Detection of clonal hematopoiesis of indeterminate potential in clinical sequencing of solid tumor specimens

Severson, Eric Allan; Riedlinger, Gregory; Connelly, Caitlin; Vergilio, Jo Anne; Goldfinger, Mendel; Ramkissoon, Shakti; Frampton, Garrett M.; Ross, Jeffrey S.; Fratella-Calabrese, Anthony; Ali, Siraj; Miller, Vincent A.; Elvin, Julia A.; Hadigol, Mohammad; Hirshfield, Kim M.; Rodrı́guez-Rodrı́guez, Lorna; Ganesan, Shridar; Khiabanian, Hossein

doi:10.1182/blood-2018-03-840629

Cited by 65 publications

(55 citation statements)

References 16 publications

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“…These results are consistent with the hypothesis that the enrichments for DNMT3A mutations in bone metastases, NOTCH1 mutations in skin metastases, and ASXL1 amplifications/PTEN deletions in brain metastases are biologically relevant, either as adaptations that arise in response to the local tumor microenvironment or as drivers of site-specific patterns of metastasis. An alternative hypothesis for the enrichment of DNMT3A mutations is clonal hematopoiesis of unknown potential, a process in which somatic mutations in hematopoietic stem cells lead to the outgrowth of distinct subclones that have been associated with cancer [64][65][66]; we provide evidence for this hypothesis in S3 Fig. We observed a different pattern in breast tumors that metastasize to lung and harbor a mutation in KEAP1, KRAS, STK11, or EGFR (Fig 3B). The lung classifier, which does not consider mutations in these four genes, scored a significantly larger fraction of these tumors as lung compared to all breast metastases (50% vs. 18%, p = 2e-5, n = 52).…”

Section: Plos Onementioning

confidence: 81%

The genomic landscape of metastatic breast cancer: Insights from 11,000 tumors

Rinaldi¹,

Sokol²,

Hartmaier³

et al. 2020

PLoS ONE

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Background Metastatic breast cancer is the leading cause of cancer death in women, but the genomics of metastasis in breast cancer are poorly studied. Methods We explored a set of 11,616 breast tumors, including 5,034 metastases, which had undergone targeted sequencing during standard clinical care. Results Besides the known hotspot mutations in ESR1, we observed a metastatic enrichment of previously unreported, lower-prevalence mutations in the ligand-binding domain, implying that these mutations may also be functional. Furthermore, individual ESR1 hotspots are significantly enriched in specific metastatic tissues and histologies, suggesting functional differences between these mutations. Other alterations enriched across all metastases include loss of function of the CDK4 regulator CDKN1B, and mutations in the transcription factor CTCF. Mutations enriched at specific metastatic sites generally reflect biology of the target tissue and may be adaptations to growth in the local environment. These include PTEN and ASXL1 alterations in brain metastases and NOTCH1 alterations in skin. We observed an enrichment of KRAS, KEAP1, STK11 and EGFR mutations in lung metastases. However, the patterns of other mutations in these tumors indicate that these are misdiagnosed lung primaries rather than breast metastases. Conclusions An order-of-magnitude increase in samples relative to previous studies allowed us to detect novel genomic characteristics of metastatic cancer and to expand and clarify previous findings.

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Section: Plos Onementioning

confidence: 81%

The genomic landscape of metastatic breast cancer: Insights from 11,000 tumors

Rinaldi¹,

Sokol²,

Hartmaier³

et al. 2020

PLoS ONE

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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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“…The prevalence of CHIP has been reported to be 20% to 95% in healthy adults aged 60–70 years, typically at a VAF < 0.1% [ 63 , 64 ]. CHIP mutations generally involve genes implicated in hematologic cancer, but can affect CRC associated genes, such as TP53 and KRAS, contributing to false-positive results [ 65 , 66 ]. False-positive results related to CHIP, however, can be mitigated by using advanced bioinformatics filters or by matching the ctDNA sequencing with that of leukocytes [ 67 ] and/or matched tumor [ 7 ] tissues, although the optimum method remains to be elucidated.…”

Section: Limitations Of Ctdnamentioning

confidence: 99%

The Promise of Circulating Tumor DNA (ctDNA) in the Management of Early-Stage Colon Cancer: A Critical Review

Chakrabarti

Xie

Urrutia

et al. 2020

Cancers

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The current standard treatment for patients with early-stage colon cancer consists of surgical resection, followed by adjuvant therapy in a select group of patients deemed at risk of cancer recurrence. The decision to administer adjuvant therapy, intended to eradicate the clinically inapparent minimal residual disease (MRD) to achieve a cure, is guided by clinicopathologic characteristics of the tumor. However, the risk stratification based on clinicopathologic characteristics is imprecise and results in under or overtreatment in a substantial number of patients. Emerging research indicates that the circulating tumor DNA (ctDNA), a fraction of cell-free DNA (cfDNA) in the bloodstream that originates from the neoplastic cells and carry tumor-specific genomic alterations, is a promising surrogate marker of MRD. Several recent studies suggest that ctDNA-guided risk stratification for adjuvant therapy outperforms existing clinicopathologic prognostic indicators. Preliminary data also indicate that, aside from being a prognostic indicator, ctDNA can inform on the efficacy of adjuvant therapy, which is the underlying scientific rationale for several ongoing clinical trials evaluating ctDNA-guided therapy escalation or de-escalation. Furthermore, serial monitoring of ctDNA after completion of definitive therapy can potentially detect cancer recurrence much earlier than conventional surveillance methods that may provide a critical window of opportunity for additional curative-intent therapeutic interventions. This article presents a critical overview of published studies that evaluated the clinical utility of ctDNA in the management of patients with early-stage colon cancer, and the potential of ctDNA to transform the adjuvant therapy strategies.

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Detection of clonal hematopoiesis of indeterminate potential in clinical sequencing of solid tumor specimens

Cited by 65 publications

References 16 publications

The genomic landscape of metastatic breast cancer: Insights from 11,000 tumors

The genomic landscape of metastatic breast cancer: Insights from 11,000 tumors

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

The Promise of Circulating Tumor DNA (ctDNA) in the Management of Early-Stage Colon Cancer: A Critical Review

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