a day. Examination of a large cohort of Dutch women who lived during the famine began in 1974. Women born between 1911 and 1945 were eligible to participate in the project, which called for the early detection of breast cancer.

Extreme population-level events: Do they have an impact on cancer?

Research designed to elicit smokers’ cognitive and affective reactions to information about chemicals that tobacco companies add to cigarettes (“additives”) found that knowledge is limited. However, little is known about smokers’ unprompted thoughts and feelings about additives. Such information could be used to shape future communication efforts. We explored the content and possible functions of spontaneous statements about cigarette additives made by smokers during a study examining reactions to learning about the genetic link to nicotine addiction. Adult smokers (N = 84) were recruited from a medium-sized Midwestern city. Focus groups (N = 13) were conducted between April-September 2012. Data were analyzed by 2 coders using thematic analysis. Comments about cigarette additives arose without prompting by the focus group moderator. Three main themes were identified: (1) discussing additives helped participants navigate the conceptual link between smoking and genetics, (2) additives were discussed as an alternative mechanism for addiction to cigarettes, and (3) additives provided an alternative mechanism by which cigarette smoking exacerbates physical harm. Notably, discussion of additives contained a pervasive tone of mistrust illustrated by words like “they” and “them,” by statements of uncertainty such as “you don’t know what they’re putting into cigarettes,” and by negative affective verbalizations such as “nasty” and “disgusting”. Participants had distinct beliefs about cigarette additives, each of which seemed to serve a purpose. Although mistrust may complicate communication about the health risks of tobacco use, health communication experts could use smokers’ existing beliefs and feelings to better design more effective anti-smoking messages.

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Smokers’ unprompted comments on cigarette additives during conversations about the genetic basis for nicotine addiction: a focus group study

Premenstrual Dysphoric Disorder (PMDD) has remained in appendices of the last two editions of The Diagnostic and Statistical Manual of Mental Disorders due to lack of empirical study. Items included in its set of research criteria are considered tentative pending evidence of diagnostic validity. The present study attempts to establish the construct validity of the PMDD criteria using the Rasch method to analyze the validity of individual items as contributors to the diagnosis, in contrast to the usual but less precise approach of using an external validator to establish the diagnostic utility of psychiatric conditions. Analysis of which items best differentiate participants with and without PMDD provides an idea of the relative ability of these items to distinguish PMDD. It is recommended that the areas of anger/irritability, depressed mood, and problems in interpersonal functioning be expanded in further studies and corresponding items added to symptom checklists.

Establishing the Diagnostic Validity of Premenstrual Dysphoric Disorder Using Rasch Analysis.

Disparities, defined as differences that are unnecessary and avoidable, exist in cancer incidence, mortality, and survival. They occur by race/ethnicity, socioeconomic status, geography (rural versus urban), and other factors. Although cancer deaths for all types of cancer decreased for both African-Americans and whites in the United States between 1999 and 2011, for example, African-American males and females had both higher cancer incidence and cancer mortality than white males and females and showed less marked improvement over that time period. Warnecke and colleagues published a multi-level framework of the determinants of cancer disparities that included three basic levels, namely distal, intermediate, and proximal.1 Distal determinants include population-level social conditions such as variation in rates of disease or poverty. Their roots are embedded in shared social norms or social practices and socioeconomic disadvantage. Intermediate determinants include the immediate social and physical contexts and social relationships in which distal effects are experienced, such as neighborhoods. Proximal determinants include biological and genetic factors and individual-level factors like health behavior. The sequencing of the human genome and increased understanding of its function have allowed the identification of genetic variants that lead to common diseases like cancer. Yet, awareness is growing, too, that genetic variants alone cannot account for cancer expression and outcomes. Consistent with the Warnecke et al. framework, it seems to be the case that social, environmental, and behavioral factors interact with genetic predisposition to produce disease, and that differential exposures and behaviors across populations and subpopulations might help to explain cancer disparities. Both the genetic variants and the exposures and behaviors must be present to produce cancers. The Precision Medicine Initiative (PMI), announced by President Obama on January 30, 2015 seeks to advance our understanding of genetic variations within diseases and develop treatments for them, beginning with cancer. President Obama requested $215 million in the next fiscal year to collect genetic data and data from electronic medical records, lab test results, and information about diet, tobacco use, lifestyle, and environment on 1,000,000 Americans. In this presentation, we argue that while the PMI has the potential to reduce cancer disparities: (1) preventing cancer and reducing death rates for everyone in the population requires collecting and analyzing consistent, accurate, reliable, and sufficiently detailed data that represent all segments of the population and that (2) developing risk assessments and interventions that are effective for everyone requires evidence on the distribution and impact of causes across subpopulations. Collecting and analyzing data that represents all segments of the population poses significant challenges essential for the PMI to contribute to decreasing disparities in cancer and other common diseases. Minority groups historically have had low participation in research, such as in clinical research trials. The 1993 NIH Revitalization Act (http://orwh.od.nih.gov/about/pdf/NIH-Revitalization-Act-1993.pdf) established a mandate that funded research would be based on valid analysis of whether the variables being studied in the trial affect minority groups. Yet a 2014 review found that only 20% of randomized controlled studies in a major cancer journal reported analyzing results by race/ethnicity.2 Likewise, a survey of its members and the general public by the American Association for the Advancement of Science (AAAS) found that while 92% of AAAS scientists considered US scientific achievement to be the best in the world or above average, only 54% of the public endorsed this ranking.3 The presentation will conclude with two recommendations for improving the PMI9s role in eliminating cancer and other disparities. First, make the effort to recruit a cohort that reflects the US population in terms of race/ethnicity, socioeconomic status, and geography. Second, do not recruit entirely from clinic populations or rely entirely on electronic medical records for social data, because this will miss those most without consistent health care, a group for whom disparities are rife. In addition, for Precision Medicine practice to contribute to the elimination of disparities, it will be important that: (1) the cost of genetic testing is covered under Medicaid, other public insurance, and less generous marketplace insurance plans; (2) the collection of social variables be systematized so that they capture the lives of minority groups; and (3) the capacity of genetic counseling is increased and that counseling services are available to all who have genetic testing. References: 1. Warnecke RB, Oh A, Gehlert S, Lurie N, Rebbeck T, Paskett E, et al. Approaching health disparities from a population perspective: the NIH Centers for Population Health and Health Disparities. American Journal of Public Health. 2008;98(9):1608-15. 2. Chen MS, Lara PN, Dang JH, Paterniti DA, Kelly K. Twenty years post-NIH Revitalization Act: enhancing minority participation in clinical trials (EMPaCT): laying the groundwork for improving minority trial accrual: renewing the case for enhancing minority participation in cancer clinical trials. Cancer. 2014 April;120 Suppl 7:1091-6. 3. Pew Research center, Public and scientists views on science and society. At http://PI_Science and Society_Report_012915.pdf. Retrieved August 25, 2015. Citation Format: Sarah J. Gehlert. Maximizing the benefits of precision medicine for cancer disparities. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr IA40.

Abstract IA40: Maximizing the benefits of precision medicine for cancer disparities

In our Cancer Prevention Program at Washington University in Saint Louis (WUSTL), we have made extraordinary efforts to create the kind of cancer prevention and control program that is both translational and transdisciplinary in nature, to accelerate the march from basic discoveries to population change. Here we present an overview of our obesity-related research currently ongoing in our Center, paying particular attention to both the translational- transdisciplinary process and to community-based participatory research. We end with our future directions for improving obesity-related cancer outcomes research. Cancer Prev Res; 9(7); 503-8. ©2016 AACR.

https://cancerpreventionresearch.aacrjournals.org/content/canprevres/9/7/503.full.pdf

Sarah Gehlert

Papers

Extreme population-level events: Do they have an impact on cancer?

Smokers’ unprompted comments on cigarette additives during conversations about the genetic basis for nicotine addiction: a focus group study

Establishing the Diagnostic Validity of Premenstrual Dysphoric Disorder Using Rasch Analysis.

Abstract IA40: Maximizing the benefits of precision medicine for cancer disparities

Toward a Modern Science of Obesity at Washington University: How We Do It and What is the Payoff?