Genetic Testing Uptake Among Patients With Newly Diagnosed Breast Cancer.
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Journal Article↗
Biomedical subjects
William D Foulkes
Publications and source records attributed to William D Foulkes.
Rare solid tumours as indicators of hereditary cancer syndromes.
Rare tumours are variously defined but usually affect not more than 1 in 100000 people. They can be present at birth, in childhood or later in life. The diagnosis of a rare tumour can sometimes point to an underlying hereditary condition, and one should take into account important considerations that can increase suspicion of a genetic cause of the disease. While some rare neoplasms are highly specific of a hereditary tumour susceptibility syndrome (and can be almost pathognomonic), thus prompting a direct genetic evaluation, most rare neoplasms may appear within the context of multi-tumour susceptibility syndromes, and here they add important weight to the global assessment when considering a genetic referral. Despite their low frequency, novel associations between rare neoplasms and hereditary conditions continue to emerge, although a solid association is often lacking. On the contrary, some infrequent tumours are nearly always non-hereditary (sporadic) in nature. Of note, the definition of rare tumours should be age-adjusted as paediatric tumours are by definition rare when compared with adult tumours in absolute terms. Therefore, in this review, in the paediatric section, we focus on tumours that occur rarely in childhood. This can include cancers that typically occur in adults, but in this case, it appears in a child. Both situations are a strong indication for genetic testing. In this review, we described different scenarios in which rare neoplasms can serve as indications (or not) for an underlying inherited cancer susceptibility.
Humans↗
Tracing the molecular route to progression in miRNA-biogenesis-defective thyroid lesions.
Germline and somatic changes in DICER1 and DGCR8 microprocessors confer risk of developing benign and malignant thyroid lesions, yet the molecular events driving malignant transformation remain unclear. We trace the molecular trajectories from benignity to malignancy in DICER1- and DGCR8-mutated thyroid lesions using multiomic profiling on over 30 DICER1-/DGCR8-mutated samples. Our findings reveal a progressive, specific, and linear accumulation of genetic changes, which when combined with enhanced downregulation of miRNAs distinguished DICER1-/DGCR8-malignant lesions from their benign counterparts. Compensatory hypomethylation of miRNA-encoding genes characterized DICER1-/DGCR8-benign lesions, but as the tumors progressed to malignancy, methylation was partly reimposed, reversing the attempts to activate miRNA-encoded genes and further compromising miRNA production. Transcriptomic analyses revealed mutation-specific effects on the microenvironment, whereby DICER1 mutations activated canonical thyroid cancer progression pathways, whereas altered DGCR8 associated with immune-related changes. This work unveils specific molecular events underlying malignant progression of miRNA-biogenesis-related thyroid tumors and identifies potential biomarkers and disease etiology mechanisms.
MicroRNAs↗
Non-invasive screening in hereditary cancer: a randomized controlled trial to test cell-free DNA-based early detection in the CHARM consortium.
Individuals with hereditary cancer syndromes are born with germline genetic variants that significantly increase their lifetime risk of developing multiple cancers. Cancer rates and overall mortality can be reduced with intensive surveillance to facilitate early cancer detection. However, participating in diagnostic imaging and endoscopy surveillance programs is often time-consuming, overwhelming, inconvenient, and anxiety-inducing. To improve this, multi-cancer early detection tests are being developed using cell-free DNA (cfDNA) sequencing analysis to detect cancers with more sensitivity than conventional screening methods. Our community (the CHARM consortium: Cell-free DNA in Hereditary And high-Risk Malignancies) has been exploring the use of cfDNA sequencing in hereditary cancer, and has launched the CHARM2 prospective randomized controlled trial, which is enrolling 1000 participants with Hereditary Breast and Ovarian Cancer, Lynch syndrome, Li-Fraumeni syndrome, Neurofibromatosis type 1 and Hereditary Diffuse Gastric Cancer to improve equitable access, early detection and surveillance for high-risk individuals. All participants will have screening as per conventional syndrome-specific surveillance recommendations. Half the participants (experimental cohort) will also have cfDNA analysis at least three times a year, with abnormal results triggering dedicated clinical imaging and diagnostic evaluation, and heightened surveillance. Vetted by our patient advisors, validated patient-reported outcome and experience measures assessing participant psychosocial outcomes, engagement, and test preferences will be administered to both arms. Our goal is to inform if and how cfDNA analysis could be implemented into routine clinical care and offer a path to equitable and more convenient cancer screening for all high-risk Canadians.
Female↗