Social Genomics as a Framework for Understanding Health Disparities Among Adolescent and Young Adult Cancer Survivors: A Commentary

Introduction

The literature on adolescent and young adult (AYA) oncology (ie, age 15-39 years at diagnosis) is replete with empirical studies documenting the effects of cancer, cancer treatment, and other cancer-related processes on morbidity, mortality, and quality-of-life (QOL) outcomes.^1-4 Markedly less is known, however, about how disruptions in psychosocial maturation, deleterious social conditions (including systemic racism), and individual coping behaviors may affect future health outcomes for AYA cancer survivors. Cancer survivorship here refers to a continuum of care that initiates at the time of diagnosis, continues through phases of treatment, and transitions to post-treatment survival and the end of life. Research in human social genomics^5,6 (also referred to as sociogenomics) has begun to identify molecular pathways through which psychological factors and characteristics of one's social environment regulate gene expression in immune cells and tumor tissue and thus affect chronic disease progression, symptom development, treatment resistance, morbidity, and mortality.^7-9 In many cases, these pathways involve social and psychological processes that affect neural and endocrine function to regulate the expression of genes that influence cancer progression (eg, inflammation, metastasis, and treatment resistance) and immune function (eg, stimulating inflammatory genes and suppressing antiviral gene transcription), as observed in the Conserved Transcriptional Response to Adversity (CTRA) transcriptome signature.^7,10

The recent National Academies of Sciences, Engineering, and Medicine Roundtable on Genomics and Precision Health reported that “the field of genomics and its translation involves many disciplines, and takes place within different economic, social, and cultural contexts, necessitating a need for increased communication and understanding across these fields.”¹¹ This forward-looking approach to psychosocial issues among AYA cancer survivors calls for research that accounts for the biologic impact of social determinants of health—the conditions in which people live, learn, work, worship, and play¹²—and the relationship of those biologic mechanisms to outcomes of interest, including mortality, morbidity, and QOL.^5,13 Efforts to link genomics and health outcomes, in the absence of examination of the social environmental context, run the risk of locating problems and solutions in the biology and genome and thus may perpetuate racism and discrimination. In this commentary, we review current knowledge on social genomics in oncology across disciplines and discuss an emerging opportunity for application in AYA oncology research.

Social Genomic Approaches to Research in Cancer Survivorship

Biologic and social environmental factors interact to affect cancer outcomes across all ages of cancer survivors. A social genomics approach to outcomes research in cancer suggests a biologic component of psychological and social influences on disease by identifying neural and molecular pathways through which psychological and social factors mechanistically influence disease development and progression (see general reviews^10,14 and cancer-specific reviews^13,15-17). Figure 1 shows a conceptual framework of social genomics in cancer survivorship by which biologic mechanisms and gene expression attenuate the effects of specific psychological and social risk and resilience factors (eg, poverty, exposures to trauma, social isolation, behavioral self-efficacy, and meaning attribution) on health outcomes and QOL for cancer survivors.

FIG 1.

A conceptual framework: social genomics in cancer survivorship. CTL, cytotoxic T lymphocyte; CTRA, Conserved Transcriptional Response to Adversity; QOL, quality of life; SNS, sympathetic nervous system.

One example of a social genomic approach is the CTRA RNA profile. Previous research (in both noncancer samples^18-22 and adult cancer samples^23-25) has found the CTRA RNA profile to be associated with social environmental risk factors, such as social isolation and low socioeconomic status (SES). The CTRA RNA profile is a neurobiologically mediated alteration in immune cell gene regulation involving increased expression of proinflammatory genes (eg, IL1B, IL6, IL8/CXCL8, and TNF) and decreased expression of genes involved in innate antiviral responses (eg, IFI, MX, and OAS family genes). It can be measured by genome-wide transcriptional profiling of circulating blood cells (eg, by RNA sequencing).

In the context of hematologic malignancies in older adults, for example, socioeconomic disadvantage has proven to be predictive of CTRA gene expression, and CTRA gene expression has, in turn, predicted adverse disease outcomes (eg, shorter disease-free survival [DFS]).^23,24 These studies have implicated CTRA gene expression as one mechanistic pathway that may mediate social disparities in cancer treatment outcomes and motivated a pilot phase II clinical trial that pharmacologically antagonized this pathway and showed favorable effects on both molecular biomarkers and clinical outcomes (eg, DFS and infection rates).²⁶ Similarly, initial studies linking social isolation to CTRA gene expression in adult breast cancer (including metastatic biomarkers in breast tumors)²⁵ motivated two phase II clinical trials of pharmacologic antagonists that also yielded favorable effects on tumor tissue biomarkers of disease progression and immune parameters.^27,28

In addition to social environmental factors, biologic and individual resilience factors interact to influence cancer outcomes. Psychological perception and evaluation in Figure 1 highlight these individual factors as part of CNS function. Previous research has also found the CTRA to be downregulated in association with epidemiologically protective psychosocial factors such as high social support and a sense of purpose and meaning in life^29-33 and downregulated by stress-reduction interventions for breast cancer survivors,³⁴ with favorable effects on subsequent DFS.³⁵ In all these cases, the CTRA leukocyte RNA profile has represented the key physiologic measure generating conceptual hypotheses about the biologic mechanisms underlying psychosocial effects on disease outcomes and serving as a biomarker of intervention impact and a predictive biomarker of subsequent clinical outcomes.

An Overview of Disparities in AYA Cancer Survivorship

AYA cancer survivors have elevated risk of multiple health problems. Study findings include a higher prevalence of asthma, chronic obstructive pulmonary disorder, stroke, and diabetes among AYA cancer survivors because of lifestyle and health behaviors.^4,36 Furthermore, AYAs possess greater than two-fold increased rate of cardiomyopathy, stroke, premature ovarian failure, chronic liver disease, and renal failure when compared with AYAs without cancer, because of cancer treatments.^37,38 SEER program cancer registry data show that not only is the risk of subsequent cancers elevated in AYA survivors, but also they have the highest absolute excess risk of subsequent primary malignancies among all age groups³⁹ and worse survival after their subsequent cancers compared with older adults.⁴⁰ AYA survivors also experience an increased risk throughout the lifespan for a broad range of comorbidities requiring hospitalization,⁴¹ including cerebrovascular,⁴² cardiovascular,^43,44 and respiratory events.⁴⁵

AYAs also experience specific and unique psychosocial stressors and life disruptions that affect their physical health, mental health, and QOL.^46-48 Substantial proportions of AYA cancer survivors report decreased abilities to hold a job, complete their education, and maintain mature relationships both during and after a cancer diagnosis.^1,49 Across all AYAs, the prevalence of depression and anxiety is elevated among AYAs compared with younger or older individuals. Specifically for AYAs with cancer, up to one third have reported symptoms of depression and anxiety⁵⁰; for some, these symptoms of distress are chronic. In a 2014 longitudinal prospective study of 215 newly diagnosed AYAs,⁵¹ 12% of study participants consistently reported clinically significant symptoms of depression and anxiety at the time of diagnosis and again at 6- and 12-month follow-ups (including post-treatment survivorship), and we anticipate this rate to be higher in the present day, given societal trends.

A cancer diagnosis and its treatment certainly disrupt healthy psychosocial functioning and human development; yet few, if any, studies have examined medical late effects or psychosocial challenges in survivors as a function of pre-existing psychological or social environmental risk and resilience factors. Evidence from both population health and cancer-specific investigations implicates lower social support, exposures to racism and discrimination by virtue of one's skin color, lower SES, and shorter time from diagnosis as risk factors.^3,52,53 Another set of studies suggest that managing stress, having goals, or a sense of purpose serve as individual protective or health-promoting resilience factors for psychosocial adjustment among AYAs with cancer.^54,55 Yet, little is known about the biologic pathways through which the known effects of social-environmental risk factors on population health and well-being influence outcomes in post-treatment AYA cancer survivors, specifically with regard to disease- or treatment-related late effects, cancer recurrence, survival, and QOL.⁵⁶

Population health outcomes and disparities in those outcomes (by race/ethnicity, sex and gender, and geographic location) are known to be associated with and largely a function of social determinants of health, including socioeconomic gradients, exposures to early childhood traumas or adversity, and accumulated experiences of discrimination.^57-63 For example, the Behavioral Risk Factor Surveillance System, a population-based data set containing data regarding health-related risk behaviors and chronic health conditions, has demonstrated strong correlations between deleterious physical and mental health outcomes in adults, including depression, suicide, alcoholism, and drug use, and reported exposures to Adverse Childhood Experiences, such as neglect, violence, or family dysfunction.⁶⁴ Although health status is positively associated with SES, we also know that this relationship varies by race: at every level of SES, persons identified as Black race have significantly worse health outcomes than do those identified as White race.⁵⁸ Conversely, health outcomes are improved among persons of all races who have adequate support networks and coping capabilities.

In the cancer context, those who have reported a sense of purpose or meaning from adverse conditions or experiences in their lives also report better health outcomes when compared with those who cannot or do not.^65-67 Among AYA Hodgkin lymphoma survivors, a recent analysis using SEER data showed racial, socioeconomic, and sex-based disparities in outcomes continue into long-term survivorship.⁶⁸ Yet, studies detailing the incidence or prevalence of, or excess risks for, long-term and late effects of cancer among AYA survivors have not accounted for the risk and resilience factors known to affect population health outcomes and explain disparities.

Applying Social Genomics to AYA Cancer Survivorship Research

A growing body of research in human social genomics has begun to map molecular pathways through which such psychological and social environmental factors regulate gene expression in immune cells and cancer cells of older adults and thus affect their risks for chronic disease, cancer recurrence, late effects, secondary cancers, and mortality (Fig 1). These pathways involve social and psychological processes that affect neural and endocrine function to regulate gene expression in tumor cells and immune cells. Several studies have documented CTRA gene regulation and associated alterations in upstream signal transduction processes in older patients with cancer (eg, breast, ovarian, prostate, and hematopoietic malignancies)^{15,18,23-25,33,61,69-71} and favorable impacts of experimental pharmacologic and behavioral interventions in reducing CTRA gene expression,^72-75 but none has explored these pathways among AYA cancer survivors.

The CTRA RNA signature represents a well-established biomarker with significant potential for clarifying the biologic mechanisms of psychosocial and social-environmental influences on health outcomes in the context of AYA cancer. As such, research in social genomics represents an emerging opportunity to investigate these mechanisms among AYA cancer survivors. Currently, little is known about the interactions between biologic, psychological, and social environmental processes for an AYA cancer population distinguished by its chronologic age and developmental life stage. Cancer diagnosed and treated during adolescence and young adulthood is a unique, socially isolating experience and embraces wide ranges of SES (because of life stage, transitions in health care coverage, and increasing financial autonomy). CTRA gene expression is also known to vary in activity as a function of these demographic factors (eg, socioeconomic conditions, age, sex, and race/ethnicity).^9,76 Furthermore, global trends affecting young people in particular, including economic precarity and financial burden, changes in developmental norms and expectations, sex and gender plurality, and expanding cultural diversity warrant transdisciplinary investigations that account for the influence and interaction of these conditions on biology and subsequent health outcomes.⁷⁷

In conclusion, the social genomic approach has proven to be successful in mapping some of the key biologic pathways of social disparities in older adult oncology outcomes and in generating new intervention strategies for mitigating the effects of adverse psychosocial conditions on cancer survivors' health. In merging two distinct scientific domains—the social and the genomic—we can further our understanding of AYA cancer survivor's distinctive health risks and social disparities and identify new opportunities to enhance their health and well-being across all sectors of the population.

AUTHOR CONTRIBUTIONS

Conception and design: All authors

Financial support: Lauren V. Ghazal, Brad Zebrack

Data analysis and interpretation: All authors

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center.

Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).