Abstract
BackgroundIn the past two decades, genetic testing for cancer risk assessment has entered mainstream clinical practice due to the availability of low-cost panels of multiple cancer-associated genes. However, the clinical value of multiple-gene panels for cancer susceptibility is not well established, especially in cases where panel testing identifies more than one pathogenic variant. The risk for specific malignancies as a result of a mutated gene is complex and likely influenced by superimposed modifier variants and/or environmental effects. Recent data suggests that the combination of multiple pathogenic variants may be fewer than reported by chance, suggesting that some mutation combinations may be detrimental. Management of patients with “incidentally” discovered mutations can be particularly challenging, especially when established guidelines call for radical procedures (e.g. total gastrectomy in CDH1) in patients and families without a classic clinical history concerning for that cancer predisposition syndrome.Case presentationWe present two cases, one of an individual and one of a family, with multiple pathogenic mutations detected by multi-gene panel testing to highlight challenges practitioners face in counseling patients about pathogenic variants and determining preventive and therapeutic interventions.ConclusionsOngoing investigation is needed to improve our understanding of inherited susceptibility to disease in general and cancer predisposition syndromes, as this information has the potential to lead to the development of more precise and patient-specific counseling and surveillance strategies. The real-world adoption of new or improved technologies into clinical practice frequently requires medical decision-making in the absence of established understanding of gene-gene interactions. In the meantime, practitioners must be prepared to apply a rationale based on currently available knowledge to clinical decision-making. Current practice is evolving to rely heavily on clinical concordance with personal and family history in making specific therapeutic decisions.
Highlights
In the past two decades, genetic testing for cancer risk assessment has entered mainstream clinical practice due to the availability of low-cost panels of multiple cancer-associated genes
PMS2, suggesting that her breast cancer was sporadic and not associated with microsatellite instability ePaternal Cousin: Renal cell carcinoma fMalignancies are color-coded according to the patients and mutations they have been associated with (BAP1, BRCA1-associated protein 1 (BAP1) and MutS Homolog 6 (MSH6), MSH6, RECQL4, BAP1 and RECQL4)
Management of patients with “incidentally” discovered mutations can be challenging, especially when established guidelines call for radical procedures in patients and families without a classic clinical history concerning for that cancer predisposition syndrome
Summary
Cancer genetics is advancing quickly as a tool for precision medicine as we move into an era of whole-exome and whole-genome sequencing. As we work to advance the field toward a more comprehensive understanding of predictive cancer genetics and the complex interplay of other genomic and environmental exposure effects, it is important that we work to individualize care for each patient while recommending a rational plan based on existing data. The practice of clinical genetics is in a period of rapidly advancing understanding of genotypephenotype correlations. While this raises puzzling and challenging questions, only through more detailed, open-ended testing and meticulous data collection will we better tease apart the complex results. This conundrum highlights the continued relevance and importance of family history as a practical guide, despite the immense and improving technology at our disposal
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