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  • Comprehensive molecular assessment of mismatch repair deficiency in Lynch associated ovarian cancers using next generation sequencing panel

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Original research
Comprehensive molecular assessment of mismatch repair deficiency in Lynch associated ovarian cancers using next generation sequencing panel
  1. Soyoun Rachel Kim1,2,3,
  2. Leslie Oldfield4,
  3. Alicia Tone3,
  4. Aaron Pollett5,6,
  5. Stephanie Pedersen7,
  6. Johanna Wellum7,
  7. Matthew Cesari8,
  8. Katherine Lajkosz9,
  9. Trevor J Pugh4,7,10 and
  10. Sarah Elizabeth Ferguson1,2,3
  1. 1 Princess Margaret Cancer Center/University Health Network/Sinai Health Systems, Toronto, Ontario, Canada
  2. 2 Department of Obstetrics and Gynecology, University of Toronto, Toronto, Ontario, Canada
  3. 3 Gynecologic Oncology, Princess Margaret Hospital Cancer Center, Toronto, Ontario, Canada
  4. 4 Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
  5. 5 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
  6. 6 Mount Sinai Hospital, Toronto, Ontario, Canada
  7. 7 Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
  8. 8 Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
  9. 9 Department of Biostatistics, University of Toronto, Toronto, Ontario, Canada
  10. 10 Ontario Institute for Cancer Research, University Health Network, Toronto, Ontario, Canada
  1. Correspondence to Dr Soyoun Rachel Kim, 610 University Avenue, OPG Wing 6-816, Toronto, Ontario, M5G 2M9, Canada; RachelSoyoun.Kim{at}uhn.ca

Abstract

Objectives Abnormalities in mismatch repair have been described in ovarian cancer, but few studies have examined the causes of mismatch repair deficiency (MMRd). To address this, we completed targeted mutational and methylation sequencing on MMRd ovarian cancer cases. The objective of this study was to explore the molecular mechanism of MMRd using our targeted next generation sequencing panel.

Methods Newly diagnosed non-serous/mucinous ovarian cancers (n=215) were prospectively recruited from three cancer centers in Ontario, Canada, between 2015 and 2018. Tumors were reflexively assessed for mismatch repair protein by immunohistochemistry. Matched tumor–normal MMRd cases were analyzed on a custom next generation sequencing panel to identify germline and somatic mutations, copy number variants, rearrangements, and promoter methylation in mismatch repair and associated genes.

Results Of 215 cases, 28 (13%) were MMRd. The MMRd cohort had a median age of 52.3 years (range 33.6–62.2), with mostly stage I (50%) and grade 1 or 2 endometrioid histotype (57%). Of the 28 cases, 22 were available for molecular analysis, and Lynch syndrome was detected in 50% of MMRd cases (11/22; seven ovarian cancer and four synchronous ovarian and endometrial cancer: seven MSH6, two MLH1, one PMS2, and one MSH2). An explanation for the observed mismatch repair phenotype was available for 22/22 deficient cases, including 12 MLH1/PMS2 deficient (nine somatic methylation, one bi-allelic somatic deletion, and two pathogenic germline variant), one PMS2 deficient (one pathogenic germline variant), seven MSH6 deficient (seven pathogenic germline variant), and two MSH2/MSH6 deficient (one pathogenic germline variant and one bi-allelic somatic mutation). Concordance between clinical germline testing and panel sequencing results was 100%.

Conclusions Use of our custom next generation sequencing panel allowed for the streamlined assessment of hereditary and somatic causes of MMRd in ovarian cancers.

  • Ovarian Cancer
  • Lynch Syndrome II

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

https://doi.org/10.1136/ijgc-2023-004815

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    Data availability statement

    All data relevant to the study are included in the article or uploaded as supplementary information.

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    Footnotes

    • Contributors SRK: data curation, formal analysis, project administration, visualization, writing—original draft, and writing—review and editing, guarantor. LO: formal analysis and writing—review and editing, guarantor. AT: conceptualization, data curation, investigation, methodology, and writing—review and editing. AP, SP, JW, and MC: investigation and writing—review and editing. KL: investigation, resources, and writing—review and editing. TJP: formal analysis, investigation, and writing—review and editing. SEF: conceptualization, formal analysis, funding acquisition, project administration, investigation, methodology, supervision, and writing—review and editing.

    • Funding We have received funding from the Canadian Cancer Society (grant No 704038).

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.