Prevalence of Clonal Hematopoiesis Mutations in Tumor-Only Clinical Genomic Profiling of Solid Tumors

Ptashkin, Ryan; Mandelker, Diana; Coombs, Catherine C.; Bolton, Kelly L.; Zhang, Liying; Hyman, David M.; Solit, David B.; Baselga, José; Arcila, Maria E.; Ladanyi, Marc; Levine, Ross L.; Berger, Michael F.; Zehir, Ahmet

doi:10.1001/jamaoncol.2018.2297

Cited by 151 publications

(134 citation statements)

References 16 publications

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“…Very low variant load found in tumors may represent intervening CHIP‐derived non‐tumor cells. This phenomenon has also been reported in next‐generation sequencing without matched controls . Similarly, TP53 mutations detected by liquid biopsy were also recently reported to be attributed to CHIP in 15% (5/33) of non‐small cell lung carcinoma patients .…”

Section: Discussionsupporting

confidence: 70%

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Mutations found in cell‐free DNAs of patients with malignant lymphoma at remission can derive from clonal hematopoiesis

et al. 2019

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Cell‐free DNA (cfDNA) analysis to detect circulating tumor DNA has been focused on monitoring malignant lymphomas. However, clonal hematopoiesis of indeterminate potential (CHIP)‐associated mutations can also be detected by cfDNA analysis. Our aim is to investigate the origin of mutations detected in cfDNA among B‐cell lymphoma patients. MYD88/CD79B, DNMT3A, and TP53 were chosen as genes of interest, representing each of the following categories: lymphoma driver genes, CHIP‐related genes, and genes shared between lymphoma and CHIP. Seventy‐five B‐cell lymphoma patients were included in this retrospective study. Serum cfDNAs at time of complete metabolic response (CMR) were sequenced for TP53 (N = 75) and DNMT3A (N = 49). MYD88 p.L265P and CD79B p.Y196C/H mutations were analyzed in diffuse large B‐cell lymphoma (DLBCL) patients whose tumor samples were available (N = 29). Two and seven mutations in TP53 and DNMT3A, respectively, were detected in cfDNA at CMR. These mutations were detected in either bone marrow mononuclear cells (BMMC) or PBMC. Although four DNMT3A mutations were also detected in tumors, median variant allele frequencies in the tumors (<1.0%) were significantly lower than those in both BMMC (6.1%) and serum (5.2%) obtained before the therapy. Conversely, five MYD88 and three CD79B mutations detected in tumors were confirmed in cfDNA before therapy, but not in BMMC nor in cfDNA at CMR. Thus, all TP53 and DNMT3A mutations detected in cfDNA at remission seemed to originate from CHIP rather than from residual disease. Results of liquid biopsy should be carefully interpreted, especially in genes shared between lymphomas and CHIP.

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Section: Discussionsupporting

confidence: 70%

“…This phenomenon has also been reported in next-generation sequencing without matched controls. 18,19 Similarly, TP53 mutations detected by liquid biopsy were also recently reported to be attributed to CHIP in 15% (5/33) of non-small cell lung carcinoma patients. 20 (2.7%) of 75 patients, respectively.…”

Section: Discussionmentioning

confidence: 69%

Mutations found in cell‐free DNAs of patients with malignant lymphoma at remission can derive from clonal hematopoiesis

et al. 2019

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“…Of note, multigene sequencing of tumor tissue in patients with solid malignancies, increasingly performed in "precision medicine" programs, may result in the detection of CH-associated mutations stemming from blood cells within the tumor specimen. [75][76][77] False-positive mutation calls due to CH can also occur in "liquid biopsy" assays using cell-free circulating DNA. 78 71 This risk increase was noted irrespective of the presence or absence of CH, although patients with CH who underwent autologous transplantation carried the highest risk.…”

Section: Ch and Risk Of Therapy-related Myeloid Malignanciesmentioning

confidence: 99%

Clonal hematopoiesis and preleukemia—Genetics, biology, and clinical implications

Hartmann

Metzeler

2019

Genes Chromosomes & Cancer

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Myeloid neoplasms including myelodysplastic syndromes and acute myeloid leukemia (AML) originate from hematopoietic stem cells through sequential acquisition of genetic and epigenetic alterations that ultimately cause the disease‐specific phenotype of impaired differentiation and increased proliferation. It has become clear that preleukemic clonal hematopoiesis (CH), characterized by an expansion of stem and progenitor cells that carry somatic mutations but are still capable of normal differentiation, can precede the development of clinically overt myeloid neoplasia by many years. CH commonly develops in the aging hematopoietic system, yet progression to myelodysplasia or AML is rare. The discovery that myeloid neoplasms frequently develop from premalignant precursor conditions that are detectable in many healthy individuals has important consequences for the diagnosis, and potentially for the treatment of these disorders. In this review, we summarize the current knowledge on CH as a precursor of myeloid cancers and the implications of CH‐related gene mutations in the diagnostic workup of patients with suspected myelodysplastic syndrome. We will discuss the risk of progression associated with CH in healthy persons and in patients undergoing chemotherapy for a non‐hematologic cancer, and the significance of CH in autologous and allogeneic stem cell transplantation. Finally, we will review the significance of preleukemic clones in AML and their persistence in patients who achieve a remission after chemotherapeutic treatment.

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“…We evaluated the frequency with which METex14 mutations co-occur with other cancer-associated mutations ( Supplemental Table 1) (11,15). Synonymous mutations and those with predicted neutral or unknown functional impact were excluded, as previously described (11), as were mutations previously associated with clonal hematopoiesis (16). 86.5% of samples contained co-occurring genomic alterations, with a mean of 2.74 alterations per sample (range 0-22), in addition to the METex14 mutation.…”

Section: Co-occurring Genomic Alterations Are Common In Advanced-stagmentioning

confidence: 99%

“…Variants with unknown or neutral predicted functional significance were filtered prior to analysis as previously described (11). Mutations previously reported as associated with clonal hematopoiesis were also excluded (16). Assignment as clonal or subclonal was performed by normalized mutational allele frequency to percentage detected using a cut off of 0.2 as previously described (11).…”

Section: Cell Lines and Reagentsmentioning

confidence: 99%

Co-occurring alterations in the RAS-MAPK pathway limit response to MET inhibitor treatment inMETexon 14 skipping mutation positive lung cancer

Rotow

Gui

et al. 2018

Preprint

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Abstract:While patients with advanced-stage non-small cell lung cancers (NSCLCs) harboring MET exon 14 skipping mutations (METex14) often benefit from MET tyrosine kinase inhibitor (TKI) treatment, their long-term survival is limited by drug resistance. The molecular basis for this resistance remains incompletely understood. Through targeted sequencing analysis of cell-free circulating tumor DNA obtained from 289 patients with advanced-stage METex14 NSCLC, we find prominent co-occurring RAS pathway gene alterations (e.g. in KRAS/NRAS, NF1). Clinical resistance to MET TKI treatment was associated with the presence of these co-occurring alterations. In a new preclinical model expressing a METex14 mutation, KRAS overexpression promoted MET TKI resistance, which was overcome by co-treatment with crizotinib and the MEK inhibitor trametinib. Our study provides a genetic landscape of co-occurring alterations in advanced-stage METex14-mutated NSCLC and suggests a potential combination therapy strategy to enhance clinical outcomes. Statement of Significance:This report describes targeted sequencing of the largest reported cohort of advanced-stage NSCLC with a MET exon 14 skipping mutation. The data uncover certain RAS pathway genetic alterations as potential mediators of MEK TKI resistance, which could be overcome by MEK and MET co-inhibition in NSCLC.Introduction:

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Prevalence of Clonal Hematopoiesis Mutations in Tumor-Only Clinical Genomic Profiling of Solid Tumors

Abstract: This study demonstrates how CH-derived mutations could lead to erroneous reporting and treatment recommendations when tumor-only sequencing is used.

Cited by 151 publications

References 16 publications

Mutations found in cell‐free DNAs of patients with malignant lymphoma at remission can derive from clonal hematopoiesis

Mutations found in cell‐free DNAs of patients with malignant lymphoma at remission can derive from clonal hematopoiesis

Clonal hematopoiesis and preleukemia—Genetics, biology, and clinical implications

Co-occurring alterations in the RAS-MAPK pathway limit response to MET inhibitor treatment inMETexon 14 skipping mutation positive lung cancer

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