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. 2021 Aug 16;12(8):e00397.
doi: 10.14309/ctg.0000000000000397.

Integrating Tumor Sequencing Into Clinical Practice for Patients With Mismatch Repair-Deficient Lynch Syndrome Spectrum Cancers

Katherine Dixon  1 , Mary-Jill Asrat  2 , Angela C Bedard  2 , Kristin Binnington  2 , Katie Compton  2 , Carol Cremin  2 , Nili Heidary  2 , Zoe Lohn  2 , Niki Lovick  2 , Mary McCullum  2 , Allison Mindlin  2 , Melanie O'Loughlin  2 , Tammy Petersen  2 , Cheryl Portigal-Todd  2 , Jenna Scott  1   2 , Genevieve St-Martin  2 , Jennifer Thompson  2 , Ruth Turnbull  2 , Sze Wing Mung  2 , Quan Hong  2 , Marjorie Bezeau  2   3 , Ian Bosdet  4 , Tracy Tucker  4 , Sean Young  4 , Stephen Yip  4 , Gudrun Aubertin  2   5 , Katherine A Blood  1   2   5 , Jennifer Nuk  1   2 , Sophie Sun  2   6 , Kasmintan A Schrader  1   2   6
Affiliations

Integrating Tumor Sequencing Into Clinical Practice for Patients With Mismatch Repair-Deficient Lynch Syndrome Spectrum Cancers

Katherine Dixon et al. Clin Transl Gastroenterol. .

Abstract

Introduction: Uninformative germline genetic testing presents a challenge to clinical management for patients suspected to have Lynch syndrome, a cancer predisposition syndrome caused by germline variants in the mismatch repair (MMR) genes or EPCAM.

Methods: Among a consecutive series of MMR-deficient Lynch syndrome spectrum cancers identified through immunohistochemistry-based tumor screening, we investigated the clinical utility of tumor sequencing for the molecular diagnosis and management of suspected Lynch syndrome families. MLH1-deficient colorectal cancers were prescreened for BRAF V600E before referral for genetic counseling. Microsatellite instability, MLH1 promoter hypermethylation, and somatic and germline genetic variants in the MMR genes were assessed according to an established clinical protocol.

Results: Eighty-four individuals with primarily colorectal (62%) and endometrial (31%) cancers received tumor-normal sequencing as part of routine clinical genetic assessment. Overall, 27% received a molecular diagnosis of Lynch syndrome. Most of the MLH1-deficient tumors were more likely of sporadic origin, mediated by MLH1 promoter hypermethylation in 54% and double somatic genetic alterations in MLH1 (17%). MSH2-deficient, MSH6-deficient, and/or PMS2-deficient tumors could be attributed to pathogenic germline variants in 37% and double somatic events in 28%. Notably, tumor sequencing could explain 49% of cases without causal germline variants, somatic MLH1 promoter hypermethylation, or somatic variants in BRAF.

Discussion: Our findings support the integration of tumor sequencing into current Lynch syndrome screening programs to improve clinical management for individuals whose germline testing is uninformative.

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Conflict of interest statement

Guarantor of the article: Kasmintan A. Schrader, MBBS, PhD

Specific author contributions: Jennifer Nuk, MSc, Sophie Sun, MD, and Kasmintan A. Schrader, MBBS, PhD, are co-senior authors. J.N., S.S., and K.A.S.: contributed to the conception and design of the study. K.D., M.-J.A., A.C.B., K.B., K.C., C.C., N.H., Z.L., N.L., M.M., A.M., M.O., T.P., C.P.-T., J.S., G.S.-M., J.T., R.T., M.B., I.B., T.T., S. Young, S. Yip, G.A., K.A.B., J.N., S.S., and K.A.S.: contributed to the acquisition of data. K.D., S.W.M., and Q.H.: contributed to the analysis of data. K.D. and K.A.S.: contributed to the interpretation of data and drafted the article. All of the authors revised the article critically for important intellectual content.

Financial support: K.A.S. is supported by the Canadian Institutes of Health Research and the Michael Smith Foundation for Health Research.

Potential competing interests: None to report.

Figures

Figure 1.
Figure 1.
Predicted origin of dMMR tumors analyzed by tumor sequencing. (a) Percent of CRC, EC, and other cancer types resulting from pathogenic or likely pathogenic germline variants, MLH1 promoter hypermethylation, double somatic events, or that remain unexplained. (b) Predicted molecular origin of dMMR tumors by immunohistochemistry status. MLH1: combined MLH1/PMS2 loss; MSH2: combined MSH2/MSH6 loss; MSH6: MSH6 loss with normal MSH2 expression; and PMS2: PMS2 loss with normal MLH1 expression. Two tumors associated with MSH6/PMS2 deficiency, 1 germline, and 1 unexplained are not shown. CRC, colorectal cancer; dMMR, deficient mismatch repair; EC, endometrial cancer.
Figure 2.
Figure 2.
Modified framework for universal Lynch syndrome screening.
See this image and copyright information in PMC

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