Cancer-related fatigue and pain after surgery are the most frequent and most incapacitating cancer-related symptoms after breast cancer treatment. Genetic influence of cancer-related fatigue and pain has not been previously investigated. Our aim was to examine the influence of catechol-O-methyltransferase (COMT) Val158Met genotypes on cancer-related fatigue, post-mastectomy pain, and pressure pain hypersensitivity in breast cancer survivors. One-hundred and twenty-eight (n = 128) breast cancer survivors who were treated with radiotherapy and chemotherapy participated in this study. After amplifying Val158Met polymorphisms by polymerase chain reaction, COMT genotype was divided into Val/Val, valine/methionine (Val/Met), or Met/Met. The Piper fatigue scale (PFS) was used to assess cancer-related fatigue. Neck and shoulder/axillary pain intensity was assessed with a numerical pain rate scale (0-10). Finally, pressure pain thresholds (PPT) were assessed bilaterally over the C5-C6 zygapophyseal joints, deltoid muscles, second metacarpal, and tibialis anterior muscles. Breast cancer survivors carrying the Met/Met genotype reported higher levels of fatigue (all subscales, P < 0.001), higher neck pain intensity, and lower PPT over C5-C6 joints and deltoid muscles (all, P < 0.001) relative to those with Val/Met or Val/Val genotypes. The results suggest that breast cancer survivors carrying the Met/Met genotype exhibit higher fatigue, neck pain, and pressure pain hypersensitivity over the neck and shoulder area. This study is important because it strives to understand the factors that predispose some breast cancer survivors to more cancer-related fatigue and increased pain sensitivity.

Stress can play an important role in development of cancer-related fatigue (CRF) by activating the hypothalamic-pituitary-adrenal (HPA) axis, the sympathetic nervous system (SNS), and altering the immune system. This study examined the influence of catechol-O-methyltransferase (COMT) Val158Met genotypes on salivary markers of HPA axis (cortisol), SNS (α-amylase) and immune (IgA) systems, as well as on CRF in breast cancer survivors (BCS). One-hundred BCS participated. After amplifying Val158Met COMT polymorphisms by polymerase chain reaction, three COMT genotypes were considered: Val/Val, Val/Met, Met/Met. Salivary cortisol, α-amylase activity, salivary flow rate, and IgA concentration were collected from non-stimulated saliva. CRF was assessed with the fatigue subscale of the Profile of Mood State (POMS) questionnaire. We found that BCS carrying Met/Met genotype reported higher cortisol concentration, α-amylase activity and greater CRF than those with Val/Met (P < 0.05) and Val/Val (P < 0.001) genotypes. No differences in salivary flow rate or IgA concentration (P > 0.20) were found. The results suggest that BCS carrying Met/Met genotype exhibit greater dysfunction of the HPA axis and SNS system associated with severe CRF. This study is important because it strives to understand biological factors that predispose some BCS to higher levels of CRF.

ABSTRACT:Our aim was to investigate the relationship between Val158Met polymorphisms, headache, and pressure hypersensitivity in children with chronic tension-type headache (CTTH). A casecontrol study with blinded assessor was conducted. Seventy children with CTTH associated with pericranial tenderness and 70 healthy children participated. After amplifying Val158Met polymorphism by polymerase chain reactions, we assessed genotype frequencies and allele distributions. We classified children according to their T ension-type headache is the most common form of head pain in both adult (1) and child (2) population. Although there has been an increasing knowledge in the pathogenesis of tension-type headache (TTH), the pathoanatomical mechanisms are not completely understood (3). As TTH has several negative repercussions for children, further studies are needed (4,5).Genetic epidemiological studies have investigated the familial aggregation of TTH. In fact, in individuals with chronic TTH (CTTH), first-degree relatives have a 3.1-fold significantly increased risk of suffered from CTTH (6,7), suggesting a possible role of genetic factors in CTTH. The catechol-Omethyltransferase (COMT) gene is one of the several potential headache genetic determinants. The COMT is an enzyme involved in the metabolic degradation of dopamine, norepinephrin, and epinephrine (8). Several studies indicate that the genetic polymorphism due to a G3 A substitution at codon 158 of the COMT gene, which leads to a valine (Val) to methionine (Met) substitution, results in differences in COMT activity: a valine (Val) at codon 158 results in a heat-stable, high-activity COMT variant (Val/Val), whereas a methionine (Met) at this position (Val/Met, or Met/Met) results in heatlabile, low-activity variants (9,10). Zubieta et al. (11) demonstrated that individuals with Val/Val genotype have a 3-to 4-fold higher activity of the COMT enzyme and reduced pain sensitivity compared with those with the Met/Met genotype, suggesting that the presence of Met/Met genotype may predispose for chronic pain.Although it might be possibly an influence of COMT polymorphisms for chronic pain, few studies have examined the association between Val158Met polymorphisms and headache. In addition, results from the studies are controversial, as one study found that the frequency of Met/Met genotype was higher in subjects with migraine (12), whereas others reported no differences in genotype distribution and allele frequency of COMT polymorphisms between migraine and healthy subjects (13,14). Another study did not find relationship of Val158Met polymorphism at the COMT in individuals with medication overuse chronic daily headache, episodic migraine without aura, and without analgesic abuse and healthy controls (15). Therefore, more studies are required.In addition, mechanical hypersensitivity is considered a clear manifestation of hyperexcitability of peripheral and central nociceptive pain pathways in TTH, in both adults (16) and children (17). Jensen et al. (18) have recently rep...

These results suggest that children with FETTH, at first instance, do not present deficits in the secretion of these cortisol and melatonin. Prospective longitudinal studies are needed to further elucidate the direction of current findings, particularly the synchronism of cortisol and melatonin and the course of the headache.

These results suggest that children with CTTH present with deficits in the immune system, but not dysfunction in the HPA axis or SNS. Future studies are needed to elucidate the direction of these relationships.