Browsing by Author "Knowlton N"

Now showing 1 - 4 of 4
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    Analysis of HER2-Low Breast Cancer in Aotearoa New Zealand: A Nationwide Retrospective Cohort Study
    (MDPI (Basel, Switzerland), 2024-09-20) Lasham A; Ramsaroop R; Wrigley A; Knowlton N; Radisky D; Lambertini M
    OBJECTIVES: To perform the first national analysis of demographic and clinicopathological features associated with the HER2 positive, HER2-low, and HER2-zero invasive breast cancers in New Zealand. The study will reveal the proportion of women who may benefit from new HER2-targeted antibody drug conjugate (ADC) therapies. METHODS: Utilising data from Te Rēhita Mate Ūtaetae (Breast Cancer Foundation NZ National Register), the study analysed data from women diagnosed with invasive breast cancer over a 21-year period. The HER2 status of tumours was classified into three categories-HER2-zero, HER2-low, HER2-positive. RESULTS: From 2009-2021, 94% of women underwent HER2 testing, with 14% diagnosed with HER2-positive breast cancer. For advanced-stage disease, 38% of those formerly classified as HER2-negative were reclassified as HER2-low. Including HER2-positive breast cancers, this indicates that 60% of women with advanced breast cancer may potentially benefit from the new HER2-directed ADCs (approximately 120 women per year). CONCLUSIONS: The findings suggest a significant proportion of women with invasive breast cancer in New Zealand could benefit from new HER2-targeted treatments. There is a need to standardise HER2 testing to enhance personalised treatment and improve outcomes.
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    Breast Cancer Patient Prognosis Is Determined by the Interplay between TP53 Mutation and Alternative Transcript Expression: Insights from TP53 Long Amplicon Digital PCR Assays
    (MDPI (Basel, Switzerland), 2021-03-26) Lasham A; Knowlton N; Mehta SY; Braithwaite AW; Print CG
    The TP53 gene locus is capable of producing multiple RNA transcripts encoding the different p53 protein isoforms. We recently described multiplex long amplicon droplet digital PCR (ddPCR) assays to quantify seven of eight TP53 reference transcripts in human tumors. Here, we describe a new long amplicon ddPCR assay to quantify expression of the eighth TP53 reference transcript encoding ∆40p53α. We then applied these assays, alongside DNA sequencing of the TP53 gene locus, to tumors from a cohort of New Zealand (NZ) breast cancer patients. We found a high prevalence of mutations at TP53 splice sites in the NZ breast cancer cohort. Mutations at TP53 intron 4 splice sites were associated with overexpression of ∆133TP53 transcripts. Cox proportional hazards survival analysis showed that interplay between TP53 mutation status and expression of TP53 transcript variants was significantly associated with patient outcome, over and above standard clinical and pathological information. In particular, patients with no TP53 mutation and a low ratio of TP53 transcripts t2 to t1, which derive from alternative intron 1 acceptor splice sites, had a remarkably good outcome. We suggest that this type of analysis, integrating mutation and transcript expression, provides a step-change in our understanding of TP53 in cancer.
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    Recurrent loss of heterozygosity correlates with clinical outcome in pancreatic neuroendocrine cancer
    (Springer Nature in partnership with the Center of Excellence in Genomic Medicine Research at King Abdulaziz University, 2018-07-20) Lawrence B; Blenkiron C; Parker K; Tsai P; Fitzgerald S; Shields P; Robb T; Yeong ML; Kramer N; James S; Black M; Fan V; Poonawala N; Yap P; Coats E; Woodhouse B; Ramsaroop R; Yozu M; Robinson B; Henare K; Koea J; Johnston P; Carroll R; Connor S; Morrin H; Elston M; Jackson C; Reid P; Windsor J; MacCormick A; Babor R; Bartlett A; Damianovich D; Knowlton N; Grimmond S; Findlay M; Print C
    Pancreatic neuroendocrine tumors (pNETs) are uncommon cancers arising from pancreatic islet cells. Here we report the analysis of gene mutation, copy number, and RNA expression of 57 sporadic well-differentiated pNETs. pNET genomes are dominated by aneuploidy, leading to concordant changes in RNA expression at the level of whole chromosomes and chromosome segments. We observed two distinct patterns of somatic pNET aneuploidy that are associated with tumor pathology and patient prognosis. Approximately 26% of the patients in this series had pNETs with genomes characterized by recurrent loss of heterozygosity (LoH) of 10 specific chromosomes, accompanied by bi-allelic MEN1 inactivation and generally poor clinical outcome. Another ~40% of patients had pNETs that lacked this recurrent LoH pattern but had chromosome 11 LoH, bi-allelic MEN1 inactivation, and universally good clinical outcome. The somatic aneuploidy allowed pathogenic germline variants (e.g., ATM) to be expressed unopposed, with RNA expression patterns showing inactivation of downstream tumor suppressor pathways. No prognostic associations were found with tumor morphology, single gene mutation, or expression of RNAs reflecting the activity of immune, differentiation, proliferative or tumor suppressor pathways. In pNETs, single gene mutations appear to be less important than aneuploidy, with MEN1 the only statistically significant recurrently mutated driver gene. In addition, only one pNET in the series had clearly actionable single nucleotide variants (SNVs) (in PTEN and FLCN) confirmed by corroborating RNA expression changes. The two clinically relevant patterns of LoH described here define a novel oncogenic mechanism and a plausible route to genomic precision oncology for this tumor type.
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    Tumor mutational burden is a determinant of immune-mediated survival in breast cancer
    (Taylor and Francis, England, 2018-07-30) Thomas A; Routh ED; Pullikuth A; Jin G; Su J; Chou JW; Hoadley KA; Print C; Knowlton N; Black MA; Demaria S; Wang E; Bedognetti D; Jones WD; Mehta GA; Gatza ML; Perou CM; Page DB; Triozzi P; Miller LD
    Mounting evidence supports a role for the immune system in breast cancer outcomes. The ability to distinguish highly immunogenic tumors susceptible to anti-tumor immunity from weakly immunogenic or inherently immune-resistant tumors would guide development of therapeutic strategies in breast cancer. Genomic, transcriptomic and clinical data from The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) breast cancer cohorts were used to examine statistical associations between tumor mutational burden (TMB) and the survival of patients whose tumors were assigned to previously-described prognostic immune subclasses reflecting favorable, weak or poor immune-infiltrate dispositions (FID, WID or PID, respectively). Tumor immune subclasses were associated with survival in patients with high TMB (TMB-Hi, P < 0.001) but not in those with low TMB (TMB-Lo, P = 0.44). This statistical relationship was confirmed in the METABRIC cohort (TMB-Hi, P = 0.047; TMB-Lo, P = 0.39), and also found to hold true in the more-indolent Luminal A tumor subtype (TMB-Hi, P = 0.011; TMB-Lo, P = 0.91). In TMB-Hi tumors, the FID subclass was associated with prolonged survival independent of tumor stage, molecular subtype, age and treatment. Copy number analysis revealed the reproducible, preferential amplification of chromosome 1q immune-regulatory genes in the PID immune subclass. These findings demonstrate a previously unappreciated role for TMB as a determinant of immune-mediated survival of breast cancer patients and identify candidate immune-regulatory mechanisms associated with immunologically cold tumors. Immune subtyping of breast cancers may offer opportunities for therapeutic stratification.