Asian-American variants of human papillomavirus 16 and risk for cervical cancer: a case-control study.

BACKGROUND: Human papillomavirus 16 (HPV16) has a number of variants, each with a different geographic distribution and some that are associated more often with invasive neoplasias. We investigated whether the high incidence of cervical cancer in Mexico (50 cases per 100 000 women) may be associated with a high prevalence of oncogenic HPV16 variants. METHODS: Cervical samples were collected from 181 case patients with cervical cancer and from 181 age-matched control subjects, all from Mexico City. HPV16 was detected with an E6/E7 gene-specific polymerase chain reaction, and variant HPV classes and subclasses were identified by sequencing regions of the E6 and L1/MY genes. Clinical data and data on tumor characteristics were also collected. All statistical tests were two-sided. RESULTS: HPV16 was detected in cervical scrapes from 50.8% (92 of 181) of case patients and from 11% (20 of 181) of control subjects. All HPV16-positive samples, except one, contained European (E) or Asian-American (AA) variants. AA and E variants were found statistically significantly more often in case patients (AA = 23.2% [42 of 181]; E = 27.1% [49 of 181]) than in control subjects (AA = 1.1% [two of 181]; E = 10% [18 of 181]) (P<.001 for case versus control subjects for either E or AA variants, chi2 test). However, the frequency of AA variants was 21 times higher in cancer patients than in control subjects, whereas that ratio for E variants was only 2.7 (P =.006, chi2 test). The odds ratio (OR) for cervical cancer associated with AA variants (OR = 27.0; 95% confidence interval [CI] = 6.4 to 113.7) was higher than that associated with E variants (OR = 3.4; 95% CI = 1.9 to 6.0). AA-positive case patients (46.2 +/- 12.5 years [mean +/- standard deviation]) were 7.7 years younger than E-positive case patients (53.9 +/- 12.2 years) (P =.004, Student's t test). AA variants were associated with squamous cell carcinomas and adenocarcinomas, but E variants were associated with only squamous cell carcinomas (P =.014, Fisher's exact test). CONCLUSIONS: The high frequency of HPV16 AA variants, which appear to be more oncogenic than E variants, might contribute to the high incidence of cervical cancer in Mexico.

Asian-american variants of human papillomavirus type 16 have extensive mutations in the E2 gene and are highly amplified in cervical carcinomas.

Human-papillomavirus (HPV)-E2 protein is involved in gene-expression regulation and replication of HPV genome. Disruption of the E2 gene during viral integration has been proposed as a mechanism of tumoral progression, since the expression of E6/E7 viral oncogenes is allowed. However, retention of E1/E2 genes and high viral amplification are frequently found in HPV16-positive carcinomas of some populations. In this study, we investigated whether retention of E1/E2 and viral amplification are associated with particular HPV16 E2 variants in cervical carcinomas. HPV16 detection, E1/E2 integrity and viral amplification were explored by Southern blot in 123 cervical carcinomas. HPV16 variants were identified by Southern blot and by sequencing E6, L1/MY and E2 regions. Of 46 HPV16-positive tumors, 34 were positive for E1/E2 and 14 of them showed a variant restriction pattern by mutations in E2. All 14 were Asian-American (AA) variants and, of 11 sub-classified, 6 were AA-a and 5 AA-c. Two E1/E2-negative tumors also contained the AA-c variant, while the remaining HPV16-positive tumors contained only European variants. The E2 gene of AA variants showed 24 mutations, 19 identical in both sub-classes. The 24 mutations were distributed throughout the entire gene and 19 result in 18 amino-acid changes. The AA variants were associated with E1/E2-positive carcinomas with more than 50 viral copies/cell (p = 0.035). The association of Asian-American E2 variants with retention of E1/E2 suggests that E2 variation may be an alternative mechanism de-regulating the expression of viral oncogenes.

Stagewise decline in the activity of brain protein synthesis factors and relationship between this decline and longevity in two rodent species.

The activities of brain initiation factor 2 and brain elongation factor 1, which function as rate-limiting in total protein synthesis, and estimations of brain weight were followed during postnatal life in the rat and the mouse. Both activities decreased in parallel while cumulative brain weight increased. Three exponential components were required for the mathematical expression of each of the three processes in semilogarithmic plots against time. The acceleration curves for the activities and tissue weight demonstrated a mirror image symmetry. Within the general pattern of diminution with age, the negative acceleration of the activities and the positive acceleration of the brain weight displayed repeated bursts. The activities of both factors could also be arranged into several regression lines in log/log plots against time. Significantly, in these plots, the regression line calculated for the whole set of data for each factor activity showed that the value of the ratio of the slopes (mouse to rat) was inversely related to the square root of the ratio of species longevity and was in agreement with the power law relating life spans of cells to species longevity (Röhme, Proc. Natl. Acad. Sci. U.S.A., 78 (1981) 5009).