RESUMO
BACKGROUND: Infection with high-risk subtypes of human papillomavirus (HPV) is a central factor in the development of cervical neoplasia. Cell-mediated immunity against HPV16 plays an important role in the resolution of HPV infection and in controlling cervical disease progression. Research suggests that stress is associated with cervical disease progression, but few studies have examined the biological mechanisms that may be driving this association. PURPOSE: This study examines whether stress is associated with immune response to HPV16 among women with cervical dysplasia. METHODS: Seventy-four women presenting for colposcopy completed measures of health behaviors, stressful life events and perceived stress. A blood sample was obtained to evaluate proliferative T-cell response to HPV16, and a cervical sample was obtained during gynecologic exam for HPV-typing. RESULTS: More than 55% tested positive for one or more HPV subtypes. Women who did not show proliferative responses to HPV (i.e. non-responders) were more likely to be HPV(+) compared to women who had a response (i.e. responders). Consistent with study hypotheses, logistic regression revealed that higher levels of perceived stress were associated with a non-response to HPV16, controlling for relevant covariates. Stressful life events were not associated with T-cell response to HPV. CONCLUSIONS: Higher levels of perceived stress are associated with impaired HPV-specific immune response in women with cervical dysplasia, suggesting a potential mechanism by which stress may influence cervical disease progression.
Assuntos
Papillomavirus Humano 16/imunologia , Infecções por Papillomavirus/psicologia , Estresse Psicológico/imunologia , Displasia do Colo do Útero/psicologia , Adulto , Estudos de Casos e Controles , Estudos Transversais , Feminino , Humanos , Pessoa de Meia-Idade , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/imunologia , Valores de Referência , Índice de Gravidade de Doença , Estresse Psicológico/complicações , Linfócitos T/imunologia , Displasia do Colo do Útero/complicações , Displasia do Colo do Útero/imunologia , Displasia do Colo do Útero/virologiaRESUMO
The contribution of BRCA1 and BRCA2 to familial and non-familial forms of breast cancer has been difficult to accurately estimate because of the myriad of potential genetic and epigenetic mechanisms that can ultimately influence their expression and involvement in cellular activities. As one of these potential mechanisms, we investigated whether allelic imbalance (AI) of BRCA1 or BRCA2 expression was associated with an increased risk of developing breast cancer. By developing a quantitative approach utilizing allele-specific real-time PCR, we first evaluated AI caused by nonsense-mediated mRNA decay in patients with frameshift mutations in BRCA1 and BRCA2. We next measured AI for BRCA1 and BRCA2 in lymphocytes from three groups: familial breast cancer patients, non-familial breast cancer patients and age-matched cancer-free females. The AI ratios of BRCA1, but not BRCA2, in the lymphocytes from familial breast cancer patients were found to be significantly increased as compared to cancer-free women (BRCA1: 0.424 versus 0.211, P = 0.00001; BRCA2: 0.206 versus 0.172, P = 0.38). Similarly, the AI ratios were greater for BRCA1 and BRCA2 in the lymphocytes of non-familial breast cancer cases versus controls (BRCA1: 0.353, P = 0.002; BRCA2: 0.267, P = 0.03). Furthermore, the distribution of under-expressed alleles between cancer-free controls and familial cases was significantly different for both BRCA1 and BRCA2 gene expression (P < 0.02 and P < 0.02, respectively). In conclusion, we have found that AI affecting BRCA1 and to a lesser extent BRCA2 may contribute to both familial and non-familial forms of breast cancer.
Assuntos
Desequilíbrio Alélico , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Predisposição Genética para Doença , Adulto , Proteínas Reguladoras de Apoptose , Estudos de Coortes , Delaware , Feminino , Humanos , Pessoa de Meia-Idade , Pennsylvania , Reação em Cadeia da Polimerase , RNA Mensageiro/metabolismo , Medição de Risco , População Branca/genéticaRESUMO
Germline mutations in the human breast cancer susceptibility genes BRCA1 and BRCA2 account for the majority of hereditary breast and ovarian cancer. In spite of the large number of sequence variants identified in BRCA1 and BRCA2 mutation analyses, many of these genetic alterations are still classified as variants of unknown significance (VUS). In this study, we evaluated 12 BRCA1/2 intronic variants in order to differentiate their pathogenic or polymorphic effects on the mRNA splicing process. We detected the existence of aberrant splicing in three BRCA1 variants (c.301-2delA/IVS6-2delA, c.441+1G>A/IVS7+1G>A, and c.4986+6T>G/IVS16+6T>G) and two BRCA2 variants (c.8487+1G>A/IVS19+1G>A and c.8632-2A>G/IVS20-2A>G). All but one of the aberrant transcripts arise from mutations affecting the conserved splice acceptor or donor sequences and all would be predicted to result in expression of truncated BRCA1 or BRCA2 proteins. However, we demonstrated that four of these splice-site mutations (i.e., c.301-2delA, c.441+1G>A, c.4986+6T>G, and c.8632-2A>G) with premature termination codons were highly unstable and were unlikely to encode for abundant expression of a mutant protein. Three variants of BRCA1 (c.212+3A>G/IVS5+3A>G, c.593+8A>G/IVS9+8A>G, and c.4986-20A>G/IVS16-20A>G) and four variants of BRCA2 (c.516-19C>T/IVS6-19C>T, c.7976-4_7976_3delTT/IVS17-4delTT, c.8487+19A>G/IVS19+19A>G, and c.9256- 18C>A/IVS24- 18C>A) in our studies show no effects on the normal splicing process, and they are considered to be benign polymorphic alterations. Our studies help to clarify the aberrant splicing in BRCA1 and BRCA2 as well as provide information that can be used clinically to help counsel breast/ovarian cancer prone families.