Abstract
Patients with mismatch repair (MMR) deficient colorectal cancer (CRC) without detectable germline pathogenic variants (PVs) or likely pathogenic variants (LPVs) in MMR genes are often labeled as Lynch-like syndrome (LLS). We sought to evaluate the efficacy of paired tumor and germline testing in risk stratification of patients with LLS in a large, community-based, integrated healthcare setting. Through the universal screening program for Lynch syndrome at Kaiser Permanente Northern California, we identified all patients with MMR deficient colorectal tumors without detectable germline PVs or LPVs between April 2011 and October 2018. These patients were categorized as LLS and were offered paired tumor and germline testing. Risk stratification and patient management were assessed upon completion of all testing. Of the 50 patients with LLS who underwent paired tumor and germline testing, 62% (n = 31) were categorized as sporadic, 6% (n = 3) had Lynch syndrome, and 32% (n = 16) remained inconclusive. Among the sporadic cases, 65% (n = 20) had a PV (n = 18) or LPV (n = 2) in combination with loss of heterozygosity while 35% (n = 11) had two somatic PVs/LPVs involving the same MMR gene. Our findings showed paired tumor and germline testing resolved the etiology in the majority of patients and is a valuable strategy in risk stratification and management of patients with LLS. Further studies are needed to assess the optimal application of paired testing in different practice settings, particularly with evolving technology and decreasing cost of molecular sequencing.
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Data availability
Data was collected from the database of Genetics Department, Kaiser Permanente, San Jose and is available from the corresponding author [H.C.] on request.
Abbreviations
- CRC:
-
Colorectal cancer
- IHC:
-
Immunohistochemistry
- KPNC:
-
Kaiser Permanente Northern California
- MMR:
-
Mismatch repair
- dMMR:
-
Mismatch repair deficiency
- LLS:
-
Lynch-like syndrome
- PV:
-
Pathogenic variant
- LPV:
-
Likely pathogenic variant
- LOH:
-
Loss of heterozygosity
- VUS:
-
Variant of uncertain significance
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Acknowledgements
We greatly appreciate the assistance from Sheng-Fang Jiang, MS, Division of Research, Kaiser Permanente Northern California, Oakland, CA for conducting statistical analysis.
Funding
Kaiser Permanente Northern California Genetics Department funding for H.C, E.H. and J.B. The Permanente Medical Group Delivery Science and Applied Research Program and the Physician Researcher Program funding for D.L.
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HC: study concept and design; acquisition of data; analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content. EH: study concept and design; drafting of the manuscript; critical revision of the manuscript for important intellectual content; acquisition of data. JB: study concept and design; critical revision of the manuscript for important intellectual content; study supervision. DL: drafting of the manuscript, critical revision of the manuscript for important intellectual content; study supervision.
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Carwana, H., Hoodfar, E., Bergoffen, J. et al. Efficacy of paired tumor and germline testing in evaluation of patients with Lynch-like syndrome in a large integrated healthcare setting. Familial Cancer 20, 223–230 (2021). https://doi.org/10.1007/s10689-020-00218-w
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DOI: https://doi.org/10.1007/s10689-020-00218-w