RESUMEN

Women who have inherited a germ-line mutation in the BRCA1 or BRCA2 (BRCA1/2) genes have a greatly increased risk of developing breast cancer compared with the general population. However, there is also substantial interindividual variability in the occurrence of breast cancer among BRCA1/2 mutation carriers. We hypothesize that genes involved in endocrine signaling may modify the BRCA1/2-associated age-specific breast cancer penetrance. We studied the effect of alleles at the AIB1 gene using a matched case-control sample of 448 women with germ-line BRCA1/2 mutations. We found that these women were at significantly higher breast cancer risk if they carried alleles with at least 28 or 29 polyglutamine repeats at AIB1, compared with women who carried alleles with fewer polyglutamine repeats [odds ratio (OR), 1.59; 95% confidence interval (CI), 1.03-2.47 and OR, 2.85; 95% CI, 1.64-4.96, respectively]. Late age at first live birth and nulliparity have been associated with increased breast cancer risk. We observed increases in BRCA1/2-associated breast cancer risk in women who were either nulliparous or had their first live birth after age 30 (OR, 3.06; 95% CI, 1.52-6.16). Women were at significantly increased risk if they were nulliparous or had a late age at first live birth and had AIB1 alleles no shorter than 28 or 29 or more AIB1 polyglutamine repeats (OR, 4.62; 95% CI, 2.02-10.56 and OR, 6.97; 95% CI, 1.71-28.43, respectively) than women with none of these risk factors. Our results support the hypothesis that pathways involving endocrine signaling, as measured through AIB1 genotype and reproductive history, may have a substantial effect on BRCA1/2-associated breast cancer risk.

Asunto(s)

Proteína BRCA1/genética , Neoplasias de la Mama/genética , Proteínas de Neoplasias/genética , Historia Reproductiva , Factores de Transcripción/genética , Adulto , Anciano , Alelos , Proteína BRCA2 , Neoplasias de la Mama/patología , Femenino , Frecuencia de los Genes , Genotipo , Mutación de Línea Germinal , Humanos , Persona de Mediana Edad , Coactivador 3 de Receptor Nuclear , Factores de Riesgo , Repeticiones de Trinucleótidos/genética

RESUMEN

In men over 30 years old, serum levels of testosterone (T) decrease with age. A shorter polymorphic CAG repeat length in exon 1 of the androgen receptor (AR) gene is associated with higher transcription activation by the AR. We determined the number of CAG repeats for 882 men aged between 40 and 70 years from the Massachusetts Male Aging Study (MMAS). MMAS is a population-based random sample survey of men for whom baseline (1987-1989, mean age 53+/-8 years) and follow-up (1995-1997, mean age 61+/-8 years) serum hormone levels were available. Multiple linear regression was used to determine if CAG repeat length would be predictive of hormone levels at follow-up. Hormone levels measured included T, free T, albumin-bound T, dihydrotestosterone (DHT), sex hormone-binding globulin (SHBG) and luteinizing hormone (LH). The CAG repeat length was significantly associated with T (P=0.041), albumin-bound T (P=0.025) and free T (P=0.003) when controlled for age, baseline hormone levels and anthropometrics. Follow-up levels of T decreased by 0.74%+/-0.36 per CAG repeat decrement. Likewise, the percentages of free and albumin-bound T decreased by 0.93%+/-0.31 and 0.71%+/-0.32 per CAG repeat decrement respectively. These results suggest that androgen levels may be modulated by AR genotype.

Asunto(s)

Envejecimiento/sangre , Andrógenos/sangre , Receptores Androgénicos/genética , Adulto , Anciano , Humanos , Masculino , Persona de Mediana Edad , Secuencias Repetitivas de Ácidos Nucleicos

RESUMEN

Compared with the general population, women who have inherited a germline mutation in the BRCA1 gene have a greatly increased risk of developing breast cancer. However, there is also substantial interindividual variability in the occurrence of breast cancer among BRCA1 mutation carriers. We hypothesize that other genes, particularly those involved in endocrine signaling, may modify the BRCA1-associated age-specific breast cancer risk. We studied the effect of the CAG repeat-length polymorphism found in exon 1 of the androgen-receptor (AR) gene (AR-CAG). AR alleles containing longer CAG repeat lengths are associated with a decreased ability to activate androgen-responsive genes. Using a sample of women who inherited germline BRCA1 mutations, we compared AR-CAG repeat length in 165 women with and 139 women without breast cancer. We found that women were at significantly increased risk of breast cancer if they carried at least one AR allele with >/=28 CAG repeats. Women who carried an AR-CAG allele of >/=28, >/=29, or >/=30 repeats were given a diagnosis 0.8, 1.8, or 6.3 years earlier than women who did not carry at least one such allele. All 11 women in our sample who carried at least one AR-CAG allele with >/=29 repeats had breast cancer. Our results support the hypothesis that age at breast cancer diagnosis is earlier among BRCA1 mutation carriers who carry very long AR-CAG repeats. These results suggest that pathways involving androgen signaling may affect the risk of BRCA1-associated breast cancer.

Asunto(s)

Neoplasias de la Mama/genética , Genes BRCA1/genética , Receptores Androgénicos/genética , Repeticiones de Trinucleótidos/genética , Adulto , Anciano , Neoplasias de la Mama/química , Femenino , Predisposición Genética a la Enfermedad/genética , Mutación de Línea Germinal/genética , Heterocigoto , Humanos , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa/métodos , Modelos de Riesgos Proporcionales , Transducción de Señal/genética

RESUMEN

BACKGROUND: CAG repeat length in exon 1 of the androgen receptor (AR) gene correlates inversely with transcriptional transactivation activity of the AR. Men with shorter AR CAG repeat lengths are at higher risk of prostate cancer. Because benign prostatic hyperplasia (BPH) is an androgen-dependent condition, we examined the hypothesis that a shorter AR gene CAG repeat length increases the risk of developing of BPH. METHODS: Among 14,916 men of the Physicians' Health Study who had provided a blood sample in 1982, we measured AR gene CAG repeat lengths for 310 men who had surgery for BPH up to 7.5 years of follow-up and 1,041 controls. RESULTS: Risk of surgery for BPH increased linearly with decreasing AR CAG repeat length (P (trend) = 0.03). Relative to men with a CAG repeat length > or = 25, men with a repeat length < or = 19 had an odds ratio of BPH surgery of 1.76 (95% confidence interval, 1.16-2.65). CONCLUSIONS: Variability in the AR gene CAG repeat influences the development of symptomatic BPH.

Asunto(s)

Hiperplasia Prostática/genética , Receptores Androgénicos/genética , Repeticiones de Trinucleótidos/genética , Humanos , Masculino , Médicos , Hiperplasia Prostática/cirugía , Estados Unidos , Procedimientos Quirúrgicos Urológicos Masculinos/estadística & datos numéricos

RESUMEN

OBJECTIVES: Shorter CAG repeat lengths in exon 1 of the androgen receptor (AR) gene are associated with a stronger transcriptional activity of the AR and with a higher risk of prostate cancer. Because benign prostatic hyperplasia (BPH) is an androgen-dependent condition, we examined the hypothesis that men with shorter AR gene CAG repeat lengths have an increased risk of developing BPH. METHODS: Using data from the Health Professionals Follow-up Study (HPFS), we evaluated the relationship between AR gene CAG repeat length and prevalent BPH, as defined by BPH surgery, by enlarged prostate gland detected by digital rectal examination, and by urinary symptoms as determined by the American Urological Association Symptom Index. RESULTS: The odds ratio for BPH surgery or enlarged prostate gland was 1.92 (95% confidence interval [CI] 1.22 to 3.03; P [trend] = 0.0002), comparing AR gene CAG repeat length of 1 9 or less to 25 or more. Results were similar for the end points of BPH surgery (P [trend] = 0.002) and for enlarged prostate gland (P [trend] = 0.001). For a six-repeat decrease in CAG repeat length, the odds ratio for having moderate or severe urinary obstructive symptoms from an enlarged prostate gland was 3.62 (95% CI 1.51 to 8.67; P = 0.004). CONCLUSIONS: Variability in the AR gene CAG repeat influences the development of symptomatic BPH, particularly in predicting obstructive urinary symptoms. Our findings support further study to establish the appropriate clinical relevance.

Asunto(s)

Hiperplasia Prostática/genética , Receptores Androgénicos/genética , Adulto , Anciano , Estudios de Cohortes , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Repeticiones de Trinucleótidos

RESUMEN

The androgen receptor (AR) gene contains a polymorphic GGN microsatellite in exon 1, which encodes polyglycine in the amino terminus of the AR. Previous work has shown that a polymorphic region of CAG repeats also in exon 1 is inversely related to the ability of the AR to transactivate other genes and to prostate cancer risk. We investigated whether AR gene GGN repeat length is related to prostate cancer in a nested study of 582 cases and 794 controls matched on age and smoking status in the Physicians' Health Study. DNA was prepared from archived blood. Using PCR, the region surrounding the GGN repeat was amplified. Fluorescence-labeled primers were used such that the fragment produced could be sized using polyacrylamide gels and Genescan software. We estimated odds ratios and 95% confidence intervals from logistic models controlling for the matching variables for the relation between GGN repeat length and total prostate cancer and by stage/grade and by age at diagnosis. Among controls, the most frequent GGN repeat lengths were 23 (53.5%) and 24 (34.0%), with a range of 10-29. There was no statistically significant difference in the mean GGN repeat length between cases (23.13) and controls (23.05). However, cases had a narrower spread of repeats lengths (parametric test, P = 0.03; nonparametric test, P = 0.07) than controls, with fewer extreme lengths in either direction. The risk of total prostate cancer was slightly increased for a GGN repeat length of 23 compared to all others (odds ratio, 1.20; 95% confidence interval 0.97-1.49); risk did not vary by tumor stage/grade. For every one repeat deviation in either direction from 23, the risk of prostate cancer decreased by 8% (P = 0.04). Although the AR gene GGN repeat probably plays only a modest role in prostate cancer, the observed relation of this repeat with prostate cancer risk supports the evaluation of the effect of GGN repeat length on AR transactivation.

Asunto(s)

Polimorfismo Genético/genética , Neoplasias de la Próstata/genética , Receptores Androgénicos/genética , Repeticiones de Trinucleótidos/genética , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias de la Próstata/patología , Factores de Riesgo , Expansión de Repetición de Trinucleótido

RESUMEN

OBJECTIVES: To evaluate the prognostic significance of reverse transcriptase polymerase chain reaction (RT PCR) detection of prostate-specific antigen (PSA) mRNA in relation to survival in patients with metastatic androgen-independent prostatic carcinoma (AIPC). METHODS: Peripheral blood from 122 men (64 from Memorial Sloan-Kettering Cancer Center [MSKCC] and 58 from the Dana Farber Cancer Institute [DFCI]) with metastatic (Stage D2) AIPC was analyzed for PSA mRNA using RT PCR. Forty-one controls without prostatic carcinoma were also evaluated. RESULTS: RT PCR positivity for PSA mRNA was present in 24 of the 64 (38%) patients seen at MSKCC and in 26 of the 58 (45%) patients followed at DFCI. All control individuals were PSA PCR negative. There was a significant correlation between RT PCR positivity and decreased survival in each of the Memorial and Dana Farber population (P = 0.028 and 0.039, respectively). Serum PSA (at time of blood collection for PCR) was not predictive of survival as a continuous variable in the MSKCC [P = 0.31] and the DFCI (P = 0.09) groups. RT PCR for PSA mRNA was found to be independent from and superior to serum PSA in predicting survival in both the MSKCC and DFCI populations (P = 0.048 and P = 0.027, respectively). CONCLUSIONS: The detection of PSA mRNA in the peripheral blood by RT PCR is a predictor of survival in patients with metastatic AIPC, and PCR is superior to a single serum PSA measurement. Further studies are needed to test the value of this factor in comparison to and coupled with other prognostic parameters.

Asunto(s)

Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Metástasis de la Neoplasia , Reacción en Cadena de la Polimerasa , Pronóstico , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/mortalidad , Neoplasias de la Próstata/patología , ARN Mensajero/análisis , Tasa de Supervivencia , Testosterona/sangre

RESUMEN

The length of a polymorphic CAG repeat sequence, occurring in the androgen receptor gene, is inversely correlated with transcriptional activity by the androgen receptor. Because heightened androgenic stimulation may increase risk of prostate cancer development and progression, we examined whether shorter CAG repeats in the androgen receptor gene are related to higher risk of prostate cancer. We conducted a nested case-control study of 587 newly diagnosed cases of prostate cancer detected between 1982 and 1995, and 588 controls without prostate cancer, within the Physician's Health Study. An association existed between fewer androgen receptor gene CAG repeats and higher risk of total prostate cancer [relative risk (RR) = 1.52; 95% confidence interval (CI) = 0.92-2.49; P trend = 0.04; for men with CAG repeat lengths < or = 18 relative to > or = 26 repeats]. In particular, a shorter CAG repeat sequence was associated with cancers characterized by extraprostatic extension or distant metastases (stage C or D) or high histologic grade (RR = 2.14; CI = 1.14-4.01; P trend = 0.001). This association was observed individually both for high stage (RR = 2.23) and high grade prostate cancer (RR = 1.89). Men with shorter repeats were at particularly high risk for distant metastatic and fatal prostate cancer. Variability in the CAG repeat length was not associated with low grade or low stage disease. These results demonstrate that a shorter CAG repeat sequence in the androgen receptor gene predicts higher grade and advanced stage of prostate cancer at diagnosis, and metastasis and mortality from the disease. The clinical implications of these results should be evaluated further.

Asunto(s)

Neoplasias de la Próstata/genética , Receptores Androgénicos/genética , Repeticiones de Trinucleótidos , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo Genético

RESUMEN

Prostate cancer (CaP) is the most commonly diagnosed, nondermatological cancer in the United States. The development and progression of CaP is influenced by androgens. 5 alpha-Reductase, type II, converts testosterone to dihydrotestosterone and is critical to the development of the prostate. A TA dinucleotide repeat polymorphism exists in the 3' untranslated region of the 5 alpha-reductase type II gene. 5 alpha-Reductase alleles with longer TA repeats are more common in African-Americans, the group with the highest incidence of CaP. It has been hypothesized that the longer TA repeat alleles might be associated with increased risk of CaP. We studied this potential association within the Physician's Health Study, a predominantly Caucasian cohort study. Using PCR we identified the TA genotype in 590 men with CaP and 802 age-matched controls. The frequency of each allele in the controls was TA(0), 0.87, TA(9), 0.13, and TA(18), 0.01. Homozygotes for the longer TA alleles, TA(9) and TA(18), were underrepresented among cases with an odds ratio of 0.47 (confidence interval, 0.20-1.12), but this was not statistically significant (P = 0.08, two tailed). Our analysis does not support the prior hypothesis that longer TA alleles confer an increased risk of CaP in a predominantly Caucasian population; in fact, longer TA alleles are more prevalent in men without CaP.

Asunto(s)

3-Oxo-5-alfa-Esteroide 4-Deshidrogenasa/genética , Regulación Enzimológica de la Expresión Génica , Polimorfismo Genético/genética , Neoplasias de la Próstata/enzimología , 3-Oxo-5-alfa-Esteroide 4-Deshidrogenasa/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Andrógenos/fisiología , Población Negra/genética , Estudios de Casos y Controles , Estudios de Cohortes , Dihidrotestosterona/metabolismo , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Frecuencia de los Genes , Genotipo , Homocigoto , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Prevalencia , Próstata/crecimiento & desarrollo , Neoplasias de la Próstata/genética , Secuencias Repetitivas de Ácidos Nucleicos , Factores de Riesgo , Testosterona/metabolismo , Población Blanca/genética

RESUMEN

OBJECTIVES: To identify distinguishing serologic features in patients with stable marked elevation in prostate-specific antigen (PSA) and multiple negative biopsies. METHODS: The study population consisted of 7 patients with a stable PSA level of greater than 20 ng/mL (average 27.0), followed for at least 34 months (average 56), and with two or more negative prostatic biopsies including transition zone biopsies. The PSA density (PSAD), rate of change in PSA, reverse transcriptase/polymerase chain reaction (RT/PCR), and free/total PSA were obtained. RESULTS: Rate of change in PSA level was stable (0.18 +/- 1.2 ng/mL/yr), suggesting that there was no occult cancer; PSAD was high (0.34 +/- 0.5 ng/mL/cc), indicating that prostate size was not the sole cause of the elevation. The RT/PCR was negative in 6 of 7 patients, further decreasing the likelihood of an occult malignancy. Free versus total PSA was not consistent, averaging 16.8%, but with a range of 6% to 34%. CONCLUSIONS: Novel PSA tests were not found to be useful in this cohort of patients with multiple negative biopsies and PSA elevations greater than 20 ng/mL. Additional studies with larger sample size are required to confirm this finding.

Asunto(s)

Antígeno Prostático Específico/sangre , Adulto , Anciano , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Próstata/diagnóstico por imagen , Neoplasias de la Próstata/diagnóstico , Ultrasonografía

RESUMEN

PURPOSE: Using prostate-specific antigen (PSA) mRNA as a marker for prostatic epithelial cells, we have developed a sensitive technique that involves reverse transcription and polymerase chain reaction (RT-PCR) to detect circulating tumor cells in the peripheral blood of men with prostatic carcinoma (CaP). PATIENTS AND METHODS: A sensitive RT-PCR assay was used to evaluate the peripheral blood of 135 men with a history of CaP. Fourteen men with benign prostate disease, many of whom had elevated serum PSA levels, were used as a control group. RESULTS: All patients with benign prostate disease had a negative result in the RT-PCR assay. Of particular interest was a subgroup of 65 patients with clinically localized CaP evaluated before definitive local therapy. Five of these patients had detectable PSA mRNA by RT-PCR, suggesting circulating tumor cells. Within this group, systemic disease was detected by RT-PCR in some men with PSA levels less than 10 ng/mL and clinical stage B disease. Blood from men with hormone-refractory and progressive CaP demonstrated a higher frequency of PSA mRNA detectable by RT-PCR (10 of 20 patients). In contrast, none of seven patients with newly diagnosed metastatic prostate cancer and only one of seven patients with metastatic, hormone-responsive disease had blood that was positive for PSA mRNA by RT-PCR. CONCLUSION: Circulating tumor cells can be detected in the blood of a subset of patients with clinically localized CaP and a larger subset of patients with progressive metastatic disease.

Asunto(s)

Biomarcadores de Tumor/sangre , Células Neoplásicas Circulantes , Antígeno Prostático Específico/genética , Neoplasias de la Próstata/diagnóstico , ARN Mensajero/sangre , Secuencia de Bases , Marcadores Genéticos , Humanos , Masculino , Datos de Secuencia Molecular , Estadificación de Neoplasias , Reacción en Cadena de la Polimerasa , Estudios Prospectivos , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/patología , Sensibilidad y Especificidad , Transcripción Genética