Tumor-specific p53 sequences in blood and peritoneal fluid of women with epithelial ovarian cancer

Swisher, Elizabeth M.; Wollan, Melissa; Mahtani, Sarita M.; Willner, Julia B.; Garcia, Rochelle L.; Goff, Barbara A.; King, Mary Claire

doi:10.1016/j.ajog.2005.01.054

Cited by 111 publications

(90 citation statements)

References 12 publications

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“…Half of the cancers were early stage (0-II). TP53 mutations were determined by NGS in all primary tumors except three occult microscopic cancers, for which Sanger sequencing was used due to the limited amount of DNA (SI Appendix, SI Materials and Methods) (18)(19)(20). A single clonal TP53 mutation was found in all tumors (SI Appendix, Table S3).…”

Section: Resultsmentioning

confidence: 99%

Ultra-deep sequencing detects ovarian cancer cells in peritoneal fluid and reveals somatic TP53 mutations in noncancerous tissues

Krimmel

Schmitt

Harrell

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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149

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Current sequencing methods are error-prone, which precludes the identification of low frequency mutations for early cancer detection. Duplex sequencing is a sequencing technology that decreases errors by scoring mutations present only in both strands of DNA. Our aim was to determine whether duplex sequencing could detect extremely rare cancer cells present in peritoneal fluid from women with highgrade serous ovarian carcinomas (HGSOCs). These aggressive cancers are typically diagnosed at a late stage and are characterized by TP53 mutations and peritoneal dissemination. We used duplex sequencing to analyze TP53 mutations in 17 peritoneal fluid samples from women with HGSOC and 20 from women without cancer. The tumor TP53 mutation was detected in 94% (16/17) of peritoneal fluid samples from women with HGSOC (frequency as low as 1 mutant per 24,736 normal genomes). Additionally, we detected extremely low frequency TP53 mutations (median mutant fraction 1/13,139) in peritoneal fluid from nearly all patients with and without cancer (35/37). These mutations were mostly deleterious, clustered in hotspots, increased with age, and were more abundant in women with cancer than in controls. The total burden of TP53 mutations in peritoneal fluid distinguished cancers from controls with 82% sensitivity (14/17) and 90% specificity (18/20). Age-associated, low frequency TP53 mutations were also found in 100% of peripheral blood samples from 15 women with and without ovarian cancer (none with hematologic disorder). Our results demonstrate the ability of duplex sequencing to detect rare cancer cells and provide evidence of widespread, low frequency, age-associated somatic TP53 mutation in noncancerous tissue.TP53 mutations | ultra-deep sequencing | ovarian cancer | clonal hematopoiesis | premalignant mutations T he detection of tumor-specific mutations in clinically accessible samples has enormous potential to transform cancer diagnostics, monitoring, and screening. However, a major limitation is insufficiently accurate sequencing methods. Conventional nextgeneration sequencing (NGS) technologies have a high false positive error rate, which precludes reliable detection of mutations at frequencies <1/100 (1). "Molecular tagging" of single-stranded DNA decreases the rate of false mutations to less than 1 per 10,000 sequenced nucleotides and has been successfully applied to the detection of mutant cancer DNA in a variety of clinical samples (2-6). However, this false positive error rate limits the specificity of this method in challenging situations in which ultra-deep sequencing is needed to detect extremely low frequency mutant molecules (e.g., <1/10,000), as is the case of ovarian cancer DNA in Pap smears (5). Because true mutations are indistinguishable from artifacts, compromised specificity leads to lower sensitivity and overall low diagnostic accuracy. Duplex sequencing is an NGS technology that employs molecular tagging of both strands of DNA independently. True mutations are defined as mutations that are present at the same...

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Section: Resultsmentioning

confidence: 99%

Ultra-deep sequencing detects ovarian cancer cells in peritoneal fluid and reveals somatic TP53 mutations in noncancerous tissues

Krimmel

Schmitt

Harrell

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

149

110

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“…Otsuka et al [53] first identified TP53 mutations in only two/12 pre-surgery plasma cfDNA of patients with ovarian cancer. A tumor-specific TP53 mutation was also detected in 21 out of 69 cfDNA samples of epithelial ovarian cancer patients in a study by Swisher et al The presence of ctDNA characterized by this mutation was significantly associated with decreased survival (p = 0.02) [54]. Mutations of KRAS gene were investigated by Dobrzycka et al in plasma cfDNA of 126 epithelial ovarian cancer patients.…”

Section: Somatic Mutationsmentioning

confidence: 99%

Liquid biopsy in ovarian cancer: recent advances on circulating tumor cells and circulating tumor DNA

Giannopoulou

Kasimir‐Bauer

Lianidou

2017

Clinical Chemistry and Laboratory Medicine (CCLM)

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Ovarian cancer remains the most lethal disease among gynecological malignancies despite the plethora of research studies during the last decades. The majority of patients are diagnosed in an advanced stage and exhibit resistance to standard chemotherapy. Circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) represent the main liquid biopsy approaches that offer a minimally invasive sample collection. Both have shown a diagnostic, prognostic and predictive value in many types of solid malignancies and recent studies attempted to shed light on their role in ovarian cancer. This review is mainly focused on the clinical value of both CTCs and ctDNA in ovarian cancer and, more specifically, on their potential as diagnostic, prognostic and predictive tumor biomarkers.

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“…Мутации в гене p53 часто выявляются в цирДНК крови больных немелкоклеточным (30%) [135] и мелкоклеточным (37%) [136] раком лёгкого, раком яичника (15%) [137], желудка (5-12%) [138,139], у 19% больных раком поджелудочной железы [140], у 6%-21% больных раком кишечника [141,142] и у 18%-40% больных раком печени [143,144]. У больных раком кишечника наличие мутаций в этом гене коррелирует со стадией заболевания и метастазами в печень [141], а у больных раком молочной железы -со стадией заболевания, размером опухоли и метастазами в лимфатические узлы [145].…”

Section: особенности строения внеклеточных днк кровиunclassified

Generation of blood circulating DNA: the sources, peculiarities of circulation and structure

Bryzgunova

Laktionov

2015

BIOMED KHIM

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Внеклеточные нуклеиновые кислоты (внНК) в циркуляции как здоровых, так и больных людей были впервые описаны в 1948 г., однако оставались без внимания до середины 60-х годов прошлого века. внНК особенно интенсивно исследуются в последние 5 лет. Основное внимание уделяется исследованию внНК как источнику диагностического материала; однако механизмы генерации внеклеточных нуклеиновых кислот, а также механизмы, обеспечивающие их долговременную циркуляцию в кровотоке, однозначно не установлены. По данным одних авторов, основным источником циркулирующих дезоксирибонуклеиновых кислот в крови (цирДНК) являются процессы некроза и апоптоза, другие ссылаются на возможную секрецию нуклеиновых кислот как здоровыми, так и опухолевыми клетками. Известно, что цирДНК могут циркулировать в крови в течение длительного времени, ускользая от действия ДНК-гидролизующих ферментов крови и, по-видимому, находясь в составе надмолекулярных комплексов. В этом обзоре представлены данные разных авторов и приведены доказательства в пользу всех предложенных теорий появления цирДНК, описаны особенности строения цирДНК, а также факторы, влияющие на время циркуляции ДНК в крови.Ключевые слова: циркулирующая ДНК, апоптоз, некроз, активная секреция, ДНКазы, метилирование.

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Tumor-specific p53 sequences in blood and peritoneal fluid of women with epithelial ovarian cancer

Cited by 111 publications

References 12 publications

Ultra-deep sequencing detects ovarian cancer cells in peritoneal fluid and reveals somatic TP53 mutations in noncancerous tissues

Ultra-deep sequencing detects ovarian cancer cells in peritoneal fluid and reveals somatic TP53 mutations in noncancerous tissues

Liquid biopsy in ovarian cancer: recent advances on circulating tumor cells and circulating tumor DNA

Generation of blood circulating DNA: the sources, peculiarities of circulation and structure

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