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Monoallelic MUTYH pathogenic variants ascertained via multi-gene hereditary cancer panels are not associated with colorectal, endometrial, or breast cancer

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Abstract

We aimed to determine whether monoallelic MUTYH pathogenic and likely pathogenic variants (PVs) are associated with colorectal, breast, and endometrial cancer. Cases were individuals with colorectal, female breast, or endometrial cancer who reported European ancestry alone and underwent a multi-gene hereditary cancer panel at a large reference laboratory. Controls were individuals of European (non-Finnish) descent from GnomAD with cancer cohorts removed. We performed a Fisher’s exact test to generate odds ratios (ORs) with 95% confidence intervals (CI). Prevalence of single MUTYH PVs in cancer cohorts versus controls, respectively, was: colorectal cancer, 2.1% vs. 1.8% (OR 1.2, 95% CI 0.99–1.5, p = 0.064); breast cancer 1.9% vs. 1.7% (OR 1.1, 95% CI 0.96–1.3, p = 0.15); and endometrial cancer, 1.7% vs. 1.7% (OR 0.98; 95% CI 0.70–1.3, p = 0.94). Using the largest colorectal and endometrial cancer cohorts and one of the largest breast cancer cohorts from a single case–control study, we did not observe a significant difference in the prevalence of monoallelic MUTYH PVs in these cohorts compared to controls. Additionally, frequencies among cancer cohorts were consistent with the published MUTYH carrier frequency of 1–2%. These findings suggest there is no association between colorectal, endometrial, or breast cancer and MUTYH heterozygosity in individuals of European ancestry.

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Data availability

The summary data supporting the findings of this study are available in the supplementary material of this article. Additional case-level data are not available due to privacy or ethical restrictions.

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Funding

This research received no grants from any funding agency in the public, commercial or not-for-profit sectors.

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Author notes

  1. Kevin Arvai

    Present address: DataRobot, Boston, MA, USA

Authors and Affiliations

  1. GeneDx, 207 Perry Pkwy, Gaithersburg, MD, 20877, USA

    Amanda Bartenbaker Thompson, Erin G. Sutcliffe, Kevin Arvai, Maegan E. Roberts, Lisa R. Susswein, Megan L. Marshall, Rebecca Torene, Kathleen S. Hruska & Shaochun Bai

  2. My Gene Team, Miami, FL, USA

    Kristen J. Vogel Postula

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Contributions

ABT: conceptualization, data curation, methodology, project administration, visualization, writing—original draft, writing—reviewing and editing. ES: data curation, writing—reviewing and editing. KA: data curation, formal analysis, software, methodology, writing—original draft, writing—reviewing and editing. MER: data curation, methodology, project administration, writing—original draft, writing—reviewing and editing. LRS: data curation, formal analysis, methodology, writing—reviewing and editing. MLM: methodology, writing—reviewing and editing. RT: formal analysis, writing—reviewing and editing. KJVP: writing—reviewing and editing. KSH: writing—reviewing and editing. SB: writing—reviewing and editing.

Corresponding author

Correspondence to Amanda Bartenbaker Thompson.

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Conflict of interest

Kathleen S. Hruska, Megan L. Marshall, Lisa R. Susswein, Rebecca Torene, and Kristen J. Vogel Postula have stock options and employment with GeneDx/BioReference Laboratories, Inc./OPKO Health. The following individuals are employees of GeneDx/BioReference Laboratories, Inc./Opko Health and have salary as the only disclosure: Amanda Bartenbaker Thompson, Erin Sutcliffe, Maegan E. Roberts, Kevin Arvai, Shaochun Bai.

Ethical approval

This study was conducted in accordance with all guidelines set forth by the Western Institutional Review Board, Puyallup, WA (WIRB 20162523).

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Informed consent for genetic testing was obtained from all individuals undergoing testing at GeneDx. Individuals or institutions who opted out of this type of data use were excluded.

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WIRB waived authorization for publication of de-identified aggregate data for both cases and controls.

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Thompson, A.B., Sutcliffe, E.G., Arvai, K. et al. Monoallelic MUTYH pathogenic variants ascertained via multi-gene hereditary cancer panels are not associated with colorectal, endometrial, or breast cancer. Familial Cancer 21, 415–422 (2022). https://doi.org/10.1007/s10689-021-00285-7

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