Publications by authors named "David F Schaeffer"

123 Publications

Clinical and cost outcomes following genomics-informed treatment for advanced cancers.

Cancer Med 2021 Jun 21. Epub 2021 Jun 21.

Cancer Control Research, BC Cancer, Vancouver, Canada.

Background: Single-arm trials are common in precision oncology. Owing to the lack of randomized counterfactual, resultant data are not amenable to comparative outcomes analyses. Difference-in-difference (DID) methods present an opportunity to generate causal estimates of time-varying treatment outcomes. Using DID, our study estimates within-cohort effects of genomics-informed treatment versus standard care on clinical and cost outcomes.

Methods: We focus on adults with advanced cancers enrolled in the single-arm BC Cancer Personalized OncoGenomics program between 2012 and 2017. All individuals had a minimum of 1-year follow up. Logistic regression explored baseline differences across patients who received a genomics-informed treatment versus a standard care treatment after genomic sequencing. DID estimated the incremental effects of genomics-informed treatment on time to treatment discontinuation (TTD), time to next treatment (TTNT), and costs. TTD and TTNT correlate with improved response and survival.

Results: Our study cohort included 346 patients, of whom 140 (40%) received genomics-informed treatment after sequencing and 206 (60%) received standard care treatment. No significant differences in baseline characteristics were detected across treatment groups. DID estimated that the incremental effect of genomics-informed versus standard care treatment was 102 days (95% CI: 35, 167) on TTD, 91 days (95% CI: -9, 175) on TTNT, and CAD$91,098 (95% CI: $46,848, $176,598) on costs. Effects were most pronounced in gastrointestinal cancer patients.

Conclusions: Genomics-informed treatment had a statistically significant effect on TTD compared to standard care treatment, but at increased treatment costs. Within-cohort evidence generated through this single-arm study informs the early-stage comparative effectiveness of precision oncology.
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http://dx.doi.org/10.1002/cam4.4076DOI Listing
June 2021

Investigation of Nano-Bio Interactions within a Pancreatic Tumor Microenvironment for the Advancement of Nanomedicine in Cancer Treatment.

Curr Oncol 2021 May 24;28(3):1962-1979. Epub 2021 May 24.

Physics and Astronomy, University of Victoria, Victoria, BC V8P 5C2, Canada.

Pancreatic cancer is one of the deadliest types of cancer, with a five-year survival rate of only 10%. Nanotechnology offers a novel perspective to treat such deadly cancers through their incorporation into radiotherapy and chemotherapy. However, the interaction of nanoparticles (NPs) with cancer cells and with other major cell types within the pancreatic tumor microenvironment (TME) is yet to be understood. Therefore, our goal is to shed light on the dynamics of NPs within a TME of pancreatic origin. In addition to cancer cells, normal fibroblasts (NFs) and cancer-associated fibroblasts (CAFs) were examined in this study due to their important yet opposite roles of suppressing tumor growth and promoting tumor growth, respectively. Gold nanoparticles were used as the model NP system due to their biocompatibility and physical and chemical proprieties, and their dynamics were studied both quantitatively and qualitatively in vitro and in vivo. The in vitro studies revealed that both cancer cells and CAFs take up 50% more NPs compared to NFs. Most importantly, they all managed to retain 70-80% of NPs over a 24-h time period. Uptake and retention of NPs within an in vivo environment was also consistent with in vitro results. This study shows the paradigm-changing potential of NPs to combat the disease.
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http://dx.doi.org/10.3390/curroncol28030183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161808PMC
May 2021

Modelling hereditary diffuse gastric cancer initiation using transgenic mouse-derived gastric organoids and single-cell sequencing.

J Pathol 2021 Jul 12;254(3):254-264. Epub 2021 May 12.

Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.

Hereditary diffuse gastric cancer (HDGC) is a cancer syndrome caused by germline variants in CDH1, the gene encoding the cell-cell adhesion molecule E-cadherin. Loss of E-cadherin in cancer is associated with cellular dedifferentiation and poor prognosis, but the mechanisms through which CDH1 loss initiates HDGC are not known. Using single-cell RNA sequencing, we explored the transcriptional landscape of a murine organoid model of HDGC to characterize the impact of CDH1 loss in early tumourigenesis. Progenitor populations of stratified squamous and simple columnar epithelium, characteristic of the mouse stomach, showed lineage-specific transcriptional programs. Cdh1 inactivation resulted in shifts along the squamous differentiation trajectory associated with aberrant expression of genes central to gastrointestinal epithelial differentiation. Cytokeratin 7 (CK7), encoded by the differentiation-dependent gene Krt7, was a specific marker for early neoplastic lesions in CDH1 carriers. Our findings suggest that deregulation of developmental transcriptional programs may precede malignancy in HDGC. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.5675DOI Listing
July 2021

Serrated Lesion Detection in a Population-based Colon Screening Program.

J Clin Gastroenterol 2021 Mar 12. Epub 2021 Mar 12.

*Department of Pathology and Laboratory Medicine, Vancouver General Hospital †BC Cancer ‡Division of Gastroenterology, University of British Columbia, Vancouver, BC, Canada.

Background: Serrated lesions give rise to 15% to 30% of all colorectal cancers, driven predominantly by the sessile serrated polyp (SSP). Fecal immunochemical test (FIT), has low sensitivity for SSPs. SSP detection rate (SSPDR) is influenced by performance of both endoscopists and pathologists, as diagnosis can be subtle both on endoscopy and histology.

Goals: To evaluate the SSPDR in a population-based screening program, and the influence of subspecialty trained pathologists on provincial reporting practices.

Study: The colon screening program database was used to identify all FIT-positive patients that received colonoscopy between January 2014 and June 2017. Patient demographics, colonoscopy quality indicators, pathologic diagnoses, and FIT values were collected. This study received IRB approval.

Results: A total of 74,605 colonoscopies were included and 26.6% had at least 1 serrated polyp removed. The SSPDR was 7.0%, with 59% of the SSPs detected having a concurrent conventional adenoma. The mean FIT value for colonoscopies with only serrated lesions was less than that for colonoscopies with a conventional adenoma or colorectal cancer (P<0.0001). Centers with a gastrointestinal subspecialty pathologist diagnosed proportionally more SSPs (P<0.0001), and right-sided SSPs than centers without subspecialists.

Conclusions: Serrated lesions often occur in conjunction with conventional adenomas and are associated with lower FIT values. Knowledge of the characteristics of SSPs is essential for pathologists to ensure accurate diagnosis of SSPs.
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http://dx.doi.org/10.1097/MCG.0000000000001519DOI Listing
March 2021

In Reply.

Arch Pathol Lab Med 2021 04;145(4):391b-391

Division of Anatomic Pathology, Vancouver General Hospital, Vancouver, British Columbia, Canada.

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http://dx.doi.org/10.5858/arpa.2020-0801-LEDOI Listing
April 2021

An expert consensus to standardise clinical, endoscopic and histologic items and inclusion and outcome criteria for evaluation of pouchitis disease activity in clinical trials.

Aliment Pharmacol Ther 2021 05 18;53(10):1108-1117. Epub 2021 Mar 18.

London, ON, Canada.

Background: Pouchitis is a condition with large unmet medical needs and no approved therapies. Lack of validated instruments to measure disease activity and treatment response is a major barrier to drug development.

Aim: To conduct a modified RAND/University of California Los Angeles appropriateness process to produce a standardised assessment of pouchitis disease activity in clinical trials.

Methods: A list of 164 items generated upon a systematic review and expert opinion were rated based on a 9-point scale (appropriate, uncertain and inappropriate), by a panel including 16 gastroenterologists, surgeons and histopathologists.

Results: Items rated as appropriate to evaluate in pouchitis clinical trials were: (a) clinical: stool frequency and faecal urgency; (b) endoscopic: primary assessment in the pouch body according to the percentage of affected area (<50%, 50%-75% and >75%), evaluation of the presence of ulcers/erosions according to size (erosions <5 mm, ulcers ≥5 mm to 2 cm and large ulcers >2 cm) and ulcerated area (<10%, 10%-30% and >30%); (c) histologic: two biopsies from each segment, from the ulcer's edge when present, or endoscopically normal areas, assessment of lamina propria chronic inflammation, epithelial and lamina propria neutrophils, epithelial damage, erosions and ulcers; and (d) clinical trial inclusion/outcome criteria: minimum histologic disease activity for inclusion, a primary endpoint based on stool frequency and assessment of clinical, endoscopic and histologic response and remission. The overall majority of items surveyed (100/164) were rated 'uncertain'.

Conclusion: We conducted a RAND/UCLA appropriateness process to help inform measurement of pouchitis disease activity within clinical trials and foster the development of novel therapies.
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http://dx.doi.org/10.1111/apt.16328DOI Listing
May 2021

An International Consensus to Standardize Integration of Histopathology in Ulcerative Colitis Clinical Trials.

Gastroenterology 2021 Jun 19;160(7):2291-2302. Epub 2021 Feb 19.

Alimentiv Inc (formerly Robarts Clinical Trials, Inc), London, Ontario, Canada; Department of Medicine, Division of Gastroenterology, Western University, London, Ontario, Canada; Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada.

Background & Aims: Histopathology is an emerging treatment target in ulcerative colitis (UC) clinical trials. Our aim was to provide guidance on standardizing biopsy collection protocols, identifying optimal evaluative indices, and defining thresholds for histologic response and remission after treatment.

Methods: An international, interdisciplinary expert panel of 19 gastroenterologists and gastrointestinal pathologists was assembled. A modified RAND/University of California, Los Angeles appropriateness methodology was used to address relevant issues. A total of 138 statements were derived from a systematic review of the literature and expert opinion. Each statement was anonymously rated as appropriate, uncertain, or inappropriate using a 9-point scale. Survey results were reviewed and discussed before a second round of voting.

Results: Histologic measurements collected using a uniform biopsy strategy are important for assessing disease activity and determining therapeutic efficacy in UC clinical trials. Multiple biopsy strategies were deemed acceptable, including segmental biopsies collected according to the endoscopic appearance. Biopsies should be scored for architectural change, lamina propria chronic inflammation, basal plasmacytosis, lamina propria and epithelial neutrophils, epithelial damage, and erosions/ulcerations. The Geboes score, Robarts Histopathology Index, and Nancy Index were considered appropriate for assessing histologic activity; use of the modified Riley score and Harpaz Index were uncertain. Histologic activity at baseline should be required for enrollment, recognizing this carries operational implications. Achievement of histologic improvement or remission was considered an appropriate and realistic therapeutic target. Current histologic indices require validation for pediatric populations.

Conclusions: These recommendations provide a framework for standardized implementation of histopathology in UC trials. Additional work is required to address operational considerations and areas of uncertainty.
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http://dx.doi.org/10.1053/j.gastro.2021.02.035DOI Listing
June 2021

Development and initial validation of a deep learning algorithm to quantify histological features in colorectal carcinoma including tumour budding/poorly differentiated clusters.

Histopathology 2021 Feb 15. Epub 2021 Feb 15.

Department of Pathology and Laboratory Medicine, Mayo Clinic Arizona, Scottsdale, AZ, USA.

Aims: To develop and validate a deep learning algorithm to quantify a broad spectrum of histological features in colorectal carcinoma.

Methods And Results: A deep learning algorithm was trained on haematoxylin and eosin-stained slides from tissue microarrays of colorectal carcinomas (N = 230) to segment colorectal carcinoma digitised images into 13 regions and one object. The segmentation algorithm demonstrated moderate to almost perfect agreement with interpretations by gastrointestinal pathologists, and was applied to an independent test cohort of digitised whole slides of colorectal carcinoma (N = 136). The algorithm correctly classified mucinous and high-grade tumours, and identified significant differences between mismatch repair-proficient and mismatch repair-deficient (MMRD) tumours with regard to mucin, inflammatory stroma, and tumour-infiltrating lymphocytes (TILs). A cutoff of >44.4 TILs per mm carcinoma gave a sensitivity of 88% and a specificity of 73% in classifying MMRD carcinomas. Algorithm measures of tumour budding (TB) and poorly differentiated clusters (PDCs) outperformed TB grade derived from routine sign-out, and compared favourably with manual counts of TB/PDCs with regard to lymphatic, venous and perineural invasion. Comparable associations were seen between algorithm measures of TB/PDCs and manual counts of TB/PDCs for lymph node metastasis (all P < 0.001); however, stronger correlations were seen between the proportion of positive lymph nodes and algorithm measures of TB/PDCs. Stronger associations were also seen between distant metastasis and algorithm measures of TB/PDCs (P = 0.004) than between distant metastasis and TB (P = 0.04) and TB/PDC counts (P = 0.06).

Conclusions: Our results highlight the potential of deep learning to identify and quantify a broad spectrum of histological features in colorectal carcinoma.
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http://dx.doi.org/10.1111/his.14353DOI Listing
February 2021

Editorial: the microscope holds the key to predict need for biologic therapy in immunotherapy-checkpoint inhibitory colitis. Authors' reply.

Aliment Pharmacol Ther 2021 03;53(5):638-639

Department of Pathology, Henry L. Moffitt Cancer Center & Research Institute, Tampa, FL, USA.

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http://dx.doi.org/10.1111/apt.16245DOI Listing
March 2021

Genomic Features and Classification of Homologous Recombination Deficient Pancreatic Ductal Adenocarcinoma.

Gastroenterology 2021 May 30;160(6):2119-2132.e9. Epub 2021 Jan 30.

PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada; Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada; Department of Surgery, University of Toronto, Toronto, Ontario, Canada; Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, Ontario, Canada. Electronic address:

Background And Aims: Homologous recombination deficiency (HRD) in pancreatic ductal adenocarcinoma (PDAC), remains poorly defined beyond germline (g) alterations in BRCA1, BRCA2, and PALB2.

Methods: We interrogated whole genome sequencing (WGS) data on 391 patients, including 49 carriers of pathogenic variants (PVs) in gBRCA and PALB2. HRD classifiers were applied to the dataset and included (1) the genomic instability score (GIS) used by Myriad's MyChoice HRD assay; (2) substitution base signature 3 (SBS3); (3) HRDetect; and (4) structural variant (SV) burden. Clinical outcomes and responses to chemotherapy were correlated with HRD status.

Results: Biallelic tumor inactivation of gBRCA or PALB2 was evident in 43 of 49 germline carriers identifying HRD-PDAC. HRDetect (score ≥0.7) predicted gBRCA1/PALB2 deficiency with highest sensitivity (98%) and specificity (100%). HRD genomic tumor classifiers suggested that 7% to 10% of PDACs that do not harbor gBRCA/PALB2 have features of HRD. Of the somatic HRDetect cases, 69% were attributed to alterations in BRCA1/2, PALB2, RAD51C/D, and XRCC2, and a tandem duplicator phenotype. TP53 loss was more common in BRCA1- compared with BRCA2-associated HRD-PDAC. HRD status was not prognostic in resected PDAC; however in advanced disease the GIS (P = .02), SBS3 (P = .03), and HRDetect score (P = .005) were predictive of platinum response and superior survival. PVs in gATM (n = 6) or gCHEK2 (n = 2) did not result in HRD-PDAC by any of the classifiers. In 4 patients, BRCA2 reversion mutations associated with platinum resistance.

Conclusions: Germline and parallel somatic profiling of PDAC outperforms germline testing alone in identifying HRD-PDAC. An additional 7% to 10% of patients without gBRCA/PALB2 mutations may benefit from DNA damage response agents.
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http://dx.doi.org/10.1053/j.gastro.2021.01.220DOI Listing
May 2021

An expert consensus to standardise the assessment of histological disease activity in Crohn's disease clinical trials.

Aliment Pharmacol Ther 2021 04 7;53(7):784-793. Epub 2021 Jan 7.

London, ON, Canada.

Background: Targeting histological remission or response in Crohn's disease (CD) is not recommended in clinical practice guidelines or as an outcome in clinical trials due to uncertainties regarding index validity and prognostic relevance.

Aims: To conduct a modified RAND/University of California Los Angeles appropriateness process with the goal of producing a framework to standardise histological assessment of CD activity in clinical trials.

Methods: A total of 115 statements generated from literature review and expert opinion were rated on a scale of 1-9 by a panel of 11 histopathologists and 6 gastroenterologists. Statements were classified as inappropriate, uncertain or appropriate based upon the median panel rating and degree of disagreement.

Results: The panellists considered it important to measure histological activity in clinical trials to determine efficacy and that absence of neutrophilic inflammation is an appropriate histological target. They were uncertain whether the Global Histological Activity Score was an appropriate instrument for measuring histological activity. The Geboes Score and Robarts Histopathology Index were considered appropriate. Two biopsies from five segments should be biopsied, and the colon and the ileum should be analysed separately for all indices. Endoscopic mucosal appearance should guide biopsy procurement site with biopsies taken from the ulcer edge, or the most macroscopically inflamed area in the absence of ulcers.

Conclusion: We evaluated the appropriateness of items for assessing histological disease activity in CD clinical trials. These items will be used to develop a novel histological index.
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http://dx.doi.org/10.1111/apt.16248DOI Listing
April 2021

Tumor infiltrating neutrophils and gland formation predict overall survival and molecular subgroups in pancreatic ductal adenocarcinoma.

Cancer Med 2021 02 28;10(3):1155-1165. Epub 2020 Dec 28.

Division of Anatomic Pathology, Vancouver General Hospital, Vancouver, BC, Canada.

Background: RNA-sequencing-based classifiers can stratify pancreatic ductal adenocarcinoma (PDAC) into prognostically significant subgroups but are not practical for use in clinical workflows. Here, we assess whether histomorphological features may be used as surrogate markers for predicting molecular subgroup and overall survival in PDAC.

Methods: Ninety-six tissue samples from 50 patients with non-resectable PDAC were scored for gland formation, stromal maturity, mucin, necrosis, and neutrophil infiltration. Prognostic PDAC gene expression classifiers were run on all tumors using whole transcriptome sequencing data from the POG trial (NCT02155621). Findings were validated using digital TCGA slides (n = 50). Survival analysis used multivariate Cox proportional-hazards tests and log-rank tests.

Results: The combination of low gland formation and low neutrophil infiltration was significantly associated with the poor prognosis PDAC molecular subgroup (basal-like or squamous) and was an independent predictor of shorter overall survival, in both frozen section (n = 47) and formalin-fixed paraffin-embedded (n = 49) tissue samples from POG patients, and in the TCGA samples. This finding held true in the subgroup analysis of primary (n = 17) and metastatic samples (n = 79). The combination of high gland formation and high neutrophils had low sensitivity but high specificity for favorable prognosis subgroups.

Conclusions: The assessment of gland formation and neutrophil infiltration on routine histological sections can aid in prognostication and allow inferences to be made about molecular subtype, which may help guide patient management decisions and contribute to our understanding of heterogeneity in treatment response.
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http://dx.doi.org/10.1002/cam4.3695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897949PMC
February 2021

Reproducibility of tumor budding assessment in pancreatic cancer based on a multicenter interobserver study.

Virchows Arch 2021 Apr 17;478(4):719-726. Epub 2020 Dec 17.

Faculty of Medicine and University Hospital Cologne, Institute of Pathology, University of Cologne, Cologne, Germany.

Tumor budding has been reported to be an independent prognostic factor in pancreatic ductal adenocarcinoma (PDAC). Its use in daily diagnostics would improve the prognostic stratification of patients. We performed a multicenter interobserver study to test various budding assessment methods for their reproducibility. Two serial sections of 50 resected, treatment-naïve PDACs were stained for Hematoxylin and Eosin (H&E) and pancytokeratin. Tumor budding was scored by independent observers at five participating centers in Switzerland, Germany, and Canada. Pathologists assessed tumor budding on a digital platform comparing H&E with pancytokeratin staining in 10 high-power fields (10HPF) and one HPF hotspot (1HPF). Additionally, tumor budding was assessed in one H&E hotspot at × 20 magnification, as suggested by the International Tumor Budding Consensus Conference (ITBCC). Correlation coefficients for bud counts between centers ranged from r = 0.58648 to r = 0.78641 for H&E and from r = 0.69288 to r = 0.81764 for pancytokeratin. The highest interobserver agreement across all centers was observed for pancytokeratin 10HPFs (ICC = 0.6). ICC values were 0.49, 0.48, 0.41, and 0.4 for H&E in 1HPF hotspot, H&E in 10HPFs, pancytokeratin in 1HPF, and H&E in one hotspot at ×20, respectively (ITBCC method). This interobserver study reveals a range between moderately poor to moderate agreement levels between pathologists for the different tumor budding assessment methods in PDAC. Acceptable levels of agreement were reached with the pancytokeratin 10HPF method, which can thus be recommended for the assessment of tumor budding in PDAC resection specimens. To improve the levels of interobserver agreement, the implementation of machine learning applications should be considered.
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http://dx.doi.org/10.1007/s00428-020-02987-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990816PMC
April 2021

Overcoming Adaptive Resistance to KRAS and MEK Inhibitors by Co-targeting mTORC1/2 Complexes in Pancreatic Cancer.

Cell Rep Med 2020 Nov 17;1(8):100131. Epub 2020 Nov 17.

Department of Integrative Oncology, BC Cancer Research Institute, Vancouver, BC V5Z 1L3, Canada.

Activating KRAS mutations are found in over 90% of pancreatic ductal adenocarcinomas (PDACs), yet KRAS has remained a difficult target to inhibit pharmacologically. Here, we demonstrate, using several human and mouse models of PDACs, rapid acquisition of tumor resistance in response to targeting KRAS or MEK, associated with integrin-linked kinase (ILK)-mediated increased phosphorylation of the mTORC2 component Rictor, and AKT. Although inhibition of mTORC1/2 results in a compensatory increase in ERK phosphorylation, combinatorial treatment of PDAC cells with either KRAS (G12C) or MEK inhibitors, together with mTORC1/2 inhibitors, results in synergistic cytotoxicity and cell death reflected by inhibition of pERK and pRictor/pAKT and of downstream regulators of protein synthesis and cell survival. Relative to single agents alone, this combination leads to durable inhibition of tumor growth and metastatic progression and increased survival. We have identified an effective combinatorial treatment strategy using clinically viable inhibitors, which can be applied to PDAC tumors with different KRAS mutations.
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http://dx.doi.org/10.1016/j.xcrm.2020.100131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691443PMC
November 2020

Uncovering Clinically Relevant Gene Fusions with Integrated Genomic and Transcriptomic Profiling of Metastatic Cancers.

Clin Cancer Res 2021 Jan 4;27(2):522-531. Epub 2020 Nov 4.

Department of Medical Oncology, BC Cancer, Vancouver, Canada.

Purpose: Gene fusions are important oncogenic drivers and many are actionable. Whole-genome and transcriptome (WGS and RNA-seq, respectively) sequencing can discover novel clinically relevant fusions.

Experimental Design: Using WGS and RNA-seq, we reviewed the prevalence of fusions in a cohort of 570 patients with cancer, and compared prevalence to that predicted with commercially available panels. Fusions were annotated using a consensus variant calling pipeline (MAVIS) and required that a contig of the breakpoint could be constructed and supported from ≥2 structural variant detection approaches.

Results: In 570 patients with advanced cancer, MAVIS identified 81 recurrent fusions by WGS and 111 by RNA-seq, of which 18 fusions by WGS and 19 by RNA-seq were noted in at least 3 separate patients. The most common fusions were in thoracic malignancies (9/69, 13%), and in colorectal cancer (4/73, 5.5%). Combined genomic and transcriptomic analysis identified novel fusion partners for clinically relevant genes, such as (novel partners: , and (novel partners: ).

Conclusions: Utilizing WGS/RNA-seq facilitates identification of novel fusions in clinically relevant genes, and detected a greater proportion than commercially available panels are expected to find. A significant benefit of WGS and RNA-seq is the innate ability to retrospectively identify variants that becomes clinically relevant over time, without the need for additional testing, which is not possible with panel-based approaches.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1900DOI Listing
January 2021

The significance of histological activity measurements in immune checkpoint inhibitor colitis.

Aliment Pharmacol Ther 2021 01 4;53(1):150-159. Epub 2020 Nov 4.

Department of Pathology, Henry L. Moffitt Cancer Center & Research Institute, Tampa, FL, USA.

Background: Colitis is a significant complication of immune checkpoint inhibitors (ICI). Currently, clinical and endoscopic severity are used to guide therapy.

Aims: To investigate associations between clinical, endoscopic, and histological features with outcomes METHODS: We identified 149 patients from seven institutions with biopsy-proven ICI colitis. Biopsies were evaluated for histological features including the Geboes score, and the Robarts histopathological index (RHI) was calculated. Clinical, endoscopic, and histological data were tested for associations with biological use and adverse colitis outcomes (biological-refractory colitis, colectomy or death from colitis).

Results: Three mutually exclusive histological patterns were identified: acute colitis, chronic active colitis and microscopic colitis. Microscopic colitis was associated with older age (68.5 vs 61 years for acute colitis pattern, P = 0.02) and longer time to colitis (5.5 vs 3 months for the other patterns, P = 0.05). Biological use was associated with earlier time to colitis (2 vs 3 months, P = 0.04) and higher RHI (18 vs 12, P = 0.007). On multivariate analysis, RHI ≥14 was associated with biological use with an odds ratio of 4.5 (95% CI 1.4-13.8; P = 0.01). Adverse colitis outcomes were associated with shorter time to colitis (2 vs 3 months, P = 0.008) and higher RHI (24 vs 14, P = 0.001). On multivariate analysis, RHI ≥24 was associated with adverse colitis outcomes with an odds ratio 9.5 (95% CI 2.1-42.3 P = 0.003).

Conclusion: Histological activity as measured by RHI is the only factor independently associated with biological use and adverse colitis outcomes. Prospective studies are needed to validate these findings to determine if histological activity should be incorporated into therapeutic algorithms.
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http://dx.doi.org/10.1111/apt.16142DOI Listing
January 2021

Subtype-Discordant Pancreatic Ductal Adenocarcinoma Tumors Show Intermediate Clinical and Molecular Characteristics.

Clin Cancer Res 2021 Jan 13;27(1):150-157. Epub 2020 Oct 13.

Pancreas Centre BC, Vancouver, British Columbia, Canada.

Purpose: RNA-sequencing-based subtyping of pancreatic ductal adenocarcinoma (PDAC) has been reported by multiple research groups, each using different methodologies and patient cohorts. "Classical" and "basal-like" PDAC subtypes are associated with survival differences, with basal-like tumors associated with worse prognosis. We amalgamated various PDAC subtyping tools to evaluate the potential of such tools to be reliable in clinical practice.

Experimental Design: Sequencing data for 574 PDAC tumors was obtained from prospective trials and retrospective public databases. Six published PDAC subtyping strategies (Moffitt regression tools, clustering-based Moffitt, Collisson, Bailey, and Karasinska subtypes) were used on each sample, and results were tested for subtype call consistency and association with survival.

Results: Basal-like and classical subtype calls were concordant in 88% of patient samples, and survival outcomes were significantly different ( < 0.05) between prognostic subtypes. Twelve percent of tumors had subtype-discordant calls across the different methods, showing intermediate survival in univariate and multivariate survival analyses. Transcriptional profiles compatible with that of a hybrid subtype signature were observed for subtype-discordant tumors, in which classical and basal-like genes were concomitantly expressed. Subtype-discordant tumors showed intermediate molecular characteristics, including subtyping gene expression ( < 0.0001) and mutant allelic imbalance ( < 0.001).

Conclusions: Nearly 1 in 6 patients with PDAC have tumors that fail to reliably fall into the classical or basal-like PDAC subtype categories, based on two regression tools aimed toward clinical practice. Rather, these patient tumors show intermediate prognostic and molecular traits. We propose close consideration of the non-binary nature of PDAC subtypes for future incorporation of subtyping into clinical practice.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2831DOI Listing
January 2021

Colorectal adenocarcinomas diagnosed following a negative faecal immunochemical test show high-risk pathological features in a colon screening programme.

Histopathology 2021 Apr 8;78(5):710-716. Epub 2020 Dec 8.

Department of Pathology and Laboratory Medicine, Vancouver General Hospital, Vancouver, BC, Canada.

Aims: The faecal immunochemical test (FIT) is used every 2 years to screen average-risk British Columbians aged 50-74 years, with follow-up colonoscopy for positive results. Non-screen-detected colorectal adenocarcinomas are defined as those detected within 25 months following a negative FIT. We aimed to more clearly characterise these malignancies.

Methods And Results: A medical chart and focused pathology review of colorectal malignancies from 926 individuals who completed FIT in the British Columbia Colon Screening Program in 2014, and whose pathology reports were available for review, was conducted. This cohort was divided into two groups: individuals with colorectal adenocarcinomas diagnosed following a positive FIT (screen-detected) and individuals with colorectal adenocarcinoma diagnosed within 25 months of a negative FIT (FIT-interval cancers). Rates of clinically relevant pathological parameters, as outlined in the American Joint Committee on Cancer (AJCC), 8th edition, were compared between the screen-detected and FIT-interval cancer groups. A total of 876 screen-detected and 50 FIT-interval cancers were identified. FIT-interval cancers exhibited higher rates of high-grade differentiation (including poorly differentiated and undifferentiated cases; P < 0.01) and aggressive histotype (signet ring cell and mucinous carcinomas; P < 0.01) than did screen-detected cancers after Bonferroni correction. Colorectal adenocarcinoma diagnosed after a negative FIT may therefore be associated with worse prognostic determinants than screen-detected cancers.

Conclusion: FIT-interval cancers are associated with high-risk pathological features; the possibility that more aggressive, fast-growing lesions which arise in the interval after truly negative FITs cannot be ruled out. Further study of a larger cohort of FIT-interval cancers controlling for interaction among the different pathologic parameters will be undertaken.
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http://dx.doi.org/10.1111/his.14278DOI Listing
April 2021

Delving into Early-onset Pancreatic Ductal Adenocarcinoma: How Does Age Fit In?

Clin Cancer Res 2021 Jan 21;27(1):246-254. Epub 2020 Sep 21.

BC Cancer, Vancouver, British Columbia, Canada.

Purpose: With the rising incidence of early-onset pancreatic cancer (EOPC), molecular characteristics that distinguish early-onset pancreatic ductal adenocarcinoma (PDAC) tumors from those arising at a later age are not well understood.

Experimental Design: We performed bioinformatic analysis of genomic and transcriptomic data generated from 269 advanced (metastatic or locally advanced) and 277 resectable PDAC tumor samples. Patient samples were stratified into EOPC (age of onset ≤55 years; = 117), intermediate (age of onset 55-70 years; = 264), and average (age of onset ≥70 years; = 165) groups. Frequency of somatic mutations affecting genes commonly implicated in PDAC, as well as gene expression patterns, were compared between EOPC and all other groups.

Results: EOPC tumors showed significantly lower frequency of somatic single-nucleotide variant (SNV)/insertions/deletions (indel) in ( = 0.0017), and were more likely to achieve biallelic mutation of through homozygous copy loss as opposed to heterozygous copy loss coupled with a loss-of-function SNV/indel mutation, the latter of which was more common for tumors with later ages of onset ( = 1.5e-4). Transcription factor forkhead box protein C2 () was significantly upregulated in EOPC tumors ( = 0.032). Genes significantly correlated with in PDAC samples were enriched for gene sets related to epithelial-to-mesenchymal transition (EMT) and included ( = 1.8e-8), ( = 6.5e-5), and ( = 2.4e-2).

Conclusions: Our comprehensive analysis of sequencing data generated from a large cohort of PDAC patient samples highlights a distinctive pattern of biallelic mutation in EOPC tumors. Increased expression of in EOPC, with the correlation between and EMT pathways, represents novel molecular characteristics of EOPC..
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1042DOI Listing
January 2021

Stroma vs epithelium-enhanced prognostics through histologic stratification in pancreatic ductal adenocarcinoma.

Int J Cancer 2021 01 29;148(2):481-491. Epub 2020 Sep 29.

Pancreas Centre BC, Vancouver General Hospital, Vancouver, British Columbia, Canada.

The mixture of epithelial and stromal components in pancreatic ductal adenocarcinoma (PDAC) may confound sequencing-based studies of tumor gene expression. Virtual microdissection has been suggested as a bioinformatics approach to segment the aforementioned components, and subsequent prognostic gene sets have emerged from this research. We examined the prognostic signature from the epithelial gene set of one such study using laser capture microdissected (LCM) epithelial samples. We also examined this gene set in matched stromal samples to determine whether prognostic findings were specific to the epithelium. LCM samples from 48 long-term and 48 short-term PDAC survivors were obtained. The resultant epithelial and stromal components were subjected to direct mRNA quantification using a 49 gene published PDAC classifier. Component-specific unsupervised hierarchical clustering was used to derive groups and survival differences were quantified. Immunohistochemical validation of particular genes was performed in an independent cohort. Clustering in the epithelial component yielded prognostic differences in univariable analysis (P = .02), but those differences were not significant when controlled for other clinicopathologic covariates (P = .06). Clustering in the stromal component yielded prognostic differences that persisted in the presence of other clinicopathologic covariates (P = .0005). Validation of selected genes in the epithelium (KRT6A-negative prognostic [P = .004]) and stroma (LY6D-improved prognostic [P = .01] and CTSV-negative prognostic [P = .0002]) demonstrated statistical independence in multivariable analysis. Although the genes used in this study were originally identified as being representative of the epithelial component of PDAC, their expression in the stroma appears to provide additional information that may aid in improved prognostication.
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http://dx.doi.org/10.1002/ijc.33304DOI Listing
January 2021

Clinical and genomic characterisation of mismatch repair deficient pancreatic adenocarcinoma.

Gut 2020 Sep 15. Epub 2020 Sep 15.

Ontario Institute for Cancer Research, Toronto, Ontario, Canada

Objective: To describe the clinical, pathological and genomic characteristics of pancreatic cancer with DNA mismatch repair deficiency (MMRD) and proficiency (MMRP).

Design: We identified patients with MMRD and MMRP pancreatic cancer in a clinical cohort (N=1213, 519 with genetic testing, 53 with immunohistochemistry (IHC)) and a genomic cohort (N=288 with whole-genome sequencing (WGS)).

Results: 12 out of 1213 (1.0%) in the clinical cohort were MMRD by IHC or WGS. Of the 14 patients with Lynch syndrome, 3 (21.4%) had an MMRP pancreatic cancer by IHC, and 4 (28.6%) were excluded because tissue was unavailable for testing. MMRD cancers had longer overall survival after surgery (weighted HR after coarsened exact matching 0.11, 95% CI 0.02 to 0.78, p=0.001). One patient with an unresectable MMRD cancer has an ongoing partial response 3 years after starting treatment with PD-L1/CTLA-4 inhibition. This tumour showed none of the classical histopathological features of MMRD. 9 out of 288 (3.1%) tumours with WGS were MMRD. Despite markedly higher tumour mutational burden and neoantigen loads, MMRD cancers were significantly less likely to have mutations in usual pancreatic cancer driver genes like and , but more likely to have mutations in genes that drive cancers with microsatellite instability like and . MMRD tumours were significantly more likely to have a basal-like transcriptional programme and elevated transcriptional markers of immunogenicity.

Conclusions: MMRD pancreatic cancers have distinct clinical, pathological and genomic profiles. Patients with MMRD pancreatic cancer should be considered for basket trials targeting enhanced immunogenicity or the unique genomic drivers in these malignancies.
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http://dx.doi.org/10.1136/gutjnl-2020-320730DOI Listing
September 2020

Variability in Synoptic Reporting of Colorectal Cancer pT4a Category and Lymphovascular Invasion.

Arch Pathol Lab Med 2021 03;145(3):343-351

From the Division of Anatomic Pathology, Vancouver General Hospital, Vancouver, British Columbia, Canada.

Context.—: Serosal involvement (pT4a category) and lymphovascular invasion have prognostic significance in colorectal carcinoma, but are subject to interobserver variation in assessment.

Objectives.—: To provide the first large-scale assessment of interobserver variability in pT4a category and lymphovascular invasion reporting in real-world practice and to explore the impact of information from guidelines on variability in reporting these features.

Design.—: Analysis of 1555 consecutive synoptic reports of colorectal carcinoma was performed using multivariate logistic regression. Interobserver variability before and after the presentation of guideline information was assessed using an image-based survey.

Results.—: Significant differences in the odds of reporting pT4a versus pT3 category, detecting lymphovascular invasion of any type, and detecting large vessel invasion were identified among hospital sites and for individual pathologists compared with the median pathologist at the same site. Consistent with these results, interobserver agreement was only moderate in the image-based survey regarding T4a staging and lymphovascular invasion (all κ ≤ 0.57). The provision of information from guidelines did not tend to increase interobserver agreement in the survey, though responses in favor of using an elastic stain increased following recommendations for their use. However, when observers were provided with elastic-stained images, interobserver agreement remained only moderate (κ = 0.55).

Conclusions.—: Real-world reporting of pT4a category and lymphovascular invasion shows substantial variability at both local and regional levels. Our study underscores the need to address these features in quality initiatives, and provides a novel method through which existing synoptic data can be harnessed to monitor reporting patterns and provide individualized feedback.
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http://dx.doi.org/10.5858/arpa.2020-0124-OADOI Listing
March 2021

Evaluating the impact of universal Lynch syndrome screening in a publicly funded healthcare system.

Cancer Med 2020 09 23;9(18):6507-6514. Epub 2020 Jul 23.

BC Cancer, Hereditary Cancer Program, Vancouver, BC, Canada.

Purpose: Referrals for Lynch syndrome (LS) assessment have traditionally been based on personal and family medical history. The introduction of universal screening practices has allowed for referrals based on immunohistochemistry tests for mismatch repair (MMR) protein expression. This study aims to characterize the effect of universal screening in a publicly funded healthcare system with comparison to patients referred by traditional criteria, from January 2012 to March 2017.

Methods: Patient files from the time of initiation of universal screening from 2012 to 2017 were reviewed. Patients were sorted into two groups: (a) universally screened and (b) referred by traditional methods. Mutation detection rates, analysis of traditional testing criteria met, and cascade carrier testing were evaluated.

Results: The mutation detection rate of the universal screening group was higher than the traditionally referred group (45/228 (19.7%) vs 50/390 (12.5%), P = .05), though each were able to identify unique patients. An analysis of testing criteria met by each patient showed that half of referred patients from the universal screening group could not meet any traditional testing criteria.

Conclusion: The implementation of universal screening in a publicly funded system will increase efficiency in detecting patients with LS. The resources available for genetic testing and counseling may be more limited in public systems, thus inclusion of secondary screening with BRAF and MLH1 promoter hypermethylation testing is key to further optimizing efficiency.
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http://dx.doi.org/10.1002/cam4.3279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520344PMC
September 2020

Improved structural variant interpretation for hereditary cancer susceptibility using long-read sequencing.

Genet Med 2020 11 6;22(11):1892-1897. Epub 2020 Jul 6.

Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC, Canada.

Purpose: Structural variants (SVs) may be an underestimated cause of hereditary cancer syndromes given the current limitations of short-read next-generation sequencing. Here we investigated the utility of long-read sequencing in resolving germline SVs in cancer susceptibility genes detected through short-read genome sequencing.

Methods: Known or suspected deleterious germline SVs were identified using Illumina genome sequencing across a cohort of 669 advanced cancer patients with paired tumor genome and transcriptome sequencing. Candidate SVs were subsequently assessed by Oxford Nanopore long-read sequencing.

Results: Nanopore sequencing confirmed eight simple pathogenic or likely pathogenic SVs, resolving three additional variants whose impact could not be fully elucidated through short-read sequencing. A recurrent sequencing artifact on chromosome 16p13 and one complex rearrangement on chromosome 5q35 were subsequently classified as likely benign, obviating the need for further clinical assessment. Variant configuration was further resolved in one case with a complex pathogenic rearrangement affecting TSC2.

Conclusion: Our findings demonstrate that long-read sequencing can improve the validation, resolution, and classification of germline SVs. This has important implications for return of results, cascade carrier testing, cancer screening, and prophylactic interventions.
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http://dx.doi.org/10.1038/s41436-020-0880-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605438PMC
November 2020

Population-based Screening for in Metastatic Colorectal Cancer Reveals Increased Prevalence and Poor Prognosis.

Clin Cancer Res 2020 09 22;26(17):4599-4605. Epub 2020 Jun 22.

BC Cancer, Vancouver, British Columbia, Canada.

Purpose: mutations portend poor prognosis in metastatic colorectal cancer (mCRC); however, the true prevalence and prognosis are unknown, as unwell patients may not undergo sequencing.

Experimental Design: We reviewed a population-based cohort of 1,898 patients with colorectal cancer that underwent reflexive IHC mismatch repair (MMR) and testing. Outcomes among IHC-detected mCRC ( ) were compared with patients with next-generation sequencing (NGS)-identified -mutated mCRC from two institutions ( ) with patients spanning from 2004 to 2018.

Results: All-stage population prevalence of was 12.5% (238/1,898) and did not differ between early and metastatic stages ( = 0.094). Prevalence among mCRC was 10.6% (61/575), of whom 51 (83.6%) were referred to oncology and 26 (42.6%) had NGS testing. had worse median overall survival (mOS) than [5.5 vs. 20.4 months; HR, 2.90; 95% confidence interval (CI), 1.89-4.45; < 0.0001], which persisted in multivariate analysis ( < 0.0001). Across a combined NGS and IHC cohort, tumors with deficient MMR showed worse mOS compared with MMR proficient tumors (8.9 vs. 17.2 months; HR, 1.46; 95% CI, 0.96-2.27; = 0.043). In this combined cohort, first-line progression-free survival was 5.9 months, with minimal differences between regimens. Within the population-based cohort, attrition between treatment lines was high with only 60.7% receiving first-line chemotherapy and 26.2% receiving second line.

Conclusions: Patients with -mutated mCRC have a worse prognosis than previously suggested, potentially arising from referral bias for testing. High attrition between lines of therapy suggests efficacious therapies need to be prioritized early for patients to benefit.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484131PMC
September 2020

Endogenous Retrovirus Transcript Levels Are Associated with Immunogenic Signatures in Multiple Metastatic Cancer Types.

Mol Cancer Ther 2020 09 9;19(9):1889-1897. Epub 2020 Jun 9.

Pancreas Centre BC, Vancouver, British Columbia, Canada.

Next-generation sequencing of solid tumors has revealed variable signatures of immunogenicity across tumors, but underlying molecular characteristics driving such variation are not fully understood. Although expression of endogenous retrovirus (ERV)-containing transcripts can provide a source of tumor-specific neoantigen in some cancer models, associations between ERV levels and immunogenicity across different types of metastatic cancer are not well established. We performed bioinformatics analysis of genomic, transcriptomic, and clinical data across an integrated cohort of 199 patients with metastatic breast, colorectal, and pancreatic ductal adenocarcinoma tumors. Within each cancer type, we identified a subgroup of viral mimicry tumors in which increased ERV levels were coupled with transcriptional signatures of autonomous antiviral response and immunogenicity. In addition, viral mimicry colorectal and pancreatic tumors showed increased expression of DNA demethylation gene Taken together, these data demonstrate the existence of an ERV-associated viral mimicry phenotype across three distinct metastatic cancer types, while indicating links between ERV abundance, epigenetic dysregulation, and immunogenicity.
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http://dx.doi.org/10.1158/1535-7163.MCT-20-0094DOI Listing
September 2020

Topography, morphology, and etiology of lymphocytic gastritis: a focus on celiac disease.

Virchows Arch 2020 Jul;477(1):167

Department of Pathology and Laboratory Medicine, Vancouver General Hospital, Vancouver, BC, Canada.

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http://dx.doi.org/10.1007/s00428-020-02847-zDOI Listing
July 2020

Loss of switch/sucrose non-fermenting complex protein expression in undifferentiated gastrointestinal and pancreatic carcinomas.

Histopathology 2020 Jul 15;77(1):46-54. Epub 2020 May 15.

Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.

Aims: Undifferentiated carcinoma refers to an epithelial malignancy that lacks morphological evidence of differentiation. Recent studies have implicated the loss of constitutively expressed switch/sucrose non-fermenting (SWI/SNF) complex subunits in undifferentiated carcinomas of the gastrointestinal tract and other sites. In this study we examine the expression of SWI/SNF and mismatch repair (MMR) proteins in a series of undifferentiated carcinomas from the gastrointestinal tract and the pancreas.

Methods And Results: We searched pathology databases from four Canadian health centres for primary undifferentiated carcinoma from gastrointestinal and pancreatic resection specimens. Upon review of 31 cases, 19 were confirmed to be undifferentiated carcinomas (eight colonic, six gastric, three pancreatic, one appendiceal and one duodenal). Immunohistochemical analysis of SMARCA4, SMARCA2, SMARCB1, ARID1A, ARID1B, MSH2, MSH6, MLH1 and PMS2 was performed on whole sections. Five of 19 (26%) showed loss of core SWI/SNF proteins (two loss of SMARCA4, one loss of SMARCB1 and two concurrent loss of ARID1A and ARID1B). SMARCA4, SMARCB1, or ARID1A/ARID1B-deficient undifferentiated carcinoma consistently exhibited sheet-like growth pattern, with cellular discohesion and rhabdoid morphology. Nine of 17 undifferentiated carcinomas tested were MMR-deficient by immunohistochemistry. In comparison, none of the 12 poorly differentiated carcinomas that were originally diagnosed as undifferentiated carcinomas showed loss of SMARCA4, SMARCA2, SMARCB1 or ARID1B.

Conclusions: Undifferentiated gastrointestinal/pancreatic carcinomas show frequent loss of expression of SWI/SNF complex proteins. The loss of these core components of SWI/SNF complex may contribute to the arrest of cellular differentiation, resulting in the undifferentiated histology and aggressive clinical behaviour.
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http://dx.doi.org/10.1111/his.14096DOI Listing
July 2020

Burden of hereditary cancer susceptibility in unselected patients with pancreatic ductal adenocarcinoma referred for germline screening.

Cancer Med 2020 06 7;9(11):4004-4013. Epub 2020 Apr 7.

Hereditary Cancer Program, BC Cancer, part of Provincial Health Services Authority, Vancouver, BC, Canada.

Background: Recent guidelines recommend consideration of germline testing for all newly diagnosed pancreatic ductal adenocarcinoma (PDAC). The primary aim of this study was to determine the burden of hereditary cancer susceptibility in PDAC. A secondary aim was to compare genetic testing uptake rates across different modes of genetic counselling.

Patients And Methods: All patients diagnosed with PDAC in the province of British Columbia, Canada referred to a population-based hereditary cancer program were eligible for multi-gene panel testing, irrespective of cancer family history. Any healthcare provider or patients themselves could refer.

Results: A total of 305 patients with PDAC were referred between July 2016 and January 2019. Two hundred thirty-five patients attended a consultation and 177 completed index germline genetic testing. 25/177 (14.1%) of unrelated patients had a pathogenic variant (PV); 19/25 PV were in known PDAC susceptibility genes with cancer screening or risk-reduction implications. PDAC was significantly associated with PV in ATM (OR, 7.73; 95% CI, 3.10 to 19.33, P = 6.14E-05) when comparing age and gender and ethnicity-matched controls tested on the same platform. The overall uptake rate for index testing was 59.2% and was significantly higher with 1-on-1 consultations and group consultations compared to telehealth consultations (88.9% vs 82.9% vs 61.8%, P < .001).

Conclusion: In a prospective clinic-based cohort of patients with PDAC referred for testing irrespective of family history, germline PV were detected in 14.1%. PV in ATM accounted for half of all PVs and were significantly associated with PDAC. These findings support recent guidelines and will guide future service planning in this population.
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http://dx.doi.org/10.1002/cam4.2973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286471PMC
June 2020

PRDM3 attenuates pancreatitis and pancreatic tumorigenesis by regulating inflammatory response.

Cell Death Dis 2020 03 16;11(3):187. Epub 2020 Mar 16.

Cancer Centre, Faculty of Health Sciences, University of Macau, 999078, Macau SAR, China.

Pancreatic ductal adenocarcinoma (PDAC) is associated with metaplastic changes in the pancreas but the transcriptional program underlying these changes is incompletely understood. The zinc finger transcription factor, PRDM3, is lowly expressed in normal pancreatic acini and its expression increases during tumorigenesis. Although PRDM3 promotes proliferation and migration of PDAC cell lines, the role of PRDM3 during tumor initiation from pancreatic acinar cells in vivo is unclear. In this study, we showed that high levels of PRDM3 expression in human pancreas was associated with pancreatitis, and well-differentiated but not poorly differentiated carcinoma. We examined PRDM3 function in pancreatic acinar cells during tumor formation and pancreatitis by inactivating Prdm3 using a conditional allele (Ptf1a;Prdm3 mice) in the context of oncogenic Kras expression and supraphysiological cerulein injections, respectively. In Prdm3-deficient mice, Kras-driven preneoplastic lesions were more abundant and progressed to high-grade precancerous lesions more rapidly. This is consistent with our observations that low levels of PRDM3 in human PDAC was correlated significantly with poorer survival in patient. Moreover, loss of Prdm3 in acinar cells elevated exocrine injury, enhanced immune cell activation and infiltration, and greatly increased acinar-to-ductal cell reprogramming upon cerulein-induced pancreatitis. Whole transcriptome analyses of Prdm3 knockout acini revealed that pathways involved in inflammatory response and Hif-1 signaling were significantly upregulated in Prdm3-depleted acinar cells. Taken together, our results suggest that Prdm3 favors the maintenance of acinar cell homeostasis through modulation of their response to inflammation and oncogenic Kras activation, and thus plays a previously unexpected suppressive role during PDAC initiation.
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http://dx.doi.org/10.1038/s41419-020-2371-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7075911PMC
March 2020
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