Short communicationVal66Met BDNF polymorphism as a vulnerability factor for inflammation-associated depressive symptoms in women with breast cancer
Introduction
For most women, receiving a breast cancer diagnosis and undergoing cancer treatment is a stressful experience. In general, this distress tends to decrease over time and is typically resolved shortly after the completion of cancer treatment (Henselmans et al., 2010). However, certain women are more profoundly and persistently impacted, with approximately 25% of breast cancer patients experiencing clinically significant depressive symptoms that persist well beyond the completion of treatment (Donovan et al., 2014). Depression reduces quality of life, and may also lead to shorter survival time in women with breast cancer (Pinquart and Duberstein, 2011).
Substantial evidence implicates inflammation in the development of depression. Elevated inflammatory markers are associated with depression in both clinical and community samples (Howren et al., 2009). Evidence of inflammation as a causal factor for depression comes from studies of patients with Hepatitis C or cancer, who commonly develop major depression after the initiation of IFN-α therapy, which elicits a potent inflammatory response (Capuron and Miller, 2004, Raison et al., 2005). Additionally, administration of inflammatory agents to healthy individuals leads to depressed mood (Reichenberg et al., 2001, Eisenberger et al., 2010). Notably, vaccine studies in healthy individuals have shown that even a mild inflammatory stimulus, one that does not cause a fever or any other symptoms of physical sickness, can lead to depressive symptoms (Wright et al., 2005).
The mechanisms by which peripheral inflammation can access the brain and potentially lead to depressed mood have begun to be elucidated. Pro-inflammatory cytokines can communicate with the brain via various routes, including passage of circulating cytokines through leaky regions in the blood brain barrier, active transport of cytokines via saturable transporters, activation of cytokine-producing cells lining the cerebral vasculature, and binding to cytokine receptors on afferent nerve fibers which then transmit inflammatory signals to the brain (Miller et al., 2013, Dantzer et al., 2008). Recent evidence has also shown that the brain possesses functional lymphatic vessels, which are able to carry immune cells from the cerebrospinal fluid (Louveau et al., 2015). Cytokines and their signaling pathways can then have wide-ranging impacts on neurotransmitter metabolism, neuroendocrine function, and neuroplasticity (Haroon et al., 2012), resulting in a constellation of emotional, cognitive and behavioral changes referred to collectively as “sickness behaviors” (Dantzer et al., 2008). These sickness behaviors include loss of appetite, anhedonia, fatigue, depression, and cognitive impairment (Dantzer et al., 2008). In the case of acute infection, sickness behaviors are thought to be an adaptive response evolved to minimize the spread of infection and promote healing, and are generally dismissed as the temporary and relatively benign byproduct of acute illness (Dantzer and Kelley, 2007). However, in the context of prolonged immune activation, ongoing inflammatory signaling to the brain may lead to more disruptive cognitive and behavioral changes, including the development of clinical or subclinical depression, even in individuals without any prior history of mental disorders (Dantzer et al., 2008).
In the context of cancer, the relationship between inflammation and depressive symptoms may be particularly salient, because factors such as tumor cell burden, tissue destruction, radiation treatments, and chemotherapy can activate inflammatory pathways (Miller et al., 2008). Indeed, studies have demonstrated associations between inflammation and depressive symptoms among cancer patients. For instance, several studies have shown that cancer patients with major depression have higher plasma levels of interleukin-6 (IL-6) compared to cancer patients without depression (Jehn et al., 2006, Musselman et al., 2001, Soygur et al., 2007). A study assessing 61 breast cancer patients prior to the initiation of chemotherapy found an association between C-reactive protein (CRP) and depressive symptoms (Pertl et al., 2013). A longitudinal study found that, among colorectal cancer patients, levels of CRP and tumor necrosis factor-alpha (TNF-α) prior to surgery predicted depressive symptoms post-surgery (Archer et al., 2012).
Although there is compelling evidence linking inflammation and depression in the context of cancer, these effects are typically modest and not found in all studies (e.g., Bower et al., 2011). Even in the context of IFN-alpha therapy, major depression only develops in about 30% of initially non-depressed subjects (Lotrich et al., 2013). This suggests that certain individuals may be more vulnerable to depression following an inflammatory stimulus. Emerging evidence suggests that a single nucleotide polymorphism (SNP) in the brain-derived neurotrophic factor (BDNF) gene could be a vulnerability factor for inflammation-induced depression. BDNF is a protein vital for neuroplasticity and neurogenesis, and decreased neurogenesis is one candidate pathway through which inflammation can lead to depressive symptoms (Song and Wang, 2011). A common variant of the BDNF gene, a valine to methionine substitution at codon 66 (Val66Met, rs6265), is associated with reduced activity-dependent secretion of BDNF (Egan et al., 2003), and may increase vulnerability for inflammation-associated depression. Indeed, Lotrich and colleagues examined the relationship between the BDNF Met allele and depressive symptoms in a sample of 209 adults undergoing IFN-α therapy for Hepatitis C (Lotrich et al., 2013). Findings indicated that the Met allele was associated with lower levels of serum BDNF, and that individuals who achieved the lowest BDNF nadirs over the course of IFN-α treatment were the most likely to develop depression (Lotrich et al., 2013). Additionally, Kim et al., 2013, Kim et al., 2015 found that both the BDNF Met allele and higher BDNF gene methylation were associated with suicidal ideation in a sample of 241 breast cancer patients assessed at one year after surgery, though inflammation was not directly measured in these studies.
Section snippets
The present study
Cancer treatments can activate inflammatory processes, and inflammation can drive the development of depression; yet, only a subset of women with breast cancer develop significant and persistent depressive symptoms. The present study examined whether the BDNF Met allele is a vulnerability factor for inflammation-associated depressive symptoms among post-treatment breast cancer survivors. Because proinflammatory cytokines can reduce BDNF (Yirmiya and Goshen, 2011), women who start out with low
Participants
Data were drawn from a larger study on cognitive functioning following cancer therapy, the Mind Body Study (MBS). Women recently diagnosed with breast cancer were primarily identified through the Los Angeles County Surveillance Epidemiology and End Results registry and invited to participate in the study, as previously described (Ganz et al., 2013, Ganz et al., 2014, Ganz et al., 2016). Eligibility criteria included females aged 21–65 years; newly diagnosed with stage 0-IIIA breast cancer;
Descriptive statistics
Table 1 presents descriptive statistics for sample characteristics and study variables by BDNF genotype at baseline. BDNF genotyping results revealed that 75 participants (67%) were Val/Val genotype; 32 participants (28.6%) were Val/Met genotype, and 5 participants (4.4%) were Met/Met genotype, which did not significantly deviate from Hardy-Weinberg equilibrium (X2=0.33, df=1, p=0.56). As is typically done in BDNF genotype studies in predominantly Caucasian samples (Herbert et al., 2012), we
Discussion
In a sample of 112 breast cancer survivors, CRP was positively associated with cognitive depressive symptoms among women carrying a BDNF Met allele, but not among Val/Val homozygotes. The positive association between CRP levels and cognitive depressive symptoms among Met carriers held at treatment completion and across the 1-year follow-up. These findings suggest that women with both the Met allele and elevated CRP at baseline had, on average, higher cognitive depressive symptoms over time
Conclusions
The present study identifies a potential vulnerability factor for inflammation-associated cognitive depressive symptoms among breast cancer survivors. Inflammation persisting into the post-treatment survivorship period, in combination with a BDNF Met allele, may amount to a “double hit” that leaves some women particularly vulnerable to depression. The present study may thus help to identify a subset of breast cancer survivors who may benefit from early identification and treatment.
Acknowledgments
This research was supported by funding from the National Cancer Institute (R01 CA 109650, PAG; P30 CA 016042, CMC), the Breast Cancer Research Foundation (PAG), the OAIC Inflammatory Biology Core (NIH/NIA P30- AG028748), the USC-UCLA Biodemography Center’s Social Genomics Core (NIH/NIA P30-AG017265) and the California Center for Population Research at UCLA (CCPR) with training support from the National Institute on Aging (T32-AG033533) and from the National Institute of General Medical Sciences
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