Germline whole genome sequencing in adults with multiple primary tumors

Yiming Wang; Qiliang Ding; Stephenie Prokopec; Kirsten M Farncombe; Jeffrey Bruce; Selina Casalino; Jeanna McCuaig; Marta Szybowska; Kalene van Engelen; Jordan Lerner-Ellis; Trevor J Pugh; Raymond H Kim

doi:10.1007/s10689-023-00343-2

Germline whole genome sequencing in adults with multiple primary tumors

Fam Cancer. 2023 Oct;22(4):513-520. doi: 10.1007/s10689-023-00343-2. Epub 2023 Jul 22.

Authors

Yiming Wang^{1

2

3}, Qiliang Ding³, Stephenie Prokopec^{1

2}, Kirsten M Farncombe^{1

2}, Jeffrey Bruce^{1

2}, Selina Casalino^{4

5}, Jeanna McCuaig^{1

6}, Marta Szybowska^{1

6}, Kalene van Engelen^{1

6

7

8

9}, Jordan Lerner-Ellis^{4

5

10}, Trevor J Pugh^{1

2}, Raymond H Kim^{11

12

13

14

15}

Affiliations

¹ Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
² Ontario Institute for Cancer Research, Toronto, ON, Canada.
³ Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada.
⁴ Mount Sinai Hospital, Sinai Health System, Toronto, ON, Canada.
⁵ Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada.
⁶ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
⁷ London Health Science Centre, London, Canada.
⁸ Medical Genetics Program of Southwestern Ontario, London Health Sciences Centre, London, ON, Canada.
⁹ Department of Pediatrics, Western University, London, ON, Canada.
¹⁰ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
¹¹ Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. [email protected].
¹² Ontario Institute for Cancer Research, Toronto, ON, Canada. [email protected].
¹³ Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada. [email protected].
¹⁴ Mount Sinai Hospital, Sinai Health System, Toronto, ON, Canada. [email protected].
¹⁵ Department of Medicine, University of Toronto, Toronto, ON, Canada. [email protected].

PMID: 37481477
DOI: 10.1007/s10689-023-00343-2

Abstract

Multiple primary tumors (MPTs) are a harbinger of hereditary cancer syndromes. Affected individuals often fit genetic testing criteria for a number of hereditary cancer genes and undergo multigene panel testing. Other genomic testing options, such as whole exome (WES) and whole genome sequencing (WGS) are available, but the utility of these genomic approaches as a second-tier test for those with uninformative multigene panel testing has not been explored. Here, we report our germline sequencing results from WGS in 9 patients with MPTs who had non-informative multigene panel testing. Following germline WGS, sequence (agnostic or 735 selected genes) and copy number variant (CNV) analysis was performed according to the American College of Medical Genetics (ACMG) standards and guidelines for interpreting sequence variants and reporting CNVs. In this cohort, WGS, as a second-tier test, did not identify additional pathogenic or likely pathogenic variants in cancer predisposition genes. Although we identified a CHEK2 likely pathogenic variant and a MUTYH pathogenic variant, both were previously identified in the multigene panels and were not explanatory for the presented type of tumors. CNV analysis also failed to identify any pathogenic or likely pathogenic variants in cancer predisposition genes. In summary, after multigene panel testing, WGS did not reveal any additional pathogenic variants in patients with MPTs. Our study, based on a small cohort of patients with MPT, suggests that germline gene panel testing may be sufficient to investigate these cases. Future studies with larger sample sizes may further elucidate the additional utility of WGS in MPTs.

Trial registration: ClinicalTrials.gov NCT03857594.

Keywords: Cancer predisposition genes; Multigene panel; Multiple primary tumors; Whole genome sequencing.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Genetic Predisposition to Disease
Genetic Testing / methods
Germ-Line Mutation
Humans
Neoplasms, Multiple Primary* / genetics
Neoplastic Syndromes, Hereditary* / genetics
Whole Genome Sequencing / methods

Associated data

ClinicalTrials.gov/NCT03857594