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PREMM5 distinguishes sporadic from Lynch syndrome-associated MMR-deficient/MSI-high colorectal cancer

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Abstract

Current algorithms for diagnosing Lynch syndrome (LS) include multistep molecular tumor tests to distinguish LS-associated from sporadic colorectal cancer (CRC), which add cost and complexity to the evaluation. We hypothesized that PREMM5, a clinical LS prediction tool, could be an alternative approach to screen for LS, thereby lessening the need for specialized molecular diagnostics. We reviewed a consecutively ascertained institutional cohort of 1058 CRC patients on whom pathologic and clinical data were available, including prior LS germline testing. Data from MMR-D/MSI-H CRC patients were reviewed and PREMM5 scores were calculated for each individual. Using a PREMM5 score cutoff ≥ 2.5% to characterize the need for germline testing, we determined the rate of pathogenic/likely pathogenic germline variants (PGVs) in LS genes in patients with PREMM5 scores ≥ 2.5% versus < 2.5%. Sensitivity and negative predictive values (NPV) of PREMM5 were calculated for all MMR-D/MSI-H CRC patients, and those with MLH1-deficient CRC. MMR IHC and/or MSI results were available on 572/1058 cases. We identified 74/572 (12.9%) cases as MMR-D/MSI-H, of which 28/74 (37.8%) harbored a LS PGV. 11/49 (22.4%) patients with MLH1-deficient CRC harbored a LS PGV. PREMM5 had 100% sensitivity (95% CI: 87.7–100 for any MMR-D/MSI-H; 95% CI: 71.5–100 for MLH1-deficient CRC) and 100% NPV (95% CI: 83.2–100 for any MMR-D/MSI-H; 95% CI: 82.4–100 for MLH1-deficient CRC) for identifying LS PGVs in these cohorts. PREMM5 accurately distinguishes LS- from non-LS-associated MMR-D/MSI-H CRC without additional somatic molecular testing. These findings are particularly relevant for limited-resource settings where advanced molecular diagnostics may be unavailable.

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Funding

Supported by the National Institutes of Health (National Cancer Institute) R01CA132829 (S.S.), The Helen Gurley Brown Presidential Initiative (C.U.), The Lesswitz Fund for Lynch Syndrome (M.B.Y.), The Sweet Family Fund (S.S.), and The Terry T. Sweet Fund for Lynch Syndrome (M.B.Y.), The Rasmussen Family Fund for Colorectal Cancer Research (M.B.Y.), The Scragg Family Fund (M.B.Y.), and The Stephani Batchelor and Andrew Robert Whittaker Family Fund for Lynch Syndrome Research (S.S.).

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Authors and Affiliations

  1. Hospital Sírio-Libanês, Brasília, Brazil

    Renata L. Sandoval

  2. Dana-Farber Cancer Institute, 450 Brookline Avenue Dana 1126, 02215, Boston, MA, USA

    Renata L. Sandoval, Miki Horiguchi, Chinedu Ukaegbu, C. Sloane Furniss, Hajime Uno, Sapna Syngal & Matthew B. Yurgelun

  3. Harvard Medical School, Boston, MA, USA

    Miki Horiguchi, Hajime Uno & Sapna Syngal

  4. Brigham and Women’s Hospital, Boston, MA, USA

    Sapna Syngal

Authors
  1. Renata L. Sandoval
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Contributions

Study conception and design (RLS, CU, CSF, SS, MBY)Acquisition and assembly of data (RLS, MH, CU, HU, MBY)Data analysis and interpretation (RLS, MH, CU, HU, SS, MBY)Statistical analysis (MH, HU)Obtained funding (CU, SS, MBY)Administrative support (SS, MBY)Study supervision (HU, SS, MBY)Drafting of the manuscript (RLS, MH, MBY)Critical revision of the manuscript (all authors)Approval of the final manuscript (all authors).

Corresponding author

Correspondence to Matthew B. Yurgelun.

Ethics declarations

Ethics approval and consent to participate

This study was approved by the Dana-Farber/Harvard Cancer Center Institutional Review Board. This study was performed in accordance with the principles of the Declaration of Helsinki.

Consent to participate

Informed consent was obtained from all individual participants included in the study.

Competing interests

Dr. Uno reports prior consulting/advisory payments from Roche. Dr. Syngal reports prior consulting fees from Myriad Genetics Laboratories, Inc., and inventor/royalties from PREMM model. Dr. Yurgelun reports consulting/scientific advisory board fees and research funding from Janssen Pharmaceuticals as well as payments for peer review services from UpToDate. Drs. Sandoval, Horiguchi, Ukaegbu and Furniss have no financial or non-financial conflicts of interest to declare.

Prior publications

Preliminary data from this manuscript were presented as an abstract at the Annual Meeting of the Collaborative Group of the Americas on Inherited Gastrointestinal Cancer (Nashville, TN) in November 11–13, 2022.

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Electronic supplementary material

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10689_2023_345_MOESM1_ESM.pdf

Supplementary Material 1: Histogram of PREMM5 scores among individuals with MMR-D/MSI-H colorectal cancer (n = 74), MLH1-deficient colorectal cancer (n = 49), and other patterns of MMR-D/MSI-H colorectal cancer, both with (LS+) and without (LS-) Lynch syndrome.

10689_2023_345_MOESM2_ESM.pdf

Supplementary Material 2: Performance characteristics of PREMM5 at different score thresholds for identifying Lynch syndrome carriers from noncarriers among individuals with MMR-D/MSI-H colorectal cancer. NPV, negative predictive value; PPV, positive predictive value.

10689_2023_345_MOESM3_ESM.pdf

Supplementary Material 3: Receiver operating characteristic (ROC) curve to discriminate Lynch syndrome carriers from noncarriers among individuals with MMR-D/MSI-H colorectal cancer. AUC, area under the ROC curve.

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Sandoval, R.L., Horiguchi, M., Ukaegbu, C. et al. PREMM5 distinguishes sporadic from Lynch syndrome-associated MMR-deficient/MSI-high colorectal cancer. Familial Cancer 22, 459–465 (2023). https://doi.org/10.1007/s10689-023-00345-0

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