White blood cell and cell-free DNA analyses for detection of residual disease in gastric cancer

Leal, Alessandro; Grieken, Nicole C.T. van; Palsgrove, Doreen N.; Phallen, Jillian; Medina, Jamie E.; Hruban, Carolyn; Broeckaert, Mark A. M.; Anagnostou, Valsamo; Adleff, Vilmos; Bruhm, Daniel C.; Canzoniero, Jenna VanLiere; Fiksel, Jacob; Nordsmark, Marianne; Warmerdam, Fabienne; Verheul, H.; Spronsen, Dick Johan van; Beerepoot, Laurens V.; Geenen, Maud M.; Portielje, Johanneke E.A.; Jansen, Edwin P.M.; Sandick, Johanna van; Kranenbarg, Elma Meershoek – Klein; Laarhoven, Hanneke W. M. van; Peet, Donald L. van der; Velde, Cornelis J.H. van de; Verheij, Marcel; Fijneman, Remond J.A.; Scharpf, Robert B.; Meijer, Gerrit A.; Cats, Annemieke; Velculescu, Victor E.

doi:10.1038/s41467-020-14310-3

Cited by 184 publications

(164 citation statements)

References 59 publications

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“…To analyze the association between cfDNA CNVs and HCC prognosis, genome-wide CNVs was taken into consideration rstly. As reported in previous studies, TFx could be used as a prognostic biomarker for HCC patients who received surgical resection and adjuvant therapies (25). Based on an extended sample size, similar result was also observed in the present study.…”

Section: Discussionsupporting

confidence: 92%

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Multiple-level copy number variations in circulating cell-free DNA for prognostic prediction of hepatocellular carcinoma with radical treatments

Wang¹,

Wang²,

Zhou³

et al. 2020

Preprint

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Background Copy number variations (CNVs) in circulating free DNA (cfDNA) are emerging as minimally invasive prognostic biomarkers for various cancers. However, little has been reported on the multiple-level analysis of cfDNA CNVs for hepatocellular carcinoma (HCC) patients with radical treatments. Methods Here, CNVs at genome-wide, chromosomal-arm and bin levels were analyzed in cfDNA from 117 HCC patients receiving radical treatments via low-coverage whole genome sequencing. Then, the relationship between cfDNA CNVs and clinical outcomes was explored. Our results showed that a concordant profile of CNVs was observed between cfDNA and tumor tissue DNA. Three genome-wide CNV indicators including tumor fraction (TFx), prediction score (P-score) and stability score (S-score) were calculated based on genome-wide cfDNA CNVs. Results Kaplan-Meier analysis showed that the patients with high TFx, P-score and S-score exhibited a significantly poorer overall survival (OS) and recurrence free survival (RFS) than those with low TFx, P-score and S-score, respectively (All P < 0.05). Furthermore, a group of high frequency cfDNA CNVs at chromosomal-arm level including loss of 4q, 17p, 19p and the gain of 8q, 1q clearly predicted prognosis of HCC patients. Finally, a bin-level risk score was constructed based on three most relevant prognostic bin regions identified by a LASSO model. Patients with high bin-score had a significantly poorer OS than those with low bin-score (P < 0.001). Conclusion Altogether, our study indicates that the multiple-level cfDNA CNVs are significantly associated with OS and RFS in HCC patients with radical treatments, suggesting that cfDNA CNVs detected by low-coverage WGS may be used as potential prognostic biomarkers of HCC patients.

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Section: Discussionsupporting

confidence: 92%

“…A possible explanation is that the detectable CNVs were diluted by predominantly normal cfDNA as background from white blood cell (WBC) (24). Further comparison of CNV pro les between cfDNA and WBC DNA will broaden our understanding on the in uence of normal cfDNA on the detection of CNVs (25).…”

Section: Discussionmentioning

confidence: 99%

Multiple-level copy number variations in circulating cell-free DNA for prognostic prediction of hepatocellular carcinoma with radical treatments

Wang¹,

Wang²,

Zhou³

et al. 2020

Preprint

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“…After a median follow-up of 42 months, all 11 patients without detectable tumor-specific mutations at the postoperative timepoint were alive and free of recurrence. On the other hand, six out of nine patients with detectable tumor-specific mutations at the postoperative timepoint developed disease recurrence and died from metastatic diseases [75]. Another recent paper in patients with operable colon cancer demonstrated a similar utility of cDNA.…”

Section: Circulating Tumor Cells (Ctcs)mentioning

confidence: 89%

Gastric Cancer with Radiographically Occult Metastatic Disease: Biology, Challenges, and Diagnostic Approaches

Sanjeevaiah

Fangman

Porembka

2020

Cancers

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Gastric adenocarcinoma is an aggressive cancer that demonstrates heterogeneous biology depending on patient ethnicity, tumor location, tumor type, and genetic profile. It remains the third leading cause of cancer deaths worldwide and was estimated to result in 782,000 deaths in 2018. Challenges exist in accurately assessing the disease burden, as available radiological staging often underestimates metastatic disease. This diagnostic handicap, along with the poor understanding of the heterogeneous biology of gastric cancer, has hindered the development of effective therapeutic solutions and thus halted improvement in patient outcomes over the last few decades. The management of occult peritoneal disease is complicated, as most patients are understaged by standard imaging studies and therefore thought to have local diseases. In this article, we systematically review recent literature on the limitations that are associated with standard radiographic staging, discuss recent molecular biology advances to better identify and diagnose occult peritoneal disease, and propose possible management strategies to approach this complicated clinical problem.

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“…Several recent studies have suggested that CH mutations present a challenge for proper filtering in highly sensitive NGS-based liquid biopsy assays [26][27][28] . We observed that the use of patient-matched normal WBC DNA in MSK-ACCESS eliminated 7,760 (77%) of variant calls below 10% VAF (Figure 4A-IV).…”

Section: Assessing the Filtering Of Putative Clonal Hematopoiesis (Chmentioning

confidence: 99%

“…We posited that the majority of these calls represent potential CH mutations. Recent reports 29 have suggested that fragments supporting CH variants have length distributions similar to cfDNA derived from non-cancerous cells and distinct from ctDNA 26,28,30 . Indeed, the sequence reads harboring variants with plasma VAF <10% and present in WBCs exhibited fragment lengths indistinguishable from wild-type and germline variants ( Figure 4C-IV) (bootstrapped p value = 0.99), adding confidence to the hypothesis that these were properly filtered WBC-derived somatic mutations associated with clonal hematopoiesis.…”

Section: Assessing the Filtering Of Putative Clonal Hematopoiesis (Chmentioning

confidence: 99%

Enhanced specificity of high sensitivity somatic variant profiling in cell-free DNA via paired normal sequencing: design, validation, and clinical experience of the MSK-ACCESS liquid biopsy assay

Brannon

Jayakumaran

Diosdado

et al. 2020

Preprint

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AbstractCirculating cell-free DNA (cfDNA) from blood plasma of cancer patients can be used to interrogate somatic tumor alterations non-invasively or when adequate tissue is unavailable. We have developed and clinically implemented MSK-ACCESS (Analysis of Circulating cfDNA to Evaluate Somatic Status), an NGS assay for detection of very low frequency somatic alterations in select exons and introns of 129 genes. Analytical validation demonstrated 92% sensitivity in de-novo mutation calling down to 0.5% allele frequency and 98% for a priori mutation profiling. To evaluate the performance and utility of MSK-ACCESS, we report results from the first 681 prospective blood samples (617 patients) that underwent clinical analysis to guide patient management. Somatic mutations, copy number, and/or structural variants were detected in 73% of the samples, and 56% of these circulating-tumor DNA (ctDNA) positive samples had clinically actionable alterations. The utilization of matched white blood cell sequencing allowed retention of somatic alterations while filtering out over 10,000 germline and clonal hematopoiesis variants, thereby greatly enhancing the specificity of the assay. Taken together, our experience illustrates the importance of analyzing a matched normal sample when interpreting cfDNA results and highlights the potential of cfDNA profiling to guide treatment selection, monitor treatment response, and identify mechanisms of treatment resistance.

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White blood cell and cell-free DNA analyses for detection of residual disease in gastric cancer

Cited by 184 publications

References 59 publications

Multiple-level copy number variations in circulating cell-free DNA for prognostic prediction of hepatocellular carcinoma with radical treatments

Multiple-level copy number variations in circulating cell-free DNA for prognostic prediction of hepatocellular carcinoma with radical treatments

Gastric Cancer with Radiographically Occult Metastatic Disease: Biology, Challenges, and Diagnostic Approaches

Enhanced specificity of high sensitivity somatic variant profiling in cell-free DNA via paired normal sequencing: design, validation, and clinical experience of the MSK-ACCESS liquid biopsy assay

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