Clinical Pathology - Research Publications

Permanent URI for this collection

http://hdl.handle.net/11343/197951

Search Results

Now showing 1 - 10 of 1489

The Colorectal cancer RISk Prediction (CRISP) trial

Emery, JD ; Jenkins, MA ; Saya, S ; Chondros, P ; Oberoi, J ; Milton, S ; Novy, K ; Habgood, E ; Karnchanachari, N ; Pirotta, M ; Trevena, L ; Bickerstaffe, A ; Lourenco, RD ; Crothers, A ; Ouakrim, D ; Flander, L ; Dowty, JG ; Walter, FM ; Clark, M ; Doncovio, S ; Etemadmoghadam, D ; Fishman, G ; Macrae, F ; Winship, I ; McIntosh, JG (ROYAL COLL GENERAL PRACTITIONERS, 2023-08)

BACKGROUND: A risk-stratified approach to colorectal cancer (CRC) screening could result in a more acceptable balance of benefits and harms, and be more cost-effective. AIM: To determine the effect of a consultation in general practice using a computerised risk assessment and decision support tool (Colorectal cancer RISk Prediction, CRISP) on risk-appropriate CRC screening. DESIGN AND SETTING: Randomised controlled trial in 10 general practices in Melbourne, Australia, from May 2017 to May 2018. METHOD: Participants were recruited from a consecutive sample of patients aged 50-74 years attending their GP. Intervention consultations included CRC risk assessment using the CRISP tool and discussion of CRC screening recommendations. Control group consultations focused on lifestyle CRC risk factors. The primary outcome was risk-appropriate CRC screening at 12 months. RESULTS: A total of 734 participants (65.1% of eligible patients) were randomised (369 intervention, 365 control); the primary outcome was determined for 722 (362 intervention, 360 control). There was a 6.5% absolute increase (95% confidence interval [CI] = -0.28 to 13.2) in risk-appropriate screening in the intervention compared with the control group (71.5% versus 65.0%; odds ratio [OR] 1.36, 95% CI = 0.99 to 1.86, P = 0.057). In those due CRC screening during follow-up, there was a 20.3% (95% CI = 10.3 to 30.4) increase (intervention 59.8% versus control 38.9%; OR 2.31, 95% CI = 1.51 to 3.53, P<0.001) principally by increasing faecal occult blood testing in those at average risk. CONCLUSION: A risk assessment and decision support tool increases risk-appropriate CRC screening in those due screening. The CRISP intervention could commence in people in their fifth decade to ensure people start CRC screening at the optimal age with the most cost-effective test.
Spectrum and Frequency of Germline FANCM Protein-Truncating Variants in 44,803 European Female Breast Cancer Cases.

Figlioli, G ; Billaud, A ; Wang, Q ; Bolla, MK ; Dennis, J ; Lush, M ; Kvist, A ; Adank, MA ; Ahearn, TU ; Antonenkova, NN ; Auvinen, P ; Behrens, S ; Bermisheva, M ; Bogdanova, NV ; Bojesen, SE ; Bonanni, B ; Brüning, T ; Camp, NJ ; Campbell, A ; Castelao, JE ; Cessna, MH ; Nbcs Collaborators, ; Czene, K ; Devilee, P ; Dörk, T ; Eriksson, M ; Fasching, PA ; Flyger, H ; Gabrielson, M ; Gago-Dominguez, M ; García-Closas, M ; Glendon, G ; Gómez Garcia, EB ; González-Neira, A ; Grassmann, F ; Guénel, P ; Hahnen, E ; Hamann, U ; Hillemanns, P ; Hooning, MJ ; Hoppe, R ; Howell, A ; Humphreys, K ; kConFab Investigators, ; Jakubowska, A ; Khusnutdinova, EK ; Kristensen, VN ; Lindblom, A ; Loizidou, MA ; Lubiński, J ; Mannermaa, A ; Maurer, T ; Mavroudis, D ; Newman, WG ; Obi, N ; Panayiotidis, MI ; Radice, P ; Rashid, MU ; Rhenius, V ; Ruebner, M ; Saloustros, E ; Sawyer, EJ ; Schmidt, MK ; Schmutzler, RK ; Shah, M ; Southey, MC ; Tomlinson, I ; Truong, T ; van Veen, EM ; Wendt, C ; Yang, XR ; Michailidou, K ; Dunning, AM ; Pharoah, PDP ; Easton, DF ; Andrulis, IL ; Evans, DG ; Hollestelle, A ; Chang-Claude, J ; Milne, RL ; Peterlongo, P (MDPI AG, 2023-06-23)

FANCM germline protein truncating variants (PTVs) are moderate-risk factors for ER-negative breast cancer. We previously described the spectrum of FANCM PTVs in 114 European breast cancer cases. In the present, larger cohort, we report the spectrum and frequency of four common and 62 rare FANCM PTVs found in 274 carriers detected among 44,803 breast cancer cases. We confirmed that p.Gln1701* was the most common PTV in Northern Europe with lower frequencies in Southern Europe. In contrast, p.Gly1906Alafs*12 was the most common PTV in Southern Europe with decreasing frequencies in Central and Northern Europe. We verified that p.Arg658* was prevalent in Central Europe and had highest frequencies in Eastern Europe. We also confirmed that the fourth most common PTV, p.Gln498Thrfs*7, might be a founder variant from Lithuania. Based on the frequency distribution of the carriers of rare PTVs, we showed that the FANCM PTVs spectra in Southwestern and Central Europe were much more heterogeneous than those from Northeastern Europe. These findings will inform the development of more efficient FANCM genetic testing strategies for breast cancer cases from specific European populations.
DNA Mismatch Repair Gene Variant Classification: Evaluating the Utility of Somatic Mutations and Mismatch Repair Deficient Colonic Crypts and Endometrial Glands

Walker, R ; Mahmood, K ; Como, J ; Clendenning, M ; Joo, JE ; Georgeson, P ; Joseland, S ; Preston, SG ; Pope, BJ ; Chan, JM ; Austin, R ; Bojadzieva, J ; Campbell, A ; Edwards, E ; Gleeson, M ; Goodwin, A ; Harris, MT ; Ip, E ; Kirk, J ; Mansour, J ; Fan, HM ; Nichols, C ; Pachter, N ; Ragunathan, A ; Spigelman, A ; Susman, R ; Christie, M ; Jenkins, MA ; Pai, RK ; Rosty, C ; Macrae, FA ; Winship, IM ; Buchanan, DD ; ANGELS, S (MDPI, 2023-10)

Germline pathogenic variants in the DNA mismatch repair (MMR) genes (Lynch syndrome) predispose to colorectal (CRC) and endometrial (EC) cancer. Lynch syndrome specific tumor features were evaluated for their ability to support the ACMG/InSiGHT framework in classifying variants of uncertain clinical significance (VUS) in the MMR genes. Twenty-eight CRC or EC tumors from 25 VUS carriers (6xMLH1, 9xMSH2, 6xMSH6, 4xPMS2), underwent targeted tumor sequencing for the presence of microsatellite instability/MMR-deficiency (MSI-H/dMMR) status and identification of a somatic MMR mutation (second hit). Immunohistochemical testing for the presence of dMMR crypts/glands in normal tissue was also performed. The ACMG/InSiGHT framework reclassified 7/25 (28%) VUS to likely pathogenic (LP), three (12%) to benign/likely benign, and 15 (60%) VUS remained unchanged. For the seven re-classified LP variants comprising nine tumors, tumor sequencing confirmed MSI-H/dMMR (8/9, 88.9%) and a second hit (7/9, 77.8%). Of these LP reclassified variants where normal tissue was available, the presence of a dMMR crypt/gland was found in 2/4 (50%). Furthermore, a dMMR endometrial gland in a carrier of an MSH2 exon 1-6 duplication provides further support for an upgrade of this VUS to LP. Our study confirmed that identifying these Lynch syndrome features can improve MMR variant classification, enabling optimal clinical care.
A Matched Molecular and Clinical Analysis of the Epithelioid Haemangioendothelioma Cohort in the Stafford Fox Rare Cancer Program and Contextual Literature Review

Abdelmogod, A ; Papadopoulos, L ; Riordan, S ; Wong, M ; Weltman, M ; Lim, R ; Mcevoy, C ; Fellowes, A ; Fox, S ; Bedo, J ; Penington, J ; Pham, K ; Hofmann, O ; Vissers, JHA ; Grimmond, S ; Ratnayake, G ; Christie, M ; Mitchell, C ; Murray, WK ; Mcclymont, K ; Luk, P ; Papenfuss, AT ; Kee, D ; Scott, CL ; Goldstein, D ; Barker, HE (MDPI, 2023-09)

BACKGROUND: Epithelioid haemangioendothelioma (EHE) is an ultra-rare malignant vascular tumour with a prevalence of 1 per 1,000,000. It is typically molecularly characterised by a WWTR1::CAMTA1 gene fusion in approximately 90% of cases, or a YAP1::TFE3 gene fusion in approximately 10% of cases. EHE cases are typically refractory to therapies, and no anticancer agents are reimbursed for EHE in Australia. METHODS: We report a cohort of nine EHE cases with comprehensive histologic and molecular profiling from the Walter and Eliza Hall Institute of Medical Research Stafford Fox Rare Cancer Program (WEHI-SFRCP) collated via nation-wide referral to the Australian Rare Cancer (ARC) Portal. The diagnoses of EHE were confirmed by histopathological and immunohistochemical (IHC) examination. Molecular profiling was performed using the TruSight Oncology 500 assay, the TruSight RNA fusion panel, whole genome sequencing (WGS), or whole exome sequencing (WES). RESULTS: Molecular analysis of RNA, DNA or both was possible in seven of nine cases. The WWTR1::CAMTA1 fusion was identified in five cases. The YAP1::TFE3 fusion was identified in one case, demonstrating unique morphology compared to cases with the more common WWTR1::CAMTA1 fusion. All tumours expressed typical endothelial markers CD31, ERG, and CD34 and were negative for pan-cytokeratin. Cases with a WWTR1::CAMTA1 fusion displayed high expression of CAMTA1 and the single case with a YAP1::TFE3 fusion displayed high expression of TFE3. Survival was highly variable and unrelated to molecular profile. CONCLUSIONS: This cohort of EHE cases provides molecular and histopathological characterisation and matching clinical information that emphasises the molecular patterns and variable clinical outcomes and adds to our knowledge of this ultra-rare cancer. Such information from multiple studies will advance our understanding, potentially improving treatment options.
Effectiveness of Opioid Switching in Advanced Cancer Pain: A Prospective Observational Cohort Study

Wong, AKK ; Somogyi, AA ; Rubio, J ; Pham, TD ; Le, B ; Klepstad, P ; Philip, J (MDPI, 2023-07)

Opioid switching is a common practice of substituting one opioid for another to improve analgesia or adverse effects; however, it has limited evidence. This study aimed to examine the effectiveness of opioid switching in advanced cancer. This multi-center prospective cohort study recruited patients assessed to switch opioids (opioid switch group) or to continue ongoing opioid treatment (control group). Clinical data (demographics, opioids) and validated instruments (pain and adverse effects) were collected over two timepoints seven days apart. Descriptive analyses were utilized. Non-parametric tests were used to determine differences. Fifty-four participants were recruited (23 control group, 31 switch group). At the follow-up, opioid switching reduced pain (worst, average, and now) (p < 0.05), uncontrolled breakthrough pain (3-fold reduction, p = 0.008), and psychological distress (48% to 16%, p < 0.005). The switch group had a ≥25% reduction in the reported frequency of seven moderate-to-severe adverse effects (score ≥ 4), compared to a reduction in only one adverse effect in the control group. The control group experienced no significant pain differences at the follow-up. Opioid switching is effective at reducing pain, adverse effects, and psychological distress in a population with advanced cancer pain, to levels of satisfactory symptom control in most patients within 1 week.
Causal relationships between breast cancer risk factors based on mammographic features

Ye, Z ; Nguyen, TL ; Dite, GS ; Macinnis, RJ ; Schmidt, DF ; Makalic, E ; Al-Qershi, OM ; Bui, M ; Esser, VFC ; Dowty, JG ; Trinh, HN ; Evans, CF ; Tan, M ; Sung, J ; Jenkins, MA ; Giles, GG ; Southey, MC ; Hopper, JL ; Li, S (BMC, 2023-10-25)

BACKGROUND: Mammogram risk scores based on texture and density defined by different brightness thresholds are associated with breast cancer risk differently and could reveal distinct information about breast cancer risk. We aimed to investigate causal relationships between these intercorrelated mammogram risk scores to determine their relevance to breast cancer aetiology. METHODS: We used digitised mammograms for 371 monozygotic twin pairs, aged 40-70 years without a prior diagnosis of breast cancer at the time of mammography, from the Australian Mammographic Density Twins and Sisters Study. We generated normalised, age-adjusted, and standardised risk scores based on textures using the Cirrus algorithm and on three spatially independent dense areas defined by increasing brightness threshold: light areas, bright areas, and brightest areas. Causal inference was made using the Inference about Causation from Examination of FAmilial CONfounding (ICE FALCON) method. RESULTS: The mammogram risk scores were correlated within twin pairs and with each other (r = 0.22-0.81; all P < 0.005). We estimated that 28-92% of the associations between the risk scores could be attributed to causal relationships between the scores, with the rest attributed to familial confounders shared by the scores. There was consistent evidence for positive causal effects: of Cirrus, light areas, and bright areas on the brightest areas (accounting for 34%, 55%, and 85% of the associations, respectively); and of light areas and bright areas on Cirrus (accounting for 37% and 28%, respectively). CONCLUSIONS: In a mammogram, the lighter (less dense) areas have a causal effect on the brightest (highly dense) areas, including through a causal pathway via textural features. These causal relationships help us gain insight into the relative aetiological importance of different mammographic features in breast cancer. For example our findings are consistent with the brightest areas being more aetiologically important than lighter areas for screen-detected breast cancer; conversely, light areas being more aetiologically important for interval breast cancer. Additionally, specific textural features capture aetiologically independent breast cancer risk information from dense areas. These findings highlight the utility of ICE FALCON and family data in decomposing the associations between intercorrelated disease biomarkers into distinct biological pathways.
Associations of height, body mass index, and weight gain with breast cancer risk in carriers of a pathogenic variant in BRCA1 or BRCA2: the BRCA1 and BRCA2 Cohort Consortium

Kast, KM ; John, EL ; Hopper, J ; Andrieu, N ; Nogues, C ; Mouret-Fourme, E ; Lasset, C ; Fricker, J-P ; Berthet, P ; Mari, V ; Salle, LK ; Schmidt, M ; Ausems, MGEM ; Garcia, EBG ; van de Beek, IR ; Wevers, M ; Evans, DG ; Tischkowitz, M ; Lalloo, F ; Cook, J ; Izatt, L ; Tripathi, V ; Snape, K ; Musgrave, H ; Sharif, S ; Murray, JV ; Colonna, SV ; Andrulis, IL ; Daly, MB ; Southey, MC ; de la Hoya, M ; Osorio, A ; Foretova, L ; Berkova, D ; Gerdes, A-M ; Olah, E ; Jakubowska, A ; Singer, CF ; Tan, Y ; Augustinsson, A ; Rantala, J ; Simard, J ; Schmutzler, RK ; Milne, RL ; Phillips, K-A ; Terry, MB ; Goldgar, D ; van Leeuwen, FE ; Mooij, TM ; Antoniou, AC ; Easton, DF ; Rookus, MA ; Engel, C (BMC, 2023-06-20)

INTRODUCTION: Height, body mass index (BMI), and weight gain are associated with breast cancer risk in the general population. It is unclear whether these associations also exist for carriers of pathogenic variants in the BRCA1 or BRCA2 genes. PATIENTS AND METHODS: An international pooled cohort of 8091 BRCA1/2 variant carriers was used for retrospective and prospective analyses separately for premenopausal and postmenopausal women. Cox regression was used to estimate breast cancer risk associations with height, BMI, and weight change. RESULTS: In the retrospective analysis, taller height was associated with risk of premenopausal breast cancer for BRCA2 variant carriers (HR 1.20 per 10 cm increase, 95% CI 1.04-1.38). Higher young-adult BMI was associated with lower premenopausal breast cancer risk for both BRCA1 (HR 0.75 per 5 kg/m2, 95% CI 0.66-0.84) and BRCA2 (HR 0.76, 95% CI 0.65-0.89) variant carriers in the retrospective analysis, with consistent, though not statistically significant, findings from the prospective analysis. In the prospective analysis, higher BMI and adult weight gain were associated with higher postmenopausal breast cancer risk for BRCA1 carriers (HR 1.20 per 5 kg/m2, 95% CI 1.02-1.42; and HR 1.10 per 5 kg weight gain, 95% CI 1.01-1.19, respectively). CONCLUSION: Anthropometric measures are associated with breast cancer risk for BRCA1 and BRCA2 variant carriers, with relative risk estimates that are generally consistent with those for women from the general population.
Preexisting immunity restricts mucosal antibody recognition of SARS-CoV-2 and Fc profiles during breakthrough infections

Selva, KJ ; Ramanathan, P ; Haycroft, ER ; Reynaldi, A ; Cromer, D ; Tan, CW ; Wang, L-F ; Wines, BD ; Hogarth, PM ; Downie, LE ; Davis, SK ; Purcell, RA ; Kent, HE ; Juno, JA ; Wheatley, AK ; Davenport, MP ; Kent, SJ ; Chung, AW (AMER SOC CLINICAL INVESTIGATION INC, 2023-09-22)

Understanding mucosal antibody responses from SARS-CoV-2 infection and/or vaccination is crucial to develop strategies for longer term immunity, especially against emerging viral variants. We profiled serial paired mucosal and plasma antibodies from COVID-19 vaccinated only vaccinees (vaccinated, uninfected), COVID-19-recovered vaccinees (recovered, vaccinated), and individuals with breakthrough Delta or Omicron BA.2 infections (vaccinated, infected). Saliva from COVID-19-recovered vaccinees displayed improved antibody-neutralizing activity, Fcγ receptor (FcγR) engagement, and IgA levels compared with COVID-19-uninfected vaccinees. Furthermore, repeated mRNA vaccination boosted SARS-CoV-2-specific IgG2 and IgG4 responses in both mucosa biofluids (saliva and tears) and plasma; however, these rises only negatively correlated with FcγR engagement in plasma. IgG and FcγR engagement, but not IgA, responses to breakthrough COVID-19 variants were dampened and narrowed by increased preexisting vaccine-induced immunity against the ancestral strain. Salivary antibodies delayed initiation following breakthrough COVID-19 infection, especially Omicron BA.2, but rose rapidly thereafter. Importantly, salivary antibody FcγR engagements were enhanced following breakthrough infections. Our data highlight how preexisting immunity shapes mucosal SARS-CoV-2-specific antibody responses and has implications for long-term protection from COVID-19.
A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk

Aglago, EK ; Kim, A ; Lin, Y ; Qu, C ; Evangelou, M ; Ren, Y ; Morrison, J ; Albanes, D ; Arndt, V ; Barry, EL ; Baurley, JW ; Berndt, S ; Bien, SA ; Bishop, DT ; Bouras, E ; Brenner, H ; Buchanan, DD ; Budiarto, A ; Carreras-Torres, R ; Casey, G ; Cenggoro, TW ; Chen, AT ; Chang-Claude, J ; Chen, X ; Conti, D ; Devall, M ; Diez-Obrero, V ; Dimou, N ; Drew, D ; Figueiredo, JC ; Gallinger, S ; Giles, GG ; Gruber, SB ; Gsur, A ; Gunter, MJ ; Hampel, H ; Harlid, S ; Hidaka, A ; Harrison, TA ; Hoffmeister, M ; Huyghe, JR ; Jenkins, MA ; Jordahl, K ; Joshi, AD ; Kawaguchi, ES ; Keku, TO ; Kundaje, A ; Larsson, SC ; Le Marchand, L ; Lewinger, JP ; Li, L ; Lynch, BM ; Mahesworo, B ; Mandic, M ; Obon-Santacana, M ; Morento, V ; Murphy, N ; Men, H ; Nassir, R ; Newcomb, PA ; Ogino, S ; Ose, J ; Pai, RK ; Palmer, JR ; Papadimitriou, N ; Pardamean, B ; Peoples, AR ; Platz, EA ; Potter, JD ; Prentice, RL ; Rennert, G ; Ruiz-Narvaez, E ; Sakoda, LC ; Scacheri, PC ; Schmit, SL ; Schoen, RE ; Shcherbina, A ; Slattery, ML ; Stern, MC ; Su, Y-R ; Tangen, CM ; Thibodeau, SN ; Thomas, DC ; Tian, Y ; Ulrich, CM ; van Duijnhoven, FJB ; Van Guelpen, B ; Visvanathan, K ; Vodicka, P ; Wang, J ; White, E ; Wolk, A ; Woods, MO ; Wu, AH ; Zemlianskaia, N ; Hsu, L ; Gauderman, WJ ; Peters, U ; Tsilidis, KK ; Campbell, PT (AMER ASSOC CANCER RESEARCH, 2023-08-01)

UNLABELLED: Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Gene-environment interactions (G × E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G × E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G × E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G × E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant G×BMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer. SIGNIFICANCE: This gene-environment interaction analysis revealed a genetic locus in FMN1/GREM1 that interacts with body mass index in colorectal cancer risk, suggesting potential implications for precision prevention strategies.
Two-step offer and return of multiple types of additional genomic findings to families after ultrarapid trio genomic testing in the acute care setting: a study protocol.

Bouffler, SE ; Lee, L ; Lynch, F ; Martyn, M ; Lynch, E ; Macciocca, I ; Curnow, L ; McCorkell, G ; Lunke, S ; Chong, B ; Marum, JE ; Delatycki, M ; Downie, L ; Goranitis, I ; Vears, DF ; Best, S ; Clausen, M ; Bombard, Y ; Stark, Z ; Gaff, CL (BMJ, 2023-06-02)

INTRODUCTION: As routine genomic testing expands, so too does the opportunity to look for additional health information unrelated to the original reason for testing, termed additional findings (AF). Analysis for many different types of AF may be available, particularly to families undergoing trio genomic testing. The optimal model for service delivery remains to be determined, especially when the original test occurs in the acute care setting. METHODS AND ANALYSIS: Families enrolled in a national study providing ultrarapid genomic testing to critically ill children will be offered analysis for three types of AF on their stored genomic data: paediatric-onset conditions in the child, adult-onset conditions in each parent and reproductive carrier screening for the parents as a couple. The offer will be made 3-6 months after diagnostic testing. Parents will have access to a modified version of the Genetics Adviser web-based decision support tool before attending a genetic counselling appointment to discuss consent for AF. Parental experiences will be evaluated using qualitative and quantitative methods on data collected through surveys, appointment recordings and interviews at multiple time points. Evaluation will focus on parental preferences, uptake, decision support use and understanding of AF. Genetic health professionals' perspectives on acceptability and feasibility of AF will also be captured through surveys and interviews. ETHICS AND DISSEMINATION: This project received ethics approval from the Melbourne Health Human Research Ethics Committee as part of the Australian Genomics Health Alliance protocol: HREC/16/MH/251. Findings will be disseminated through peer-review journal articles and at conferences nationally and internationally.

Clinical Pathology - Research Publications

Permanent URI for this collection

Filters

Date

Author

Type

Settings

Sort By

Results per page

Statistics

Citations

Search Results