Differential distribution of sequence variations in HPV-16 E6.

OBJECTIVE: The E6 regions of the oncogenic human papillomaviruses (HPVs) are important in carcinogenesis and immune recognition. We examined the E6 DNA sequence from HPV-16-associated cervical cancers to determine the frequency and degree of variation from the consensus sequence in selected populations. METHODS: Samples positive for HPV-16 were analyzed using polymerase chain reaction followed by automated DNA sequencing: 62 from U.S. women, 20 each from Italian and Indian women, and 21 from Thai women. RESULTS: Of 151 codons, 18 contained 24 base substitutions, reflecting the overall conserved nature of this region. The HPV-16 E6 region from U. S. women showed considerably more sequence variation than that from European and Asian women. Five patterns common to U.S. and European and Asian samples accounted for 78% of all tumor-associated viruses. The E6 regions known to be involved in p53 binding and degradation are involved with a surprising degree of sequence variation, whereas the carboxy end of the molecule is highly conserved. CONCLUSIONS: The area of greatest sequence variation includes a proposed human leukocyte antigen interaction site. A novel large deletion in one sample results in loss of all functional regions of E6. These findings were analyzed for possible significance with regard to immune selection and functional importance of the carboxy end of the E6 protein.

Hyperestrogenism: a relevant risk factor for the development of cancer from endometriosis.

OBJECTIVE: Endometriosis is extremely common in developed countries. Obesity is a major health concern and may cause hyperestrogenism. Hormonal replacement, particularly unopposed estrogens after hysterectomy, is becoming popular. Because endometriosis is ectopic endometrium, hyperestrogenism (either endogenous or exogenous) may cause hyperplasia or transformation into cancer. This study was conducted to describe the main clinical and pathologic features of malignancies in endometriosis and define the treatment and outcome and to compare patients who had cancer arising in endometriosis with patients who had endometriosis but no cancer. METHODS: Patients who had tumors from endometriosis diagnosed from 1986 to 1997 were analyzed retrospectively. Each patient was matched with two control patients (endometriosis without cancer) treated during the same study interval. Clinical and epidemiologic variables were compared to identify risk factors for the development of cancer. RESULT: We identified 31 patients with cancer developing from endometriosis. Fifteen women were obese, 9 had a history of endometriosis, and 9 were taking unopposed estrogen. Endometrioid adenocarcinoma was the most common histologic type (16 patients). When the patients with cancer were compared with controls, no significantly higher risk for the development of cancer was found with prolonged use of unopposed estrogens or with higher body mass index, but a trend was observed. When obesity and use of unopposed estrogens were considered together, the difference was statistically significant (P = 0.05). CONCLUSION: Hyperestrogenism, either endogenous or exogenous, is a significant risk factor for the development of cancer from endometriosis. The prevalences of endometriosis, obesity, and use of hormonal replacement therapy in women in developed countries are increasing, and this trend justifies the assumption that cancer developing in endometriosis might become more common in the future.

Concordance of DNA ploidy pattern as measured by flow cytometry in primary, metastatic, and persistent ovarian carcinoma.

In an attempt to evaluate the stability of DNA content in ovarian carcinoma, 66 tumor specimens from 25 patients with stage III disease were analyzed by flow cytometry. For all patients, both primary tumor and omental metastasis were available, and for 16 patients the persistent tumor found at second-look operation was also available. The concordance of the tumor DNA content in the primary tumor and in the corresponding omental metastasis was 72%; the concordance in persistent tumor at second-look operation was 63%. When diploid and aneuploid tumors with very low DNA index were considered together, the concordance of the DNA content in primary and metastatic tumors reached 84%. According to our data, if DNA ploidy is used to differentiate patients with a favorable prognosis (DNA diploid and DNA aneuploid with low DNA index) from those with an unfavorable prognosis (DNA aneuploid with high DNA index), a 16% risk of misclassification appears unacceptable in prospective studies. Hence, the assessment of two specimens (preferably the primary lesion and a metastatic site) to determine the most abnormal DNA ploidy result would reduce the risk of underclassification of tumor.

Flow-cytometric DNA analysis of stages IB and IIA cervical carcinoma.

The prognostic significance of flow-cytometric DNA analysis was assessed in 375 stages IB and IIA squamous cell carcinoma patients treated with radical hysterectomy and lymphadenectomy at the Mayo Clinic between 1956 and 1985. Paraffin-embedded samples containing at least 20% tumor were dewaxed, rehydrated, stained with propidium iodide, and analyzed. Among 344 assessable samples, 136 (40%) were diploid and 208 (60%) were nondiploid (26 tetraploid, 158 aneuploid, and 24 polyploid). Diploid cases were further subclassified: 25 high proliferative phase (HPP) (S+G2M greater than 20%) and 111 low proliferative phase. No significant correlation was noted between DNA diploid patterns and stage, tumor size, grade, or histotype, but HPP diploid tumors had a significantly higher risk of nodal metastasis. With a mean follow-up period of 150 months, 62 patients died of disease. No significant difference was observed in survival rates (SR) between diploid and nondiploid tumors, but the subset of HPP diploid tumors had a prognosis significantly worse than that of any other group (P less than 0.01). Other significant variables included nodal metastases, parametrial extension, age, and clinical stage. While ploidy patterns did not assign additional risk to node-positive lesions, HPP diploid tumors in node-negative patients were associated with a significantly lower SR. Multivariate analyses in node-negative patients demonstrated that stage, histologic subtype, and HPP diploid patterns retained prognostic independence.