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Evaluation of DNA from the Papanicolaou test to detect ovarian and endometrial cancers.

ABSTRACT: Papanicolaou (Pap) smears have revolutionized the management of patients with cervical cancers by permitting the detection of early, surgically curable tumors and their precursors. In recent years, the traditional Pap smear has been replaced by a liquid-based method, which allows not only cytologic evaluation but also collection of DNA for detection of human papillomavirus, the causative agent of cervical cancer. We reasoned that this routinely collected DNA could be exploited to detect somatic mutations present in rare tumor cells that accumulate in the cervix once shed from endometrial or ovarian cancers. A panel of genes that are commonly mutated in endometrial and ovarian cancers was assembled with new whole-exome sequencing data from 22 endometrial cancers and previously published data on other tumor types. We used this panel to search for mutations in 24 endometrial and 22 ovarian cancers and identified mutations in all 46 samples. With a sensitive massively parallel sequencing method, we were able to identify the same mutations in the DNA from liquid Pap smear specimens in 100% of endometrial cancers (24 of 24) and in 41% of ovarian cancers (9 of 22). Prompted by these findings, we developed a sequence-based method to query mutations in 12 genes in a single liquid Pap smear specimen without previous knowledge of the tumor's genotype. When applied to 14 samples selected from the positive cases described above, the expected tumor-specific mutations were identified. These results demonstrate that DNA from most endometrial and a fraction of ovarian cancers can be detected in a standard liquid-based Pap smear specimen obtained during routine pelvic examination. Although improvements need to be made before applying this test in a routine clinical manner, it represents a promising step toward a broadly applicable screening methodology for the early detection of gynecologic malignancies.

SUBMITTER: Kinde I

PROVIDER: S-EPMC3757513 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Evaluation of DNA from the Papanicolaou test to detect ovarian and endometrial cancers.

Kinde Isaac I Bettegowda Chetan C Wang Yuxuan Y Wu Jian J Agrawal Nishant N Shih Ie-Ming IeM Kurman Robert R Dao Fanny F Levine Douglas A DA Giuntoli Robert R Roden Richard R Eshleman James R JR Carvalho Jesus Paula JP Marie Suely Kazue Nagahashi SK Papadopoulos Nickolas N Kinzler Kenneth W KW Vogelstein Bert B Diaz Luis A LA

Science translational medicine 20130101 167

Papanicolaou (Pap) smears have revolutionized the management of patients with cervical cancers by permitting the detection of early, surgically curable tumors and their precursors. In recent years, the traditional Pap smear has been replaced by a liquid-based method, which allows not only cytologic evaluation but also collection of DNA for detection of human papillomavirus, the causative agent of cervical cancer. We reasoned that this routinely collected DNA could be exploited to detect somatic ...[more]

PMID: 23303603

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Project description:ObjectivesThe aim of this study was to identify tumor-derived DNA from Papanicolaou (Pap) smear and plasma specimens collected from patients with endometrial cancer or atypical hyperplasia (EC/AH) or epithelial ovarian cancer (OC).MethodsTumor tissues, peripheral blood, and Pap smear samples were collected from patients with EC/AH and patients with epithelial OC. Somatic mutations of tumor specimens in EC/AH and OC were examined by whole-exome sequencing using a 127-driver gene panel from The Cancer Genome Atlas (TCGA). A nine-gene EC/AH panel and an eight-gene OC panel were established based on the identified significantly mutated genes in the EC/AH and OC tumor specimens. Circulating single-molecule amplification and resequencing technology (cSMART) was applied to evaluate somatic mutations in Pap smear DNA and plasma circulating cell-free DNA (ccfDNA) using the EC/AH and OC gene panels.ResultsIn EC/AH group, there existed 22 tumors and 14 of the 22 tumors contributed hot spot mutations for the EC/AH nine-gene panel. In the Pap smear subgroup, all 21 Pap smears tested positive. Nine out of 11 (81.8%) identified the same gene mutations with their matched tumors and the remaining 10 Pap smears all tested positive. In the plasma subgroup, 10 out of 26 (38.5%) plasmas tested positive. One out of 13 (7.7%) identified the same gene mutation with its matched tumor and 5 out of the remaining 13 plasmas (38.5%) tested positive. In OC group, there existed 17 tumors and 16 of the 17 tumors contributed hot spot mutations for the OC eight-gene panel. In the Pap smear subgroup, all 11 Pap smears tested positive. Five out of 10 (50.0%) identified the same gene mutations with their matched tumors and the remaining one Pap smear also tested positive. In the plasma subgroup, all 22 plasmas tested positive. Ten out of 14 (71.4%) identified the same gene mutation with their matched tumors and the remaining 4 plasmas all tested positive.ConclusionsTumor-derived DNA can be detected in Pap smears and plasmas from patients with EC/AH or epithelial OC. Using a small gene-panel, early detection of EC/AH and OC might be promising. However, the value of plasma ccfDNA for EC/AH requires further investigation.

Project description:BackgroundCervical cancer remains the fourth most frequently diagnosed cancer among women, and its impact is particularly significant in women residing in less developed countries. This study aims to assess socioeconomic inequality in using Papanicolaou tests, commonly known as Pap tests, which are crucial for detecting cervical cancer. The research also seeks to decompose this inequality, identifying its contributing factors. This investigation is conducted within a sizable population-based study focused on the Kurdish population, with an additional examination of potential variations between urban and rural areas.MethodThe study utilized baseline data from the Ravansar Non-Communicable Disease Cohort Study (RaNCD), involving 3,074 ever-married women aged 35-65. Asset data was employed to determine socioeconomic status (SES), and Principal Component Analysis was applied. The uptake of Papanicolaou tests was assessed for inequality using the Concentration Index (Cn). Additionally, decomposition analysis was conducted to identify and understand the factors contributing to socioeconomic inequality.ResultsThe study found that overall, 86% of women reported having undergone cervical cancer screening at least once in their lifetime. The Concentration Index (Cn) for the total population was 0.21 (p < 0.0001), indicating a higher concentration of Papanicolaou test uptake among wealthier groups. In urban areas, the Cn was 0.34 (p < 0.0001), reflecting a significant concentration among the rich. However, in rural areas, the Cn was -0.10 (p = 0.3006), suggesting no significant socioeconomic inequality. Factors such as socioeconomic status (SES), education, and age contributed to reducing inequality, explaining 62.7%, 36.0%, and 1.7% of the observed inequality, respectively. Interestingly, place of residence had a negative influence on inequality.ConclusionThe uptake of Papanicolaou tests varies across different socioeconomic status levels, with a higher concentration among wealthier groups. The results enable health policymakers and researchers to tailor health intervention toward increasing public awareness, especially among women with lower levels of education women in economically deprived groups.

Project description:Despite improved outcomes in the past 30 years, less than half of all women diagnosed with epithelial ovarian cancer live five years beyond their diagnosis. Although typically treated as a single disease, epithelial ovarian cancer includes several distinct histological subtypes, such as papillary serous and endometrioid carcinomas. To address whether the morphological differences seen in these carcinomas represent distinct characteristics at the molecular level we analyzed DNA methylation patterns in 11 papillary serous tumors, 9 endometrioid ovarian tumors, 4 normal fallopian tube samples and 6 normal endometrial tissues, plus 8 normal fallopian tube and 4 serous samples from TCGA. For comparison within the endometrioid subtype we added 6 primary uterine endometrioid tumors and 5 endometrioid metastases from uterus to ovary. Data was obtained from 27,578 CpG dinucleotides occurring in or near promoter regions of 14,495 genes. We identified 36 locations with significant increases or decreases in methylation in comparisons of serous tumors and normal fallopian tube samples. Moreover, unsupervised clustering techniques applied to all samples showed three major profiles comprising mostly normal samples, serous tumors, and endometrioid tumors including ovarian, uterine and metastatic origins. The clustering analysis identified 60 differentially methylated sites between the serous group and the normal group. An unrelated set of 25 serous tumors validated the reproducibility of the methylation patterns. In contrast, >1,000 genes were differentially methylated between endometrioid tumors and normal samples. This finding is consistent with a generalized regulatory disruption caused by a methylator phenotype. Through DNA methylation analyses we have identified genes with known roles in ovarian carcinoma etiology, whereas pathway analyses provided biological insight to the role of novel genes. Our finding of differences between serous and endometrioid ovarian tumors indicates that intervention strategies could be developed to specifically address subtypes of epithelial ovarian cancer.

Dataset Information

Evaluation of DNA from the Papanicolaou test to detect ovarian and endometrial cancers.

Publications

Evaluation of DNA from the Papanicolaou test to detect ovarian and endometrial cancers.

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