Detection of leukemia-associated mutations in peripheral blood DNA of hematologically normal elderly individuals

Score, Joannah; Chase, Andrew; Forsberg, Lars A.; Feng, Li; Waghorn, Katherine; Jones, Amy V.; Rasi, Chiara; Linch, David C.; Dumanski, Jan P.; Gale, Rosemary E.; Cross, Nicholas C. P.

doi:10.1038/leu.2015.13

Cited by 16 publications

(14 citation statements)

References 12 publications

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“…However, these aberrations may not always be causative in the development of a primary tumor. This is reminiscent of our results and those of others showing that clonal cell expansions in normal blood are common and do not always lead to development of a clinical phenotype in subjects carrying such clones (Forsberg et al 2012(Forsberg et al , 2013(Forsberg et al , 2014Jacobs et al 2012;Laurie et al 2012;Holstege et al 2014;Score et al 2015). Furthermore, as shown in multiple figures, the aberrations detected in both UMs and PTs were present in PT samples in a considerably higher percentage of cells and were often accompanied by many additional aberrations that were present in PTs only.…”

Section: Propagation Of Genetic Aberrations From Ums Into Ptssupporting

confidence: 69%

Signatures of post-zygotic structural genetic aberrations in the cells of histologically normal breast tissue that can predispose to sporadic breast cancer

et al. 2015

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Sporadic breast cancer (SBC) is a common disease without robust means of early risk prediction in the population. We studied 282 females with SBC, focusing on copy number aberrations in cancer-free breast tissue (uninvolved margin, UM) outside the primary tumor (PT). In total, 1162 UMs (1–14 per breast) were studied. Comparative analysis between UM(s), PT(s), and blood/skin from the same patient as a control is the core of the study design. We identified 108 patients with at least one aberrant UM, representing 38.3% of cases. Gains in gene copy number were the principal type of mutations in microscopically normal breast cells, suggesting that oncogenic activation of genes via increased gene copy number is a predominant mechanism for initiation of SBC pathogenesis. The gain of ERBB2, with overexpression of HER2 protein, was the most common aberration in normal cells. Five additional growth factor receptor genes (EGFR, FGFR1, IGF1R, LIFR, and NGFR) also showed recurrent gains, and these were occasionally present in combination with the gain of ERBB2. All the aberrations found in the normal breast cells were previously described in cancer literature, suggesting their causative, driving role in pathogenesis of SBC. We demonstrate that analysis of normal cells from cancer patients leads to identification of signatures that may increase risk of SBC and our results could influence the choice of surgical intervention to remove all predisposing cells. Early detection of copy number gains suggesting a predisposition toward cancer development, long before detectable tumors are formed, is a key to the anticipated shift into a preventive paradigm of personalized medicine for breast cancer.

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Section: Propagation Of Genetic Aberrations From Ums Into Ptssupporting

confidence: 69%

Signatures of post-zygotic structural genetic aberrations in the cells of histologically normal breast tissue that can predispose to sporadic breast cancer

et al. 2015

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“…We termed these mutations "biological background" to distinguish them from tumor-specific TP53 mutations. Previous studies have reported somatic mutation of cancerassociated genes in normal tissue (blood and skin), but generally in relatively small subsets of older individuals (27)(28)(29)(30)(31)(32)(33)35). Here, we show that low frequency, cancer-like TP53 mutations in noncancerous tissue are very common, but almost exclusively occur at allele frequencies <0.001, which is below the limit of detection of conventional sequencing methods.…”

Section: Ovarian Cancer Patients Control Patients Tp53 Mutaɵon Burdenmentioning

confidence: 79%

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.

149

110

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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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“…Importantly, acquired 6p CN-LOH is characteristic and relatively specific to AA, as compared to MDS, where it occurs at only~1% frequency (Mohamedali et al, 2015). Additionally, 6p CN-LOH is exceedingly rare in the general population, where its prevalence is estimated at~0Á09% (1 of 1153) (Score et al, 2015). 6p CN-LOH appears to ‡Focused solely on the presented abnormality.…”

Section: Structural Genomic Variants: Recurrent Cytogenetic Abnormalimentioning

confidence: 99%

“…Importantly, acquired 6p CN-LOH is characteristic and relatively specific to AA, as compared to MDS, where it occurs at only ~1% frequency(Mohamedali, et al 2015). Additionally, 6p CN-LOH is exceedingly rare in the general population, where its prevalence is estimated at ~ 0.09% (1 of 1153)(Score, et al 2015). 6p CN-LOH appears to favour the loss of specific human leucocyte antigen (HLA) alleles, including HLA-A*02:01, -A*02:06, -A*31:01, -B*40:02 and -B*14:02, suggesting specificity to the underlying immune attack in AA(Betensky, et al 2016, Katagiri, et al 2011).…”

Section: Markers Of Clonal Haematopoiesis In Aamentioning

confidence: 99%

Recent advances in understanding clonal haematopoiesis in aplastic anaemia

2017

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Summary Acquired aplastic anaemia (AA) is an immune-mediated bone marrow failure disorder inextricably linked to clonal haematopoiesis. The majority of AA patients have somatic mutations and/or structural chromosomal abnormalities detected as early as at diagnosis. In contrast to other conditions linked to clonal haematopoiesis, the clonal signature of AA reflects its immune pathophysiology. The most common alterations are clonal expansions of cells lacking glycophosphotidylinositol-anchored proteins, loss of human leucocyte antigen alleles, and mutations in BCOR/BCORL1, ASXL1 and DNMT3A. Here, we present the current knowledge of clonal haematopoiesis in AA as it relates to aging, inherited bone marrow failure, and the grey-zone overlap of AA and myelodysplastic syndrome (MDS). We conclude by discussing the significance of clonal haematopoiesis both for improved diagnosis of AA, as well as for a more precise, personalized approach to prognostication of outcomes and therapy choices.

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Detection of leukemia-associated mutations in peripheral blood DNA of hematologically normal elderly individuals

Cited by 16 publications

References 12 publications

Signatures of post-zygotic structural genetic aberrations in the cells of histologically normal breast tissue that can predispose to sporadic breast cancer

Signatures of post-zygotic structural genetic aberrations in the cells of histologically normal breast tissue that can predispose to sporadic breast cancer

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

Recent advances in understanding clonal haematopoiesis in aplastic anaemia

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