Characterization of TP53 mutations in Pap test DNA of women with and without serous ovarian carcinoma

Krimmel-Morrison, Jeffrey; Ghezelayagh, Talayeh S.; Lian, Shenyi; Zhang, Yuezheng; Fredrickson, Jeanne; Nachmanson, Daniela; Baker, Kathryn T.; Radke, Marc R.; Hun, Enna; Norquist, Barbara M.; Emond, Mary J.; Swisher, Elizabeth M.; Risques, Rosa Ana

doi:10.1016/j.ygyno.2019.11.124

Cited by 15 publications

(19 citation statements)

References 38 publications

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“…All these mutations had low MAF (<0.02). As in prior studies (24)(25)(26), the number of mutations tended to increase with the number of duplex nucleotides sequenced (Supplementary Fig. S2).…”

Section: Crispr-ds Enables Ultra-sensitive Detection Of Mutations In Normal Colon and Crc Cell Linessupporting

confidence: 75%

“…We have also demonstrated the presence of cancer driver TP53 mutations in the peritoneal fluid (25), uterine lavage (24) and Pap test DNA (26) of women with and without ovarian cancer. Women with cancer tended to have higher TP53 mutation burden (25,26), suggesting increased TP53 somatic evolution in association with cancer progression.…”

Section: Introductionmentioning

confidence: 65%

“…We have used DS to perform ultra-deep sequencing of TP53 in normal gynecological tissues across the human lifespan, revealing a progressive enrichment of TP53 pathogenic mutations with older age (24). We have also demonstrated the presence of cancer driver TP53 mutations in the peritoneal fluid (25), uterine lavage (24) and Pap test DNA (26) of women with and without ovarian cancer. Women with cancer tended to have higher TP53 mutation burden (25,26), suggesting increased TP53 somatic evolution in association with cancer progression.…”

Section: Introductionmentioning

confidence: 96%

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Colorectal cancer is associated with the presence of cancer driver mutations in normal colon

Matas

Kohrn

Fredrickson

et al. 2021

Preprint

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While somatic mutations in colorectal cancer (CRC) are well characterized, little is known about the accumulation of cancer mutations in the normal colon prior to cancer. Here we have developed and applied an ultra-sensitive, single-molecule mutational test based on CRISPR-DS technology, which enables mutation detection at extremely low frequency (<0.001) in normal colon from patients with and without CRC. We found oncogenic KRAS mutations in the normal colon of about one third of patients with CRC but in none of the patients without CRC. Patients with CRC also carried more TP53 mutations than patients without cancer, and these mutations were more pathogenic and formed larger clones, especially in patients with early onset CRC. Most mutations in normal colon were different from the driver mutations in tumors suggesting that the occurrence of independent clones with pathogenic KRAS and TP53 mutations is a common event in the colon of individuals that develop CRC.

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Section: Crispr-ds Enables Ultra-sensitive Detection Of Mutations In Normal Colon and Crc Cell Linessupporting

confidence: 75%

Section: Introductionmentioning

confidence: 65%

Section: Introductionmentioning

confidence: 96%

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Colorectal cancer is associated with the presence of cancer driver mutations in normal colon

Matas

Kohrn

Fredrickson

et al. 2021

Preprint

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“…Another limitation worth noting is that we evaluated only tumor-matched TP53 clonal variants. Somatic evolution in nonneoplastic tissues implies that, owing to aging or other physiological processes, multiple somatic variants are normally present ubiquitously at the mosaic level 14,15. Therefore, prospective clinical studies conceived and designed on large populations of women are required to validate our findings.ConclusionsThis cohort study found specific variants in multiple Papanicolaou tests from the same patients conducted up to 6 years before the diagnosis of HGS-EOC.…”

mentioning

confidence: 85%

Detection of TP53 Clonal Variants in Papanicolaou Test Samples Collected up to 6 Years Prior to High-Grade Serous Epithelial Ovarian Cancer Diagnosis

et al. 2020

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IMPORTANCE The low 5-year survival rate of women with high-grade serous epithelial ovarian cancer (HGS-EOC) is related to its late diagnosis; thus, improvement in diagnosis constitutes a crucial step to increase the curability of this disease. OBJECTIVE To determine whether the presence of the clonal pathogenic TP53 variant detected in matched primary tumor biopsies can be identified in DNA purified from Papanicolaou test samples collected from women with HGS-EOC years before the diagnosis.

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“…Since the entire gynecological tract is a communicating lumen, several research groups attempted to detect TP53 mutated ctDNA from exfoliated cells of HGOC and STIC lesions using Papanicolau cytology smear or uterine lavage samples. [19][20][21][22] Maritschnegg et al published their experience of performing utero-tubal lavage with a new proprietary catheter in 22 healthy patients. 23 Although overall promising, this technique required local cervical anesthesia and cervical dilatation in a large fraction of the cases.…”

Section: Introductionmentioning

confidence: 99%

Proteomic signature for detection of high‐grade ovarian cancer in germline BRCA mutation carriers

Bahar‐Shany

Barnabas

Deutsch

et al. 2022

Intl Journal of Cancer

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No current screening methods for high‐grade ovarian cancer (HGOC) guarantee effective early detection for high‐risk women such as germline BRCA mutation carriers. Therefore, the standard‐of‐care remains risk‐reducing salpingo‐oophorectomy (RRSO) around age 40. Proximal liquid biopsy is a promising source of biomarkers, but sensitivity has not yet qualified for clinical implementation. We aimed to develop a proteomic assay based on proximal liquid biopsy, as a decision support tool for monitoring high‐risk population. Ninety Israeli BRCA1 or BRCA2 mutation carriers were included in the training set (17 HGOC patients and 73 asymptomatic women), (BEDOCA trial; ClinicalTrials.gov Identifier: NCT03150121). The proteome of the microvesicle fraction of the samples was profiled by mass spectrometry and a classifier was developed using logistic regression. An independent cohort of 98 BRCA mutation carriers was used for validation. Safety information was collected for all women who opted for uterine lavage in a clinic setting. We present a 7‐protein diagnostic signature, with AUC >0.97 and a negative predictive value (NPV) of 100% for detecting HGOC. The AUC of the biomarker in the independent validation set was >0.94 and the NPV >99%. The sampling procedure was clinically acceptable, with favorable pain scores and safety. We conclude that the acquisition of Müllerian tract proximal liquid biopsies in women at high‐risk for HGOC and the application of the BRCA‐specific diagnostic assay demonstrates high sensitivity, specificity, technical feasibility and safety. Similar classifier for an average‐risk population is warranted.

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Characterization of TP53 mutations in Pap test DNA of women with and without serous ovarian carcinoma

Cited by 15 publications

References 38 publications

Colorectal cancer is associated with the presence of cancer driver mutations in normal colon

Colorectal cancer is associated with the presence of cancer driver mutations in normal colon

Detection of TP53 Clonal Variants in Papanicolaou Test Samples Collected up to 6 Years Prior to High-Grade Serous Epithelial Ovarian Cancer Diagnosis

Proteomic signature for detection of high‐grade ovarian cancer in germline BRCA mutation carriers

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