Review

. 2023 Oct 5;110(10):1616-1627.

doi: 10.1016/j.ajhg.2023.08.014.

Current and new frontiers in hereditary cancer surveillance: Opportunities for liquid biopsy

Kirsten M Farncombe¹, Derek Wong², Maia L Norman², Leslie E Oldfield², Julia A Sobotka², Mark Basik³, Yvonne Bombard⁴, Victoria Carile⁵, Lesa Dawson⁶, William D Foulkes⁷, David Malkin⁸, Aly Karsan⁹, Patricia Parkin¹⁰, Lynette S Penney¹¹, Aaron Pollett¹², Kasmintan A Schrader¹³, Trevor J Pugh¹⁴, Raymond H Kim¹⁵; CHARM consortium

Collaborators, Affiliations

Collaborators

CHARM consortium:
Adriana Aguilar-Mahecha, Melyssa Aronson, Mark Basik, Nancy N Baxter, Phil Bedard, Hal Berman, Marcus Q Bernardini, Yvonne Bombard, Victoria Carile, Clarissa F Chan, Tulin Cil, Blaise Clarke, Lesa Dawson, Irfan Dhalla, Christine Elser, Gabrielle Ev Ene, Kirsten M Farncombe, Sarah Ferguson, William D Foulkes, Laura Genge, Robert Gryfe, Michelle R Jacobson, Aly Karsan, Monika Kastner, Pardeep Kaurah, Raymond H Kim, Josiane Lafleur, Jordan Lerner-Ellis, Stephanie Lheureux, Shelley M MacDonald, Jeanna McCuaig, Brian Mckee, Nicole Mittmann, Maia L Norman, Leslie E Oldfield, Seema Panchal, Lynette S Penney, Carolyn Piccinin, Aaron Pollett, Trevor J Pugh, Dean Regier, Zoulikha Rezoug, Krista Rideout, Kasmintan A Schrader, Kara Semotiuk, Sara Singh, Lillian Siu, Julia A Sobotka, Sophie Sun, Emily Thain, Karin Wallace, Thomas Ward, Shelley Westergard, Stacy Whittle, Wei Xu, Celeste Yu

Affiliations

¹ Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada; Ontario Institute for Cancer Research, Toronto, ON, Canada.
² Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
³ Department of Surgery, McGill University Medical School, Montreal, QC, Canada; Department of Oncology, McGill University Medical School, Montreal, QC, Canada.
⁴ Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada; Genomics Health Services Research Program, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Unity Health Toronto, Toronto, ON, Canada.
⁵ Jewish General Hospital Stroll Cancer Prevention Centre, Montreal, QC, Canada.
⁶ Memorial University, St. John's, NL, Canada; Eastern Health Authority, St. John's, NL, Canada.
⁷ Jewish General Hospital Stroll Cancer Prevention Centre, Montreal, QC, Canada; Department of Human Genetics, McGill University, Montreal, QC, Canada.
⁸ Division of Hematology-Oncology, Hospital for Sick Children, Toronto, ON, Canada; Department of Pediatrics, University of Toronto, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
⁹ BC Cancer, Vancouver, BC, Canada.
¹⁰ Department of Pediatrics, University of Toronto, Toronto, ON, Canada; Division of Pediatric Medicine, The Hospital for Sick Children, Toronto, ON, Canada.
¹¹ Dalhousie University, Halifax, NS, Canada.
¹² Mount Sinai Hospital, Toronto, ON, Canada.
¹³ BC Cancer, Vancouver, BC, Canada; University of British Columbia, Vancouver, BC, Canada.
¹⁴ Ontario Institute for Cancer Research, Toronto, ON, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada. Electronic address: trevor.pugh@utoronto.ca.
¹⁵ Ontario Institute for Cancer Research, Toronto, ON, Canada; Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Sinai Health System, Toronto, ON, Canada; Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada; Department of Medicine, University of Toronto, Toronto, ON, Canada. Electronic address: raymond.kim@uhn.ca.

PMID: 37802042
PMCID: PMC10577078
DOI: 10.1016/j.ajhg.2023.08.014

Review

Current and new frontiers in hereditary cancer surveillance: Opportunities for liquid biopsy

Kirsten M Farncombe et al. Am J Hum Genet. 2023.

. 2023 Oct 5;110(10):1616-1627.

doi: 10.1016/j.ajhg.2023.08.014.

Authors

Collaborators

CHARM consortium:
Adriana Aguilar-Mahecha, Melyssa Aronson, Mark Basik, Nancy N Baxter, Phil Bedard, Hal Berman, Marcus Q Bernardini, Yvonne Bombard, Victoria Carile, Clarissa F Chan, Tulin Cil, Blaise Clarke, Lesa Dawson, Irfan Dhalla, Christine Elser, Gabrielle Ev Ene, Kirsten M Farncombe, Sarah Ferguson, William D Foulkes, Laura Genge, Robert Gryfe, Michelle R Jacobson, Aly Karsan, Monika Kastner, Pardeep Kaurah, Raymond H Kim, Josiane Lafleur, Jordan Lerner-Ellis, Stephanie Lheureux, Shelley M MacDonald, Jeanna McCuaig, Brian Mckee, Nicole Mittmann, Maia L Norman, Leslie E Oldfield, Seema Panchal, Lynette S Penney, Carolyn Piccinin, Aaron Pollett, Trevor J Pugh, Dean Regier, Zoulikha Rezoug, Krista Rideout, Kasmintan A Schrader, Kara Semotiuk, Sara Singh, Lillian Siu, Julia A Sobotka, Sophie Sun, Emily Thain, Karin Wallace, Thomas Ward, Shelley Westergard, Stacy Whittle, Wei Xu, Celeste Yu

Affiliations

¹ Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada; Ontario Institute for Cancer Research, Toronto, ON, Canada.
² Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
³ Department of Surgery, McGill University Medical School, Montreal, QC, Canada; Department of Oncology, McGill University Medical School, Montreal, QC, Canada.
⁴ Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada; Genomics Health Services Research Program, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Unity Health Toronto, Toronto, ON, Canada.
⁵ Jewish General Hospital Stroll Cancer Prevention Centre, Montreal, QC, Canada.
⁶ Memorial University, St. John's, NL, Canada; Eastern Health Authority, St. John's, NL, Canada.
⁷ Jewish General Hospital Stroll Cancer Prevention Centre, Montreal, QC, Canada; Department of Human Genetics, McGill University, Montreal, QC, Canada.
⁸ Division of Hematology-Oncology, Hospital for Sick Children, Toronto, ON, Canada; Department of Pediatrics, University of Toronto, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
⁹ BC Cancer, Vancouver, BC, Canada.
¹⁰ Department of Pediatrics, University of Toronto, Toronto, ON, Canada; Division of Pediatric Medicine, The Hospital for Sick Children, Toronto, ON, Canada.
¹¹ Dalhousie University, Halifax, NS, Canada.
¹² Mount Sinai Hospital, Toronto, ON, Canada.
¹³ BC Cancer, Vancouver, BC, Canada; University of British Columbia, Vancouver, BC, Canada.
¹⁴ Ontario Institute for Cancer Research, Toronto, ON, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada. Electronic address: trevor.pugh@utoronto.ca.
¹⁵ Ontario Institute for Cancer Research, Toronto, ON, Canada; Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Sinai Health System, Toronto, ON, Canada; Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada; Department of Medicine, University of Toronto, Toronto, ON, Canada. Electronic address: raymond.kim@uhn.ca.

PMID: 37802042
PMCID: PMC10577078
DOI: 10.1016/j.ajhg.2023.08.014

Abstract

At least 5% of cancer diagnoses are attributed to a causal pathogenic or likely pathogenic germline genetic variant (hereditary cancer syndrome-HCS). These individuals are burdened with lifelong surveillance monitoring organs for a wide spectrum of cancers. This is associated with substantial uncertainty and anxiety in the time between screening tests and while the individuals are awaiting results. Cell-free DNA (cfDNA) sequencing has recently shown potential as a non-invasive strategy for monitoring cancer. There is an opportunity for high-yield cancer early detection in HCS. To assess clinical validity of cfDNA in individuals with HCS, representatives from eight genetics centers from across Canada founded the CHARM (cfDNA in Hereditary and High-Risk Malignancies) Consortium in 2017. In this perspective, we discuss operationalization of this consortium and early data emerging from the most common and well-characterized HCSs: hereditary breast and ovarian cancer, Lynch syndrome, Li-Fraumeni syndrome, and Neurofibromatosis type 1. We identify opportunities for the incorporation of cfDNA sequencing into surveillance protocols; these opportunities are backed by examples of earlier cancer detection efficacy in HCSs from the CHARM Consortium. We seek to establish a paradigm shift in early cancer surveillance in individuals with HCSs, away from highly centralized, regimented medical screening visits and toward more accessible, frequent, and proactive care for these high-risk individuals.

Keywords: cell-free DNA; genetic predisposition; hereditary cancer syndromes; liquid biopsy; surveillance.

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Conflict of interest statement

Declaration of interests William D. Foulkes has research funding from AstraZeneca. Sophie Sun has a consulting and advisory relationship with Novartis, Bristol-Myers Squibb, Pfizer, Purdue, Takeda, and AstraZeneca. Kasmintan A. Schrader has a consulting and advisory relationship with and has received honoraria from AstraZeneca Canada and Pfizer and research funding from AstraZeneca Canada. Dean Regier has a consulting/advisory relationship with Roche Canada and AstraZeneca. Trevor J. Pugh has a consulting and advisory relationship with Chrysalis Biomedical Advisors and the Canadian Pension Plan Investment Board, is on the scientific advisory board for Illumina, has received honoraria from AstraZeneca, Merck, PACT Pharma, and SAGA Diagnostics, and has research funding from Roche (Genentech), the National Institutes of Health, and the US Department of Defense. Yvonne Bombard has ownership interests and intellectual property rights as an inventor and patent holder with Genetics Adviser. The other authors declare no competing interests.

Figures

**Figure 1**
Targeted panel sequencing showing the detection of a missense somatic *TP53* variant five months prior to the clinical diagnosis of lung cancer Left: Oncoplot showing germline (top) and somatic (bottom) *TP53* variants identified in this individual. Right: clinical timeline highlighting plasma timepoints (top) and cancer diagnoses (bottom) for this participant.

**Figure 2**
Shallow whole-genome sequencing from an individual with LFS and prostate cancer Top: copy-number track showing copy-number alterations detected in the plasma of an individual with LFS and active prostate cancer. Bottom: the ratio of short (90–150 bp)/long (151–220 bp) cfDNA fragments across the genome (fragmentation profile) of the individual with LFS and prostate cancer (red) in comparison to the median of a cohort of healthy controls (gray).

See this image and copyright information in PMC

References

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Current and new frontiers in hereditary cancer surveillance: Opportunities for liquid biopsy

Collaborators

Affiliations

Current and new frontiers in hereditary cancer surveillance: Opportunities for liquid biopsy

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Research Materials