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Organisations and governments seeking to implement genomics into clinical practice face numerous challenges across multiple, diverse aspects of the health care system. It is not sufficient to tackle any one aspect in isolation: to create a system that supports genomic medicine, they must be addressed simultaneously. The growing body of global knowledge can guide decision-making, but each jurisdiction or organisation needs a model for genomic (or personalised) medicine that is tailored to its unique context, its priorities and the funds available. Poor decisions could greatly reduce the benefits that could potentially arise from genomic medicine. Demonstration projects enable models to be tested, providing valuable evidence and experience for subsequent implementation. Here, we present the Melbourne Genomics Health Alliance demonstration project as an exemplar of a collaborative, holistic approach to phased implementation of genomics across multiple autonomous institutions. The approach and lessons learned may assist others in determining how best to integrate genomics into their healthcare system.

Background Germ-line mutations in the exonuclease domains of the POLE and POLD1 genes are associated with an increased, but yet unquantified, risk of colorectal cancer (CRC). Methods We identified families with POLE or POLD1 variants by searching PubMed for relevant studies prior to October 2016 and by genotyping 669 population-based CRC cases diagnosed in patients under 60 years of age, from the Australasian Colorectal Cancer Family Registry. We estimated the age-specific cumulative risks (penetrance) using a modified segregation analysis. Results We observed 67 CRCs (mean age at diagnosis = 50.2 (SD = 13.8) years) among 364 first- and second- degree relatives from 41 POLE families, and 6 CRCs (mean age at diagnosis = 39.7 (SD = 6.83) years) among 69 relatives from 9 POLD1 families. We estimated risks of CRC up to the age of 70 years (95% confidence interval) for males and females, respectively, to be 40% (26–57%) and 32% (20–47%) for POLE mutation carriers and 63% (15–99%) and 52% (11–99%) for POLD1 mutation carriers. Conclusion CRC risks for POLE mutation carriers are sufficiently high to warrant consideration of annual colonoscopy screening and implementation of management guidelines comparable to those applied in cases of Lynch syndrome. Refinement of estimates of CRC risk for POLD1 carriers is needed; however, clinical management recommendations could follow those made for POLE carriers.

Background Multigene panel tests for breast cancer predisposition routinely include ATM as it is now a well-established breast cancer predisposition gene. Methods We included ATM in a multigene panel test applied to the Australian Breast Cancer Family Registry (ABCFR), a population-based case–control–family study of breast cancer, with the purpose of estimating the prevalence and penetrance of heterozygous ATM pathogenic variants from the family data, using segregation analysis. Results The estimated breast cancer hazard ratio for carriers of pathogenic ATM variants in the ABCFR was 1.32 (95% confidence interval 0.45–3.87; P  = 0.6). The estimated cumulative risk of breast cancer to age 80 years for heterozygous  ATM pathogenic variant carriers was estimated to be 13% (95% CI 4.6–30). Conclusions Although ATM has been definitively identified as a breast cancer predisposition gene, further evidence, such as variant-specific penetrance estimates, are needed to inform risk management strategies for carriers of pathogenic variants to increase the clinical utility of population testing of this gene.

This letter indicates that immunohistochemical analysis to detect succinic dehydrogenase subunit B (SDHB) protein can screen renal tumors for underlying SDHB germline mutations at a fraction of the time and cost of formal genetic testing. To the Editor: The genes for the succinate dehydrogenase subunits A, B, C, and D ( SDHA, SDHB, SDHC, and SDHD, respectively) encode proteins that form part of the mitochondrial complex II, which links the Krebs cycle and the electron-transport chain. Heterozygous germline mutations of SDHB, SDHC, and SDHD cause the well-characterized familial pheochromocytoma-paraganglioma syndromes known respectively as PGL4, PGL3, and PGL1. 1 SDHB, SDHC, and SDHD mutations have also been linked to gastrointestinal stromal tumor, and SDHB and SDHD have been linked to renal-cell carcinoma. These kindreds are rarely recognized when they present with gastrointestinal stromal tumor and they are . . .

The Ehlers-Danlos syndromes (EDS) comprise a group of inherited connective tissue disorders presenting with variable fragility to skin, soft tissue, and certain internal organs, which can cause significant complications, particularly arterial rupture, bowel perforation and joint difficulties. Currently, there are 14 proposed subtypes of EDS, with all except one subtype (hypermobile EDS) having an identified genetic etiology. An understanding of the extracutaneous features and complications within each subtype is key to maximizing clinical care and reducing the risk of further complications. A systematic review of EDS-related extracutaneous features and complications was undertaken. We identified 839 EDS cases that met the inclusion criteria. We noted a high prevalence of joint hypermobility amongst kyphoscoliotic (39/39, 100%), spondylodysplastic (24/25, 96.0%), and hypermobile (153/160, 95.6%) EDS subtypes. The most common musculoskeletal complications were decreased bone density (39/43, 90.7%), joint pain (217/270, 80.4%), and hypotonia/weakness (79/140, 56.4%). Vascular EDS presented with cerebrovascular events (25/153, 16.3%), aneurysm (77/245, 31.4%), arterial dissection/rupture (89/250, 35.5%), and pneumothorax/hemothorax. Chronic pain was the most common miscellaneous complication, disproportionately affecting hypermobile EDS patients (139/157, 88.5%). Hypermobile EDS cases also presented with chronic fatigue (61/63, 96.8%) and gastrointestinal complications (57/63, 90.5%). Neuropsychiatric complications were noted in almost all subtypes. Understanding the extracutaneous features and complications of each EDS subtype may help diagnose and treat EDS prior to the development of substantial comorbidities and/or additional complications. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022308151, identifier CRD42022308151.

Genetic susceptibility to familial colorectal cancer (CRC), including for individuals classified as Familial Colorectal Cancer Type X (FCCTX), remains poorly understood. We describe a multi-generation CRC-affected family segregating pathogenic variants in both BRCA1 , a gene associated with breast and ovarian cancer and RNF43 , a gene associated with Serrated Polyposis Syndrome (SPS). A single family out of 105 families meeting the criteria for FCCTX (Amsterdam I family history criteria with mismatch repair (MMR)-proficient CRCs) recruited to the Australasian Colorectal Cancer Family Registry (ACCFR; 1998–2008) that underwent whole exome sequencing (WES), was selected for further testing. CRC and polyp tissue from four carriers were molecularly characterized including a single CRC that underwent WES to determine tumor mutational signatures and loss of heterozygosity (LOH) events. Ten carriers of a germline pathogenic variant BRCA1 :c.2681_2682delAA p.Lys894ThrfsTer8 and eight carriers of a germline pathogenic variant RNF43 :c.988 C > T p.Arg330Ter were identified in this family. Seven members carried both variants, four of which developed CRC. A single carrier of the RNF43 variant met the 2019 World Health Organization (WHO 2019 ) criteria for SPS, developing a BRAF p.V600 wildtype CRC. Loss of the wildtype allele for both BRCA1 and RNF43 variants was observed in three CRC tumors while a LOH event across chromosome 17q encompassing both genes was observed in a CRC. Tumor mutational signature analysis identified the homologous recombination deficiency (HRD)-associated COSMIC signatures SBS3 and ID6 in a CRC for a carrier of both variants. Our findings show digenic inheritance of pathogenic variants in BRCA1 and RNF43 segregating with CRC in a FCCTX family. LOH and evidence of BRCA1-associated HRD supports the importance of both these tumor suppressor genes in CRC tumorigenesis.

The Australian National Bowel Cancer Screening Programme (NBCSP) was introduced in 2006. When fully implemented, the programme will invite people aged 50 to 74 to complete an immunochemical faecal occult blood test (iFOBT) every 2 years. To investigate colorectal cancer (CRC) screening occurring outside of the NBCSP, we classified participants (n = 2,480) in the Australasian Colorectal Cancer Family Registry (ACCFR) into 3 risk categories (average, moderately increased, and potentially high) based on CRC family history and assessed their screening practices according to national guidelines. We developed a microsimulation to compare hypothetical screening scenarios (70% and 100% uptake) to current participation levels (baseline) and evaluated clinical outcomes and cost for each risk category. The 2 main limitations of this study are as follows: first, the fact that our cost-effectiveness analysis was performed from a third-party payer perspective, which does not include indirect costs and results in overestimated cost-effectiveness ratios, and second, that our natural history model of CRC does not include polyp sojourn time, which determines the rate of cancerous transformation. Screening uptake was low across all family history risk categories (64%-56% reported no screening). For participants at average risk, 18% reported overscreening, while 37% of those in the highest risk categories screened according to guidelines. Higher screening levels would substantially reduce CRC mortality across all risk categories (95 to 305 fewer deaths per 100,000 persons in the 70% scenario versus baseline). For those at average risk, a fully implemented NBCSP represented the most cost-effective approach to prevent CRC deaths (AUS$13,000-16,000 per quality-adjusted life year [QALY]). For those at moderately increased risk, higher adherence to recommended screening was also highly cost-effective (AUS$19,000-24,000 per QALY). Investing in public health strategies to increase adherence to appropriate CRC screening will save lives and deliver high value for money.

Background MLH1 epimutation is characterised by constitutional monoallelic MLH1 promoter hypermethylation, which can cause colorectal cancer (CRC). Tumour molecular profiles of MLH1 epimutation CRCs were used to classify germline MLH1 promoter variants of uncertain significance and MLH1 methylated early-onset CRCs (EOCRCs). Genome-wide DNA methylation and somatic mutational profiles of tumours from two germline MLH1 : c.-11C > T and one MLH1 : c.-[28A > G; 7C > T] carriers and three MLH1 methylated EOCRCs (< 45 years) were compared with 38 reference CRCs. Methylation-sensitive droplet digital PCR (ddPCR) was used to detect mosaic MLH1 methylation in blood, normal mucosa and buccal DNA. Results Genome-wide methylation-based Consensus Clustering identified four clusters where the tumour methylation profiles of germline MLH1 : c.-11C > T carriers and MLH1 methylated EOCRCs clustered with the constitutional MLH1 epimutation CRCs but not with the sporadic MLH1 methylated CRCs. Furthermore, monoallelic MLH1 methylation and APC promoter hypermethylation in tumour were observed in both MLH1 epimutation and germline MLH1 : c.-11C > T carriers and MLH1 methylated EOCRCs. Mosaic constitutional MLH1 methylation in MLH1 : c.-11C > T carriers and 1 of 3 MLH1 methylated EOCRCs was identified by methylation-sensitive ddPCR. Conclusions Mosaic MLH1 epimutation underlies the CRC aetiology in MLH1 : c.-11C > T germline carriers and a subset of MLH1 methylated EOCRCs. Tumour profiling and ultra-sensitive ddPCR methylation testing can be used to identify mosaic MLH1 epimutation carriers.

Objective The unknown aetiology of Serrated Polyposis Syndrome (SPS) impedes risk prediction and prevention. We investigated risk factors for SPS, overall and stratified by World Health Organization (WHO) 2010 clinical criteria and by colorectal cancer (CRC). Method A retrospective case-control study involving a cross-sectional analysis from 350 unrelated individuals with SPS from the Genetics of Colonic Polyposis Study and 714 controls from the Australasian Colorectal Cancer Family Registry. Univariate and multivariate logistic regression modelling was used to determine the association between risk factors and SPS and risk factors associated with CRC in SPS. Results Female biological sex (odds ratio (OR) = 4.54; 95%Confidence interval (CI) = 2.77–7.45), increasing body mass index (BMI) at age 20 years (OR = 1.09; 95%CI = 1.04–1.13), hormone replacement therapy (OR = 0.44; 95%CI = 0.20.98), and increasing weekly folate intake (OR = 0.82; 95%CI = 0.75–0.90) were associated with SPS by multivariate analysis. Increasing weekly calcium intake (OR = 0.79; 95%CI = 0.64–0.97) and smoking > 10 cigarettes daily (OR = 0.45; 95%CI = 0.23–0.86) were associated with WHO criterion I only. The consumption of 1-100 g of alcohol per week (OR = 0.39; 95%CI = 0.18–0.83) was associated with WHO criterion III only. Smoking 1–5 cigarettes daily (OR = 2.35; 95%CI = 1.09–5.05), weekly non-steroidal anti-inflammatory drug (NSAIDs) intake (OR = 0.88; 95%CI = 0.78–0.99), and increased height (OR = 1.09; 95% = 1.05–1.13), were associated with SPS fulfilling both WHO criteria I and III. Moreover, weekly NSAIDs intake (OR = 0.81; 95%CI = 0.67–0.98) was associated with a reduced likelihood of CRC in SPS. Conclusion We identified novel risk and potential protective factors associated with SPS, some specific for certain WHO 2010 criteria. Weekly use of NSAIDs may reduce the risk of CRC in people with SPS.

Abstract The Ehlers-Danlos syndromes (EDS) comprise a group of inherited connective tissue disorders presenting with features of skin hyperextensibility, joint hypermobility, abnormal scarring and fragility of skin, blood vessels and some organs. The disease is generally diagnosed through the cluster of clinical features, though the addition of genetic analysis is the gold standard for diagnosis of most subtypes. All subtypes display skin manifestations, which are essential to the accurate clinical diagnosis of the condition. Furthermore, cutaneous features can be the first and/or only presenting feature in some cases of EDS and thus understanding these signs is vital for diagnosis. This review focuses on particular cutaneous features of each EDS subtype and their clinical importance. Provision of a specific diagnosis is important for management, prognosis and genetic counselling, often for family members beyond the individual.