Publications by authors named "Jennifer Lickiss"

8 Publications

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Utility of clinical comprehensive genomic characterization for diagnostic categorization in patients presenting with hypocellular bone marrow failure syndromes.

Haematologica 2021 01 1;106(1):64-73. Epub 2021 Jan 1.

Clinical Haematology, Peter MacCallum Cancer Centre/Royal Melbourne Hospital, Melbourne, Australia.

Bone marrow failure (BMF) related to hypoplasia of hematopoietic elements in the bone marrow is a heterogeneous clinical entity with a broad differential diagnosis including both inherited and acquired causes. Accurate diagnostic categorization is critical to optimal patient care and detection of genomic variants in these patients may provide this important diagnostic and prognostic information. We performed real-time, accredited (ISO15189) comprehensive genomic characterization including targeted sequencing and whole exome sequencing in 115 patients with BMF syndrome (median age 24 years, range 3 months - 81 years). In patients with clinical diagnoses of inherited BMF syndromes, acquired BMF syndromes or clinically unclassifiable BMF we detected variants in 52% (12/23), 53% (25/47) and 56% (25/45) respectively. Genomic characterization resulted in a change of diagnosis in 30/115 (26%) including the identification of germline causes for 3/47 and 16/45 cases with pre-test diagnoses of acquired and clinically unclassifiable BMF respectively. The observed clinical impact of accurate diagnostic categorization included choice to perform allogeneic stem cell transplantation, disease-specific targeted treatments, identification of at-risk family members and influence of sibling allogeneic stem cell donor choice. Multiple novel pathogenic variants and copy number changes were identified in our cohort including in TERT, FANCA, RPS7 and SAMD9. Whole exome sequence analysis facilitated the identification of variants in two genes not typically associated with a primary clinical manifestation of BMF but also demonstrated reduced sensitivity for detecting low level acquired variants. In conclusion, genomic characterization can improve diagnostic categorization of patients presenting with hypoplastic BMF syndromes and should be routinely performed in this group of patients.
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http://dx.doi.org/10.3324/haematol.2019.237693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7776333PMC
January 2021

Severe chemotherapy toxicity in a 10-year-old with T-acute lymphoblastic lymphoma harboring biallelic variants.

Leuk Lymphoma 2020 05 16;61(5):1257-1259. Epub 2020 Jan 16.

Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Australia.

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http://dx.doi.org/10.1080/10428194.2019.1711075DOI Listing
May 2020

The price of success-health economics of personalized diffuse large B-cell lymphoma treatment.

Leuk Lymphoma 2018 07 7;59(7):1517-1519. Epub 2017 Dec 7.

a Peter MacCallum Cancer Centre , Melbourne , VIC , Australia.

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http://dx.doi.org/10.1080/10428194.2017.1408088DOI Listing
July 2018

Dominant Mutations in GRM1 Cause Spinocerebellar Ataxia Type 44.

Am J Hum Genet 2017 Sep;101(3):451-458

Nuffield Department of Clinical Neurosciences, University of Oxford, 6th Floor West Wing, John Radcliffe Hospital, Oxford OX3 9DU, UK; Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Trust, Oxford OX3 7HE, UK. Electronic address:

The metabotropic glutamate receptor 1 (mGluR1) is abundantly expressed in the mammalian central nervous system, where it regulates intracellular calcium homeostasis in response to excitatory signaling. Here, we describe heterozygous dominant mutations in GRM1, which encodes mGluR1, that are associated with distinct disease phenotypes: gain-of-function missense mutations, linked in two different families to adult-onset cerebellar ataxia, and a de novo truncation mutation resulting in a dominant-negative effect that is associated with juvenile-onset ataxia and intellectual disability. Crucially, the gain-of-function mutations could be pharmacologically modulated in vitro using an existing FDA-approved drug, Nitazoxanide, suggesting a possible avenue for treatment, which is currently unavailable for ataxias.
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http://dx.doi.org/10.1016/j.ajhg.2017.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5591020PMC
September 2017

Multiplex PCR and Next Generation Sequencing for the Non-Invasive Detection of Bladder Cancer.

PLoS One 2016 22;11(2):e0149756. Epub 2016 Feb 22.

Institute of Cancer & Genomic Sciences, University of Birmingham, Birmingham, B15 2TT, United Kingdom.

Background: Highly sensitive and specific urine-based tests to detect either primary or recurrent bladder cancer have proved elusive to date. Our ever increasing knowledge of the genomic aberrations in bladder cancer should enable the development of such tests based on urinary DNA.

Methods: DNA was extracted from urine cell pellets and PCR used to amplify the regions of the TERT promoter and coding regions of FGFR3, PIK3CA, TP53, HRAS, KDM6A and RXRA which are frequently mutated in bladder cancer. The PCR products were barcoded, pooled and paired-end 2 x 250 bp sequencing performed on an Illumina MiSeq. Urinary DNA was analysed from 20 non-cancer controls, 120 primary bladder cancer patients (41 pTa, 40 pT1, 39 pT2+) and 91 bladder cancer patients post-TURBT (89 cancer-free).

Results: Despite the small quantities of DNA extracted from some urine cell pellets, 96% of the samples yielded mean read depths >500. Analysing only previously reported point mutations, TERT mutations were found in 55% of patients with bladder cancer (independent of stage), FGFR3 mutations in 30% of patients with bladder cancer, PIK3CA in 14% and TP53 mutations in 12% of patients with bladder cancer. Overall, these previously reported bladder cancer mutations were detected in 86 out of 122 bladder cancer patients (70% sensitivity) and in only 3 out of 109 patients with no detectable bladder cancer (97% specificity).

Conclusion: This simple, cost-effective approach could be used for the non-invasive surveillance of patients with non-muscle-invasive bladder cancers harbouring these mutations. The method has a low DNA input requirement and can detect low levels of mutant DNA in a large excess of normal DNA. These genes represent a minimal biomarker panel to which extra markers could be added to develop a highly sensitive diagnostic test for bladder cancer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0149756PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4762704PMC
July 2016