Efficacy of paired tumor and germline testing in evaluation of patients with Lynch-like syndrome in a large integrated h
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ORIGINAL ARTICLE
Efficacy of paired tumor and germline testing in evaluation of patients with Lynch‑like syndrome in a large integrated healthcare setting Holly Carwana1 · Elizabeth Hoodfar2 · JoAnn Bergoffen1 · Dan Li3,4 Received: 1 June 2020 / Accepted: 10 November 2020 © Springer Nature B.V. 2020
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, communitybased, 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. Keywords Lynch-like syndrome · Lynch syndrome · Colorectal cancer · Pathogenic variant · Somatic testing · Paired testing Abbreviations CRC Colorectal cancer IHC Immunohistochemistry KPNC Kaiser Permanente Northern California MMR Mismatch repair Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10689-020-00218-w) contains supplementary material, which is available to authorized users. * Holly Carwana [email protected] 1
Department of Genetics, Kaiser Permanente Northern California, 5755 Cottle Road, Building 21, San Jose, CA 95123, USA
2
Department of Genetics, Kaiser Permanente Northern California, Roseville, CA, USA
3
Department of Gastroenterology, Kaiser Permanente Northern California, Santa Clara, CA, USA
4
Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
dMMR Mismatch repair deficiency LLS Lynch-like syndrome PV Pathogenic variant LPV Likely pathogenic variant LOH Loss of heterozygosity VUS Variant of uncertain significance
Introduction Lynch syndrome is the most common inherited colorectal cancer (CRC) syndrome. It is caused by autosomal
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