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Comprehensive molecular assessment of mismatch repair deficiency in Lynch associated ovarian cancers using next
Soyoun Rachel Kim1,2,3, Leslie Oldfield4, Alicia Tone3
1Princess Margaret Cancer Center/University Health Network/Sinai Health Systems, Toronto, Ontario, Canada RachelSoyoun.Kim@uhn.ca.
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.
Insights
Mismatch repair deficiency (MMRd) affects 13% of ovarian cancers. Our study identified Lynch syndrome in 50% of MMRd cases, revealing both hereditary and somatic causes through targeted next-generation sequencing.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Mismatch repair deficiency (MMRd) is observed in ovarian cancer, but its underlying molecular mechanisms are not fully understood.
- Investigating the causes of MMRd is crucial for understanding ovarian cancer development and potential therapeutic strategies.
Purpose of the Study:
- To explore the molecular mechanisms of mismatch repair deficiency (MMRd) in ovarian cancer.
- To identify the hereditary and somatic causes of MMRd using a targeted next-generation sequencing panel.
Main Methods:
- Prospective recruitment of 215 newly diagnosed non-serous/mucinous ovarian cancer cases.
- Immunohistochemistry assessment for mismatch repair protein expression.
- Targeted next-generation sequencing of matched tumor-normal MMRd cases to detect mutations, copy number variants, rearrangements, and promoter methylation.
Main Results:
- 28 out of 215 (13%) ovarian cancer cases exhibited mismatch repair deficiency (MMRd).
- Lynch syndrome was detected in 50% of MMRd cases (11/22), with mutations in MSH6, MLH1, PMS2, and MSH2.
- The study identified specific molecular explanations for MMRd in all analyzed cases, including somatic methylation, deletions, and germline variants.
Conclusions:
- A custom next-generation sequencing panel effectively assessed hereditary and somatic causes of MMRd in ovarian cancers.
- This streamlined approach aids in understanding the molecular landscape of MMRd in ovarian cancer.
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