Publications by authors named "James Hicks"

176 Publications

Safety factors as a 'design' principle of animal form and function: an historical perspective.

J Exp Biol 2021 Nov 16;224(22). Epub 2021 Nov 16.

Zoophysiology Section, Bioscience, Aarhus University, 8000C Aarhus,Denmark.

For well over 150 years, factors of safety (also known as safety factors) have been a fundamental engineering concept that expresses how much stronger a system is compared with the intended load. The pioneering work of Robert McNeill Alexander in the early 1980s applied this engineering concept to biomechanics. Over the next decade, evidence from comparative biomechanics supported the idea that safety factors are a fundamental principle of animal form and function. In terms of physiology, Jared Diamond related the maximal capacity of a physiological process to normal functional demands and incorporated evolutionary thinking into the concept of safety factors. It was proposed that evolutionary reasoning is required to understand the magnitudes of biological reserve capacities, an idea called 'quantitative evolutionary design'. However, the general idea of safety factors as related to organismal form and function is much older. In 1906, Samuel James Meltzer, a physiologist and physician, presented the 5th Harvey Lecture to the New York Academy of Medicine; a lecture entitled 'The Factors of Safety in Animal Structure and Animal Economy', which was later published in Science in 1907. The 1907 paper is rarely cited and has never been cited within comparative biomechanics or comparative physiology. The purpose of this Commentary is to highlight Meltzer's historical contribution to the concept of safety factors as a general principle of organismal 'design'.
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http://dx.doi.org/10.1242/jeb.243324DOI Listing
November 2021

Aqueous Humor as a Liquid Biopsy for Retinoblastoma: Clear Corneal Paracentesis and Genomic Analysis.

J Vis Exp 2021 09 7(175). Epub 2021 Sep 7.

The Vision Center, Children's Hospital Los Angeles; USC Roski Eye Institute, Keck School of Medicine of the University of Southern California; Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California; The Saban Research Institute, Children's Hospital Los Angeles;

There is significant potential clinical utility for the application of a liquid biopsy platform for retinoblastoma, given that direct tumor biopsy is prohibited in these patients. The aqueous humor (AH) forms in a separate compartment from the tumor but is enclosed within the same ocular space. Thus, it is an enriched source of eye-specific tumoral genomic information that can be used as a liquid biopsy or surrogate to tumor biopsy for this disease. This manuscript details a methodology for safely extracting the AH from retinoblastoma eyes via clear corneal paracentesis. Additionally, the steps for genomic analysis, including cell-free DNA isolation and purification, next-generation sequencing, somatic copy number alteration (SCNA) analysis, RB1 single nucleotide variant (SNV) mutation identification, and tumor fraction estimation are presented. The pre-analytical, analytical, and early clinical validity of the AH liquid biopsy platform have been evaluated; however, it is not without limitations. These are largely a consequence of the quantity of cell-free DNA that is required for certain steps of the assay. Compared to other blood-based liquid biopsy platforms currently under investigation for retinoblastoma, an AH-based platform is limited by the volume of biofluid (and thus the quantity of DNA) that can be extracted from the eye; the benefit is that AH is eye-specific. The platform discussed here is unique in that it detects circulating tumor DNA in the AH via two mechanisms (SCNAs and RB1 SNVs), yielding a higher sensitivity for identifying tumoral genomic information. The AH liquid biopsy has the potential for direct clinical application to precision oncology for retinoblastoma patients, with particular importance for patients with bilateral disease as the AH is specific to the tumors in each eye. There is ongoing research with applications of this platform to patients with other ocular tumors as well.
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http://dx.doi.org/10.3791/62939DOI Listing
September 2021

Platelet-Coated Circulating Tumor Cells Are a Predictive Biomarker in Patients with Metastatic Castrate-Resistant Prostate Cancer.

Mol Cancer Res 2021 Aug 30. Epub 2021 Aug 30.

Convergent Science Institute in Cancer, Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, California.

Metastatic castration-resistant prostate cancer (mCRPC) includes a subset of patients with particularly unfavorable prognosis characterized by combined defects in at least two of three tumor suppressor genes: , , and as aggressive variant prostate cancer molecular signature (AVPC-MS). We aimed to identify circulating tumor cells (CTC) signatures that could inform treatment decisions of patients with mCRPC with cabazitaxel-carboplatin combination therapy versus cabazitaxel alone. Liquid biopsy samples were collected prospectively from 79 patients for retrospective analysis. CTCs were detected, classified, enumerated through a computational pipeline followed by manual curation, and subjected to single-cell genome-wide copy-number profiling for AVPC-MS detection. On the basis of immunofluorescence intensities, detected rare cells were classified into 8 rare-cell groups. Further morphologic characterization categorized CTC subtypes from 4 cytokeratin-positive rare-cell groups, utilizing presence of mesenchymal features and platelet attachment. Of 79 cases, 77 (97.5%) had CTCs, 24 (30.4%) were positive for platelet-coated CTCs (pc.CTCs) and 25 (38.5%) of 65 sequenced patients exhibited AVPC-MS in CTCs. Survival analysis indicated that the presence of pc.CTCs identified the subset of patients who were AVPC-MS-positive with the worst prognosis and minimal benefit from combination therapy. In AVPC-MS-negative patients, its presence showed significant survival improvement from combination therapy. Our findings suggest the presence of pc.CTCs as a predictive biomarker to further stratify AVPC subsets with the worst prognosis and the most significant benefit of additional platinum therapy. IMPLICATIONS: HDSCA3.0 can be performed with rare cell detection, categorization, and genomic characterization for pc.CTC identification and AVPC-MS detection as a potential predictive biomarker of mCRPC.
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http://dx.doi.org/10.1158/1541-7786.MCR-21-0383DOI Listing
August 2021

Inter-eye genomic heterogeneity in bilateral retinoblastoma via aqueous humor liquid biopsy.

NPJ Precis Oncol 2021 Jul 27;5(1):73. Epub 2021 Jul 27.

The Vision Center, Children's Hospital Los Angeles, Los Angeles, CA, USA.

Germline alterations in the RB1 tumor suppressor gene predispose patients to develop retinoblastoma (RB) in both eyes. While similar treatment is given for each eye, there is often a variable therapeutic response between the eyes. Herein, we use the aqueous humor (AH) liquid biopsy to evaluate the cell-free tumor DNA (ctDNA) from each eye in a patient with bilateral RB. Despite the same predisposing germline RB1 mutation, AH analysis identified a different somatic RB1 mutation as well as separate and distinct chromosomal alterations in each eye. The longitudinal alterations in tumor fraction (TFx) corresponded to therapeutic responses in each eye. This case demonstrates that bilateral RB tumors develop separate genomic alterations, which may play a role in tumorigenesis and prognosis for eye salvage. Identifying these inter-eye differences without the need for enucleated tumor tissue may help direct active management of RB, with particular usefulness in bilateral cases.
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http://dx.doi.org/10.1038/s41698-021-00212-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8316348PMC
July 2021

Comprehensive Somatic Copy Number Analysis Using Aqueous Humor Liquid Biopsy for Retinoblastoma.

Cancers (Basel) 2021 Jul 3;13(13). Epub 2021 Jul 3.

The Vision Center at Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.

Aqueous humor (AH) liquid biopsy has been established as a surrogate tumor biopsy for retinoblastoma (RB). Previous AH studies have focused on highly recurrent RB somatic copy number alterations (SCNAs) including gain of 1q, 2p, 6p, and loss of 13q and 16q. In this retrospective study, we provide a comprehensive, whole-genome analysis of RB SCNAs and evaluate associated clinical features for 68 eyes of 64 RB patients from whom AH was obtained between December 2014 and October 2020. Shallow whole-genome sequencing of AH cell-free DNA was performed to assess for SCNAs. The prevalence of specific non-highly recurrent SCNAs, such as 20q gain and 8p loss, differed between primarily and secondarily enucleated eyes. Increases in chromosomal instability predict more advanced seeding morphology ( = 0.015); later age of diagnosis ( < 0.0001); greater odds of an endophytic tumor growth pattern (without retinal detachment; = 0.047); tumor heights >10 mm ( = 0.09); and containing 6p gain, a biomarker of poor ocular prognosis ( = 0.004). The AH liquid biopsy platform is a high-yield method of whole-genome RB SCNA analysis, and SCNAs are associated with numerous clinical findings in RB eyes. Prospective analyses are encouraged to further elucidate the clinical relevance of specific SCNAs in RB.
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http://dx.doi.org/10.3390/cancers13133340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268955PMC
July 2021

Co-occurrence of Blount's disease and Legg-Calvé-Perthes disease: is obesity a factor?

J Pediatr Orthop B 2021 Jun 17. Epub 2021 Jun 17.

Lebanese American University, Gilbert and Rose-Marie Chagoury School of Medicine, Byblos, Lebanon Department of Orthopedic Surgery, University of Alabama at Birmingham Department of Pediatric Orthopaedics, Children's Hospital of Alabama, Alabama, USA.

Objectives: Legg-Calvé-Perthes disease (LCPD) and Blount's disease share a similar presenting age in addition to similar symptoms such as limp or knee pain. A little overlap is mentioned about both diseases. We sought to present cases of children having both conditions to discuss the implications of this co-occurrence on diagnosis and management.

Methods: After institutional review board approval, we retrospectively reviewed records of four children who developed both Blount's disease and LCPD. Patient details and outcomes were analyzed. Radiographs were evaluated for the lateral pillar classification, Stulberg classification, tibial metaphyseal-diaphyseal angle and tibiofemoral angle.

Results: Two of the cases were initially diagnosed with Blount's disease and subsequently developed Perthes, one case presented initially with both disorders and the final case had Perthes followed by Blount's. Three children were obese and one was overweight. The common symptom to all patients was an abnormal gait, which was painless in two children and painful in two. Blount's disease required surgery in three children. Radiographs showed Lateral Pillar B, B/C border and C hips, and the final Stulberg was stage II (n = 2) or stage IV (n = 2).

Conclusion: Obesity is associated with Blount's disease and LCPD, so obese children can be at an increased risk of developing both disorders. Therefore, a child with Blount's disease who has persistent, recurrent or worsening symptoms such as gait disturbance or thigh or knee pain might benefit from a careful physical exam of the hips to prevent a delayed or even missed LCPD diagnosis.
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http://dx.doi.org/10.1097/BPB.0000000000000888DOI Listing
June 2021

Efficacy of tyrosine kinase inhibitors against lung cancer with EGFR exon 18 deletion: Case report and pooled analysis.

Cancer Treat Res Commun 2021 26;28:100407. Epub 2021 May 26.

Thoracic Oncology Department, H. Lee Moffitt Cancer Center and Research Institute, United States. Electronic address:

Background: Within the exon 18 of EGFR, a complex, in-frame deletion-delE709_T710ins-has been described among pulmonary adenocarcinomas with an estimated prevalence of 0.3%. Available evidences suggest that some EGFR tyrosine kinase inhibitors (TKI) have activity against this cancer. However, due to the rarity of this mutation, it remains unclear which TKI is the most effective.

Methods: We reported our experience using afatinib followed by osimertinib in a patient with this mutation. We performed a systematic review of literature and conducted a pooled analysis to compare the outcomes of treatment with first generation TKIs vs. afatinib. Cases with compound mutations were excluded.

Results: Our patient achieved a partial response to afatinib with a progression-free survival of 11 months. Upon disease progression, osimertinib failed to control the disease. Literature review identified 14 cases being reported: 8 received first generation TKI and 6 received afatinib. Among those with tumor response assessed, partial response occurred in 2 out of 7 patients (28.6%) treated with first generation TKI compared with 6 out of 6 patients (100%) treated with afatinib, p = 0.03. The median progression-free survival (PFS) was 3.1 months vs. 7.0 months, respectively, p = 0.005. Insufficient evidences were available to assess for the efficacy of osimertinib.

Conclusion: Based on currently available data, afatinib was associated with a greater tumor response rate and a longer PFS than the first generation TKIs.
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http://dx.doi.org/10.1016/j.ctarc.2021.100407DOI Listing
May 2021

Head impact exposure and concussion in women's collegiate club lacrosse.

Res Sports Med 2021 May 17:1-6. Epub 2021 May 17.

Department of Ecology and Evolutionary Biology, University of California, Irvine, Irvine, California, USA.

This study sought to describe head impact exposure in women's collegiate club lacrosse. Eleven women's collegiate club lacrosse players wore head impact sensors during eight intercollegiate competitions. Video recordings of competitions were used to verify impact data. Athletes completed questionnaires detailing their concussion history and perceived head impact exposure. During the monitored games, no diagnosed concussions were sustained. Three athletes reported sustaining head impacts (median = 0; range: 0-3 impacts per game). Six impacts registered by the sensors were verified on video across a total of 81 athlete-game exposures. Verified impacts had a median peak linear acceleration of 21.0 g (range: 18.3 g - 48.3 g) and peak rotational acceleration of 1.1 krad/s (range: 0.7 krad/s - 5.7 krad/s). Women competing in collegiate club lacrosse are at a low risk of sustaining head impacts, comparable to previous reports of the high school and collegiate varsity levels of play.
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http://dx.doi.org/10.1080/15438627.2021.1929226DOI Listing
May 2021

Establishing the Clinical Utility of ctDNA Analysis for Diagnosis, Prognosis, and Treatment Monitoring of Retinoblastoma: The Aqueous Humor Liquid Biopsy.

Cancers (Basel) 2021 Mar 13;13(6). Epub 2021 Mar 13.

The Vision Center at Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.

Because direct tumor biopsy is prohibited for retinoblastoma (RB), eye-specific molecular biomarkers are not used in clinical practice for RB. Recently, we demonstrated that the aqueous humor (AH) is a rich liquid biopsy source of cell-free tumor DNA. Herein, we detail clinically-relevant molecular biomarkers from the first year of prospective validation data. Seven eyes from 6 RB patients who had AH sampled at diagnosis and throughout therapy with ≥12 months of follow-up were included. Cell-free DNA (cfDNA) from each sample was isolated and sequenced to assess genome-wide somatic copy number alterations (SCNAs), followed by targeted resequencing for pathogenic variants using a and custom hybridization panel. Tumoral genomic information was detected in 100% of diagnostic AH samples. Of the seven diagnostic AH samples, 5/7 were positive for RB SCNAs. Mutational analysis identified variants in 5/7 AH samples, including the 2 samples in which no SCNAs were detected. Two eyes failed therapy and required enucleation; both had poor prognostic biomarkers (chromosome 6p gain or amplification) present in the AH at the time of diagnosis. In the context of previously established pre-analytical, analytical, and clinical validity, this provides evidence for larger, prospective studies to further establish the clinical utility of the AH liquid biopsy and its applications to precision oncology for RB.
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http://dx.doi.org/10.3390/cancers13061282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001323PMC
March 2021

Large Extracellular Vesicle Characterization and Association with Circulating Tumor Cells in Metastatic Castrate Resistant Prostate Cancer.

Cancers (Basel) 2021 Mar 2;13(5). Epub 2021 Mar 2.

USC Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA 90089, USA.

Liquid biopsies hold potential as minimally invasive sources of tumor biomarkers for diagnosis, prognosis, therapy prediction or disease monitoring. We present an approach for parallel single-object identification of circulating tumor cells (CTCs) and tumor-derived large extracellular vesicles (LEVs) based on automated high-resolution immunofluorescence followed by downstream multiplexed protein profiling. Identification of LEVs >6 µm in size and CTC enumeration was highly correlated, with LEVs being 1.9 times as frequent as CTCs, and additional LEVs were identified in 73% of CTC-negative liquid biopsy samples from metastatic castrate resistant prostate cancer. Imaging mass cytometry (IMC) revealed that 49% of cytokeratin (CK)-positive LEVs and CTCs were EpCAM-negative, while frequently carrying prostate cancer tumor markers including AR, PSA, and PSMA. HSPD1 was shown to be a specific biomarker for tumor derived circulating cells and LEVs. CTCs and LEVs could be discriminated based on size, morphology, DNA load and protein score but not by protein signatures. Protein profiles were overall heterogeneous, and clusters could be identified across object classes. Parallel analysis of CTCs and LEVs confers increased sensitivity for liquid biopsies and expanded specificity with downstream characterization. Combined, it raises the possibility of a more comprehensive assessment of the disease state for precise diagnosis and monitoring.
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http://dx.doi.org/10.3390/cancers13051056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958848PMC
March 2021

COVID-19 and Acute Cervical Spinal Cord Injury-Case Report of 2 Patients: Do We Need to Rethink Our Standard Treatment Strategy?

Clin Spine Surg 2021 08;34(7):269-272

Department of Orthopaedic Surgery, University of Alabama at Birmingham, Birmingham, AL.

Study Design: This was a case series.

Objective: The authors sought to examine the high-risk population of COVID-positive patients with acute cervical spinal cord injury (SCI) in a large level 1 trauma and tertiary referral center.

Summary Of Background Data: There are limited studies regarding the surgical management of patients with acute SCI in the setting of the recent coronavirus pandemic.

Methods: The authors describe the cases of 2 patients who died from COVID-related complications after acute cervical SCI.

Results: Patients with SCI are at increased risk of pulmonary complications. COVID-19 infection represents a double hit in this patient population, increasing potential morbidity and mortality in the perioperative time frame. Careful consideration must be made regarding the timing of potential surgical intervention in the treatment of acute SCI.

Conclusions: Nationwide database of COVID-positive patients with acute spinal cord injury should be collected and analyzed to better understand how to manage acute SCI in the COVID-19 era. The authors recommend preoperative discussion in patients with acute cervical SCI with COVID-19, specifically emphasizing the increased risk of respiratory complications and mortality.
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http://dx.doi.org/10.1097/BSD.0000000000001162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8354562PMC
August 2021

Arterial blood gases during maximum metabolic demands: Patterns across the vertebrate spectrum.

Comp Biochem Physiol A Mol Integr Physiol 2021 04 25;254:110888. Epub 2020 Dec 25.

Section for Zoophysiology, Department of Bioscience, Aarhus University, Universitetsparken, 8000 Aarhus C, Denmark.

Elevations of metabolic rate, for example during physical activity, elicit immediate and coordinated respiratory and cardiovascular responses that ensure adequate diffusive and convective fluxes of O from the environment (water or air) to the mitochondria where ATP is produced. The same physiological responses also provide for CO to be removed in the opposite direction. There is significant variation in the morphology of the cardiovascular and respiratory structures among vertebrates, and a varying reliance on aerobic versus anaerobic metabolism to power activity. However, gas exchange in all vertebrates can be decribed as diffusive and convective steps in series, and we summarise data on the diffusive step across the respiratory surface of gills and lungs in this graphical review. Based on relatively constant arterial partial pressures of O and CO from rest to near maximal levels of physical activity, we conclude that under normoxic conditions, the diffusive step within the respiratory system exert no or small limitations for either O or CO exchange at or near maximal rate of oxygen consumption (VOmax). However, there are exceptions, such as the exercise-induced arterial hypoxemia (EIAH) in racehorses, and elite human athletes. Our analysis also indicates that exercise-induced arterial hypercapnia (i.e. a rise in arterial PCO) at or near VOmax is not common among vertebrates. Across the vertebrate spectrum, the diffusive and perfusive conductances (D/βQ) of water and air-breathing vertebrates are well-matched to maximal rates of gas exchange, and diffusion is not a limiting factor when aerobic metabolism increases.
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http://dx.doi.org/10.1016/j.cbpa.2020.110888DOI Listing
April 2021

N-Acetyl-L-cysteine Promotes Growth and Expansion of Single Circulating Tumor Cells by Mitigating Cellular Stress Responses.

Mol Cancer Res 2021 03 10;19(3):441-450. Epub 2020 Dec 10.

Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California.

Circulating tumor cells (CTC) can be isolated via a minimally invasive blood draw and are considered a "liquid biopsy" of their originating solid tumors. CTCs contain a small subset of metastatic precursors that can form metastases in secondary organs and provide a resource to identify mechanisms underlying metastasis-initiating properties. Despite technological advancements that allow for highly sensitive approaches of detection and isolation, CTCs are very rare and often present as single cells, posing an extreme challenge for expansion after isolation. Here, using previously established patient-derived CTC lines, we performed a small-molecule drug screen to identify compounds that can improve culture efficiency for single CTCs. We found that N-acetyl-L-cysteine (NAC) and other antioxidants can promote expansion of single CTCs, by reducing oxidative and other stress particularly at the initial stage of single-cell expansion. RNA-seq analysis of growing clones and nongrowing clones confirmed the effect by NAC, but also indicates that NAC-induced decrease in oxidative stress is insufficient for promoting proliferation of a subset of cells with predominant senescent features. Despite the challenge in expanding all CTCs, NAC treatment led to establishment of single CTC clones that have similar tumorigenic features. IMPLICATIONS: Through a small molecule screen and validation study, we found that NAC could improve the success of expansion of single CTCs by mitigating the initial stress, with the potential to facilitate the investigation of functional heterogeneity in CTCs.
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http://dx.doi.org/10.1158/1541-7786.MCR-20-0482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925378PMC
March 2021

Treatment response and tumor evolution: lessons from an extended series of multianalyte liquid biopsies in a metastatic breast cancer patient.

Cold Spring Harb Mol Case Stud 2020 12 17;6(6). Epub 2020 Dec 17.

Convergent Science Institute in Cancer, Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, California 90089, USA.

Currently, clinical characterization of metastatic breast cancer is based on tissue samples taken at time of diagnosis. However, tissue biopsies are invasive and tumors are continuously evolving, which indicates the need for minimally invasive longitudinal assessment of the tumor. Blood-based liquid biopsies provide minimal invasive means for serial sampling over the course of treatment and the opportunity to adjust therapies based on molecular markers. Here, we aim to identify cellular changes that occur in breast cancer over the lifespan of an affected patient through single-cell proteomic and genomic analysis of longitudinally sampled solid and liquid biopsies. Three solid and 17 liquid biopsies from peripheral blood of an ER/HER2 metastatic breast cancer patient collected over 4 years and eight treatment regimens were analyzed for morphology, protein expression, copy-number alterations, and single-nucleotide variations. Analysis of 563 single morphometrically similar circulating tumor cells (CTCs) and 13 cell-free DNA (cfDNA) samples along with biopsies of the primary and metastatic tumor revealed progressive genomic evolution away from the primary tumor profiles, along with changes in ER expression and the appearance of resistance mutations. Both the abundance and the genomic alterations of CTCs and cfDNA were highly correlated and consistent with genomic alterations in the tissue samples. We demonstrate that genomic evolution and acquisition of drug resistance can be detected in real time and at single-cell resolution through liquid biopsy analytes and highlight the utility of liquid biopsies to guide treatment decisions.
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http://dx.doi.org/10.1101/mcs.a005819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784493PMC
December 2020

Publishing Characteristics of Foot and Ankle Research Over a 15-Year Time Interval: A Review of The Journal of Bone & Joint Surgery from 2004 to 2018.

J Bone Joint Surg Am 2020 Oct;102(20):e117

Departments of Orthopaedic Surgery (B.K.A., J.W.H., A.A., B.B.C., S.F.S., A.J.J., G.M., and A.S.) and Epidemiology (G.M.), University of Alabama at Birmingham, Birmingham, Alabama.

Background: As the foot and ankle subspecialty continues to grow in orthopaedics, trends in published literature provide valuable insights to help understand and strengthen the field. The current study evaluates the changes in the characteristics of foot and ankle articles in The Journal of Bone & Joint Surgery (American Volume) (JBJS-A) from 2004 to 2018.

Methods: Foot and ankle-related articles in JBJS-A from 2004 to 2018 were identified and categorized by type of study, level of evidence, number of authors, academic degree(s) of the first and last authors, male and female authorship, number of citations, number of references, region of publication, and use of patient-reported outcomes (PROs).

Results: A total of 336 foot and ankle articles from 2004 to 2018 were reviewed. The type of study published has changed over time, with more clinical therapeutic evidence and less case reports. The level of evidence grades, as rated by JBJS-A and objective evaluators, have increased over the past 15 years. The total number of authors per article has increased, and female authorship has increased significantly. The number of references per article has increased, and the number of citations per year has decreased. The field of foot and ankle surgery has seen an increase in global publications.

Conclusions: The results of this study suggest that the foot and ankle literature that has been published in JBJS-A has continued to increase in quality and diversity over the past 15 years.
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http://dx.doi.org/10.2106/JBJS.20.00367DOI Listing
October 2020

Cell-Free DNA Tumor Fraction in the Aqueous Humor Is Associated With Therapeutic Response in Retinoblastoma Patients.

Transl Vis Sci Technol 2020 09 30;9(10):30. Epub 2020 Sep 30.

The Vision Center at Children's Hospital Los Angeles, Los Angeles, CA, USA.

Purpose: The aqueous humor (AH) liquid biopsy enables in vivo evaluation of tumor-derived cell-free DNA (cfDNA) from retinoblastoma (RB) eyes. Herein, we test our hypothesis that longitudinal dynamics of AH cfDNA-including tumor fraction (TFx) and somatic copy number alteration (SCNA) amplitude-correspond to therapeutic response.

Methods: Eyes with ≥3 AH extractions during intravitreal chemotherapy (IVM) or at secondary enucleation between 2015 to 2019 were included. AH cfDNA was sequenced to assess RB SCNA amplitude; ichorCNA software was used to estimate TFx. Eyes without SCNAs or with TFx < 0.10 across all samples were excluded. Therapeutic responses for each eye were determined from clinical records. Statistical analyses included Mann-Whitney U and Pearson correlation tests.

Results: Twenty eyes of 20 patients underwent ≥3 AH extractions; 6 eyes lacked SCNAs or had TFx < 0.10 throughout sampling and were excluded. Clinical progression was associated with significantly higher SCNA amplitudes and TFx values than regression ( ≤ 0.04). Relative increases in TFx (ΔTFx 1.86 ± 2.22) were associated with disease progression, whereas relative decreases in TFx (ΔTFx 0.53 ± 0.36) were associated with disease regression ( < 0.00001). A ≥15% increase in TFx relative to baseline during treatment was associated with an over 90-fold increased likelihood of clinical progression (odds ratio = 90.67, 95% confidence interval = 8.30-990.16, = 0.0002). TFx and SCNA amplitude were significantly positively correlated throughout sampling ( ≤ 0.002).

Conclusions: Longitudinal changes in AH-derived cfDNA TFx and SCNA amplitude are concordant with clinical responses of intraocular RB during active therapy.

Translational Relevance: Longitudinal evaluation of AH cfDNA may provide an objective, quantitative way to monitor therapeutic response and disease burden in RB patients.
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http://dx.doi.org/10.1167/tvst.9.10.30DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7533735PMC
September 2020

Modeling the Onset of Symptoms of COVID-19.

Front Public Health 2020 13;8:473. Epub 2020 Aug 13.

USC Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA, United States.

COVID-19 is a pandemic viral disease with catastrophic global impact. This disease is more contagious than influenza such that cluster outbreaks occur frequently. If patients with symptoms quickly underwent testing and contact tracing, these outbreaks could be contained. Unfortunately, COVID-19 patients have symptoms similar to other common illnesses. Here, we hypothesize the order of symptom occurrence could help patients and medical professionals more quickly distinguish COVID-19 from other respiratory diseases, yet such essential information is largely unavailable. To this end, we apply a Markov Process to a graded partially ordered set based on clinical observations of COVID-19 cases to ascertain the most likely order of discernible symptoms (i.e., fever, cough, nausea/vomiting, and diarrhea) in COVID-19 patients. We then compared the progression of these symptoms in COVID-19 to other respiratory diseases, such as influenza, SARS, and MERS, to observe if the diseases present differently. Our model predicts that influenza initiates with cough, whereas COVID-19 like other coronavirus-related diseases initiates with fever. However, COVID-19 differs from SARS and MERS in the order of gastrointestinal symptoms. Our results support the notion that fever should be used to screen for entry into facilities as regions begin to reopen after the outbreak of Spring 2020. Additionally, our findings suggest that good clinical practice should involve recording the order of symptom occurrence in COVID-19 and other diseases. If such a systemic clinical practice had been standard since ancient diseases, perhaps the transition from local outbreak to pandemic could have been avoided.
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http://dx.doi.org/10.3389/fpubh.2020.00473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7438535PMC
May 2021

Generic Protocols for the Analytical Validation of Next-Generation Sequencing-Based ctDNA Assays: A Joint Consensus Recommendation of the BloodPAC's Analytical Variables Working Group.

Clin Chem 2020 09;66(9):1156-1166

BloodPAC, Chicago, IL.

Liquid biopsy, particularly the analysis of circulating tumor DNA (ctDNA), has demonstrated considerable promise for numerous clinical intended uses. Successful validation and commercialization of novel ctDNA tests have the potential to improve the outcomes of patients with cancer. The goal of the Blood Profiling Atlas Consortium (BloodPAC) is to accelerate the development and validation of liquid biopsy assays that will be introduced into the clinic. To accomplish this goal, the BloodPAC conducts research in the following areas: Data Collection and Analysis within the BloodPAC Data Commons; Preanalytical Variables; Analytical Variables; Patient Context Variables; and Reimbursement. In this document, the BloodPAC's Analytical Variables Working Group (AV WG) attempts to define a set of generic analytical validation protocols tailored for ctDNA-based Next-Generation Sequencing (NGS) assays. Analytical validation of ctDNA assays poses several unique challenges that primarily arise from the fact that very few tumor-derived DNA molecules may be present in circulation relative to the amount of nontumor-derived cell-free DNA (cfDNA). These challenges include the exquisite level of sensitivity and specificity needed to detect ctDNA, the potential for false negatives in detecting these rare molecules, and the increased reliance on contrived samples to attain sufficient ctDNA for analytical validation. By addressing these unique challenges, the BloodPAC hopes to expedite sponsors' presubmission discussions with the Food and Drug Administration (FDA) with the protocols presented herein. By sharing best practices with the broader community, this work may also save the time and capacity of FDA reviewers through increased efficiency.
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http://dx.doi.org/10.1093/clinchem/hvaa164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462123PMC
September 2020

Author Correction: SMURF-seq: efficient copy number profiling on long-read sequencers.

Genome Biol 2020 Aug 25;21(1):214. Epub 2020 Aug 25.

Quantitative and Computational Biology Section, Department of Biological Sciences, University of Southern California, 1050 Childs Way, Los Angeles, 90089, USA.

An amendment to this paper has been published and can be accessed via the original article.
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http://dx.doi.org/10.1186/s13059-020-02149-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447571PMC
August 2020

Simultaneous identification of clinically relevant mutations and copy number alterations in aqueous humor of retinoblastoma eyes.

Ophthalmic Genet 2020 12 17;41(6):526-532. Epub 2020 Aug 17.

The Vision Center, Children's Hospital Los Angeles , Los Angeles, California, USA.

Background: Detection of germline mutations is critical for risk assessment of retinoblastoma (RB) patients. Assessment of somatic copy number alterations (SCNAs) is also critically important because of their prognostic significance. Herein we present a refined approach for the simultaneous identification of variants and SCNAs in the aqueous humor (AH) of RB eyes.

Materials And Methods: Subjects included 7 eyes of 6 RB patients that underwent AH extraction, and 4 matched tumor samples. Cell-free DNA (cfDNA) was isolated and sequenced to assess genome-wide SCNAs. The same sequencing libraries then underwent targeted resequencing and mutation detection using a custom hybridization panel that targets and . Illumina paired-end 2x150bp sequencing was used to characterize single-nucleotide variants (SNVs) and loss of heterozygosity (LOH). Results were compared to peripheral blood testing. Tumor fraction (TFx) was calculated using ichorCNA.

Results: Four of 7 AH samples contained clinically significant SCNAs. Of the 3 other samples, 1 showed focal amplification and 1 showed focal deletion. All 4 enucleated tumors contained SCNAs. Mutational analysis of tumor DNA identified all first hits (2 germline SNVs, 2 germline CNAs) and second hits (4 SNVs). variants in AH were concordant with those obtained from corresponding tumor tissue and blood. In AH samples without paired tumor, both hits were identified with high variant allele frequency, even in the absence of SCNAs.

Conclusions: AH liquid biopsy is a minimally invasive, alternative to tissue analysis for the simultaneous identification of variants and SCNAs in RB eyes.
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http://dx.doi.org/10.1080/13816810.2020.1799417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806277PMC
December 2020

Correction: Opportunities to implement a sustainable genomic medicine program: lessons learned from the IGNITE Network.

Genet Med 2020 Oct;22(10):1730

Center for Applied Genomics & Precision Medicine, Duke University School of Medicine Durham, Durham, NC, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41436-020-0911-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521989PMC
October 2020

Liquid Biopsy in Colorectal Carcinoma: Clinical Applications and Challenges.

Cancers (Basel) 2020 May 27;12(6). Epub 2020 May 27.

Convergent Science Institute in Cancer, Michelson Center for Convergent Bioscience, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA 90089, USA.

Colorectal carcinoma (CRC) is characterized by wide intratumor heterogeneity with general genomic instability and there is a need for improved diagnostic, prognostic, and therapeutic tools. The liquid biopsy provides a noninvasive route of sample collection for analysis of circulating tumor cells (CTCs) and genomic material, including cell-free DNA (cfDNA), as a complementary biopsy to the solid tumor tissue. The solid biopsy is critical for molecular characterization and diagnosis at the time of collection. The liquid biopsy has the advantage of longitudinal molecular characterization of the disease, which is crucial for precision medicine and patient-oriented treatment. In this review, we provide an overview of CRC and the different methodologies for the detection of CTCs and cfDNA, followed by a discussion on the potential clinical utility of the liquid biopsy in CRC patient care, and lastly, current challenges in the field.
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http://dx.doi.org/10.3390/cancers12061376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352156PMC
May 2020

Chromosome 6p Amplification in Aqueous Humor Cell-Free DNA Is a Prognostic Biomarker for Retinoblastoma Ocular Survival.

Mol Cancer Res 2020 08 20;18(8):1166-1175. Epub 2020 May 20.

The Vision Center at Children's Hospital Los Angeles, Los Angeles, California.

Aqueous humor contains tumor-derived cell-free DNA (cfDNA) and can serve as a liquid biopsy for retinoblastoma. We previously associated somatic copy-number alteration (SCNA) 6p gain with a 10-fold increased risk of enucleation. Here we provide a 2-year update to further explore 6p gain as a prognostic biomarker for ocular survival. Patients diagnosed with retinoblastoma from December 2014 to July 2019 from whom aqueous humor was sampled were included. cfDNA was extracted and shallow whole-genome sequencing performed to identify highly recurrent retinoblastoma SCNAs (gain of 1q, 2p, 6p, loss of 13q, 16q). 116 aqueous humor samples from 50 eyes of 46 patients were included: 27 eyes were salvaged, 23 were enucleated. Highly recurrent retinoblastoma SCNAs were found in 66% eyes. 6p gain was the most prevalent SCNA (50% eyes). It was particularly more prevalent in enucleated eyes (73.9%) than in salvaged eyes (29.6%; = 0.004). 6p gain in aqueous humor cfDNA portended nearly 10-fold increased odds of enucleation (OR = 9.87; 95% confidence interval = 1.75-55.65; = 0.009). In the enucleated eyes, 6p gain was associated with aggressive histopathologic features, including necrosis, higher degrees of anaplasia, and focal invasion of ocular structures. With extended follow-up and nearly double the aqueous humor samples, we continue to demonstrate 6p gain as a potential prognostic biomarker for retinoblastoma. IMPLICATIONS: Aqueous humor is a high-yield source of tumor-derived DNA in retinoblastoma eyes. Detection of 6p gain in the aqueous humor allows for targeted, patient-centered therapies based on this molecular prognostic marker. Prospective, multicenter studies with aqueous humor sampled from all eyes at diagnosis are warranted to validate these findings.
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http://dx.doi.org/10.1158/1541-7786.MCR-19-1262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415535PMC
August 2020

Novel insights into breast cancer copy number genetic heterogeneity revealed by single-cell genome sequencing.

Elife 2020 05 13;9. Epub 2020 May 13.

Cold Spring Harbor Laboratory, Cold Spring Harbor, United States.

Copy number alterations (CNAs) play an important role in molding the genomes of breast cancers and have been shown to be clinically useful for prognostic and therapeutic purposes. However, our knowledge of intra-tumoral genetic heterogeneity of this important class of somatic alterations is limited. Here, using single-cell sequencing, we comprehensively map out the facets of copy number alteration heterogeneity in a cohort of breast cancer tumors. Ou/var/www/html/elife/12-05-2020/backup/r analyses reveal: genetic heterogeneity of non-tumor cells (i.e. stroma) within the tumor mass; the extent to which copy number heterogeneity impacts breast cancer genomes and the importance of both the genomic location and dosage of sub-clonal events; the pervasive nature of genetic heterogeneity of chromosomal amplifications; and the association of copy number heterogeneity with clinical and biological parameters such as polyploidy and estrogen receptor negative status. Our data highlight the power of single-cell genomics in dissecting, in its many forms, intra-tumoral genetic heterogeneity of CNAs, the magnitude with which CNA heterogeneity affects the genomes of breast cancers, and the potential importance of CNA heterogeneity in phenomena such as therapeutic resistance and disease relapse.
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http://dx.doi.org/10.7554/eLife.51480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220379PMC
May 2020

Variability in retinoblastoma genome stability is driven by age and not heritability.

Genes Chromosomes Cancer 2020 10 9;59(10):584-590. Epub 2020 Jun 9.

The Vision Center at Children's Hospital Los Angeles, Los Angeles, California, USA.

Retinoblastoma (RB) is a childhood intraocular cancer initiated by biallelic inactivation of the RB tumor suppressor gene (RB1 ). RB can be hereditary (germline RB1 pathogenic allele is present) or non-hereditary. Somatic copy number alterations (SCNAs) contribute to subsequent tumorigenesis. Previous studies of only enucleated RB eyes have reported associations between heritability status and the prevalence of SCNAs. Herein, we use an aqueous humor (AH) liquid biopsy to investigate RB genomic profiles in the context of germline RB1 status, age, and International Intraocular Retinoblastoma Classification (IIRC) clinical grouping for both enucleated and salvaged eyes. Between 2014 and 2019, AH was sampled from a total of 54 eyes of 50 patients. Germline RB1 status was determined from clinical blood testing, and cell-free DNA from AH was analyzed for SCNAs. Of the 50 patients, 23 (46.0%; 27 eyes) had hereditary RB, and 27 (54.0%, 27 eyes) had non-hereditary RB. Median age at diagnosis was comparable between hereditary (13 ± 10 months) and non-hereditary (13 ± 8 months) eyes (P = 0.818). There was no significant difference in the prevalence or number of SCNAs based on (1) hereditary status (P > 0.56) or (2) IIRC grouping (P > 0.47). There was, however, a significant correlation between patient age at diagnosis, and (1) number of total SCNAs (r[52] = 0.672, P < 0.00001) and (2) number of highly-recurrent RB SCNAs (r[52] = 0.616, P < 0.00001). This evidence does not support the theory that specific molecular or genomic subtypes exist between hereditary and non-hereditary RB; rather, the prevalence of genomic alterations in RB eyes is strongly related to patient age at diagnosis.
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http://dx.doi.org/10.1002/gcc.22859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441809PMC
October 2020

Single-Cell Circulating Tumor Cell Analysis Reveals Genomic Instability as a Distinctive Feature of Aggressive Prostate Cancer.

Clin Cancer Res 2020 08 27;26(15):4143-4153. Epub 2020 Apr 27.

Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.

Purpose: Aggressive variant prostate cancer (AVPC) represents a clinical subset distinguished by therapy resistance and poor prognosis, linked to combined losses of the tumor suppressor genes (TSG) , and . Circulating tumor cells (CTC) provide a minimally invasive opportunity for identification and molecular characterization of AVPC. We aimed to evaluate the incidence and clinical significance of compound (2+)TSG losses and genomic instability in prostate cancer CTC, and to expand the set genomic biomarkers relevant to AVPC.

Experimental Design: Genomic analysis of chromosomal copy-number alterations (CNA) at single-cell resolution was performed in CTC from patients with and without AVPC before initiating chemotherapy with cabazitaxel or cabazitaxel and carboplatin. We evaluated associations between single-CTC genomics and clinical features, progression-free survival, and overall survival.

Results: A total of 257 individual CTC were sequenced from 47 patients (1-22 CTC/patient). Twenty patients (42.6%) had concurrent 2+TSG losses in at least one CTC in association with poor survival and increased genomic instability, inferred by high large-scale transitions scores. Higher LST in CTC were independent of CTC enumerated, clinically more indicative of aggressive behavior than co-occurring TSG losses, and molecularly associated with gains in chromosomal regions including , and ; increased androgen receptor expression; and loss. In 57 patients with matched cell-free tumor DNA data, CTC were more frequently detectable and evaluable for CNA analysis (in 73.7% vs. 42.1%, respectively).

Conclusions: Our findings suggest that genomic instability in CTC is a hallmark of advanced prostate cancer aggressiveness, and support single-CTC sequencing as a compelling tool to noninvasively characterize cancer heterogeneity.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-4100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043601PMC
August 2020

Patterns of head impact exposure in men's and women's collegiate club water polo.

J Sci Med Sport 2020 Oct 20;23(10):927-931. Epub 2020 Mar 20.

Department of Ecology and Evolutionary Biology, University of California-Irvine, United States.

Objectives: Recent reports have demonstrated a risk of concussion and subconcussive head impacts in collegiate varsity and international elite water polo. We sought to characterize patterns of head impact exposure at the collegiate club level of water polo.

Design: Prospective cohort study.

Methods: Head impact sensors (SIM-G, Triax Technologies) were worn by men's (n=16) and women's (n=15) collegiate club water polo players during 11 games. Peak linear acceleration (PLA) and peak rotational acceleration (PRA) of head impacts were recorded by the sensors. Two streams of competition video were used to verify and describe the nature of head impacts.

Results: Men's players sustained 52 verified head impacts of magnitude 39.7±16.3g PLA and 5.2±3.2 krad/s PRA, and women's players sustained 43 verified head impacts of magnitude 33.7±12.6g PLA and 4.0±2.8krad/s PRA. Impacts sustained by men had greater PLA than those sustained by women (p=.045). Athletes were impacted most frequently at the offensive center position, to the back of the head, and by an opponent's torso or limb.

Conclusions: Our cohort of male and female athletes sustained relatively infrequent head impacts during water polo competitions played at the collegiate club level. The amount of head impact exposure in our cohort was dependent on player position, with offensive centers prone to sustaining the most impacts. Head impact sensors are subject to large amounts of false positives and should be used in conjunction with video recordings to verify the validity of impact data.
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http://dx.doi.org/10.1016/j.jsams.2020.03.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8095352PMC
October 2020

A Dose Relationship Between Brain Functional Connectivity and Cumulative Head Impact Exposure in Collegiate Water Polo Players.

Front Neurol 2020 2;11:218. Epub 2020 Apr 2.

Department of Neurology, University of California, Irvine, Irvine, CA, United States.

A growing body of evidence suggests that chronic, sport-related head impact exposure can impair brain functional integration and brain structure and function. Evidence of a robust inverse relationship between the frequency and magnitude of repeated head impacts and disturbed brain network function is needed to strengthen an argument for causality. In pursuing such a relationship, we used cap-worn inertial sensors to measure the frequency and magnitude of head impacts sustained by eighteen intercollegiate water polo athletes monitored over a single season of play. Participants were evaluated before and after the season using computerized cognitive tests of inhibitory control and resting electroencephalography. Greater head impact exposure was associated with increased phase synchrony [ > 0.626, < 0.03 corrected], global efficiency [ > 0.601, < 0.04 corrected], and mean clustering coefficient [ > 0.625, < 0.03 corrected] in the functional networks formed by slow-wave (delta, theta) oscillations. Head impact exposure was not associated with changes in performance on the inhibitory control tasks. However, those with the greatest impact exposure showed an association between changes in resting-state connectivity and a dissociation between performance on the tasks after the season [ = 0.481, = 0.043] that could also be attributed to increased slow-wave synchrony [ = 113.546, < 0.001]. Collectively, our results suggest that athletes sustaining the greatest head impact exposure exhibited changes in whole-brain functional connectivity that were associated with altered information processing and inhibitory control.
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http://dx.doi.org/10.3389/fneur.2020.00218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145392PMC
April 2020

Whole-Exome Sequencing Analysis of the Progression from Non-Low-Grade Ductal Carcinoma to Invasive Ductal Carcinoma.

Clin Cancer Res 2020 07 27;26(14):3682-3693. Epub 2020 Mar 27.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: Ductal carcinoma (DCIS) is a nonobligate precursor of invasive breast cancer. Here, we sought to investigate the level of intralesion genetic heterogeneity in DCIS and the patterns of clonal architecture changes in the progression from DCIS to invasive disease.

Experimental Design: Synchronous DCIS ( = 27) and invasive ductal carcinomas of no special type (IDC-NSTs; = 26) from 25 patients, and pure DCIS ( = 7) from 7 patients were microdissected separately and subjected to high-depth whole-exome ( = 56) or massively parallel sequencing targeting ≥410 key cancer-related genes ( = 4). Somatic genetic alterations, mutational signatures, clonal composition, and phylogenetic analyses were defined using validated computational methods.

Results: DCIS revealed genetic alterations similar to those of synchronously diagnosed IDC-NSTs and of non-related IDC-NSTs from The Cancer Genome Atlas (TCGA), whereas pure DCIS lacked mutations. Clonal decomposition and phylogenetic analyses based on somatic mutations and copy number alterations revealed that the mechanisms of progression of DCIS to invasive carcinoma are diverse, and that clonal selection might have constituted the mechanism of progression from DCIS to invasive disease in 28% (7/25) of patients. DCIS displaying a pattern of clonal selection in the progression to invasive cancer harbored higher levels of intralesion genetic heterogeneity than DCIS where no clonal selection was observed.

Conclusions: Intralesion genetic heterogeneity is a common feature in DCIS synchronously diagnosed with IDC-NST. DCIS is a nonobligate precursor of IDC-NST, whose mechanisms of progression to invasive breast cancer are diverse and vary from case to case.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-2563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367727PMC
July 2020
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