Risk of Cancer in Family Members of Patients with Lynch-Like Syndrome.

María Dolores Picó,Cristina Alenda,Alexandra Gisbert-Beamud,Ariadna Sánchez,Catalina Garau,Óscar Murcia,Gemma Llort,Antoni Castells,Marta Carrillo-Palau,Francesc Balaguer,Inmaculada Salces,Rodrigo Jover,Laura Rivas,Carmen Yagüe,Mar Giner-Calabuig,Francisco Javier Lacueva,Adela Castillejo,Pedro Zapater,Miren Alustiza,Maite Herraiz,Ana Beatriz Sánchez-Heras,Luís Bujanda ,María Jesús Martín López ,Letícia Moreira ,Cristina Álvarez–Urturi ,María Pellisé ,Teresa Ramón Y Cajal ,Joaquín Cubiella ,Adrià López‐Fernández ,José Luís Soto

doi:10.3390/cancers12082225

Abstract

Lynch syndrome (LS) is a common cause of hereditary colorectal cancer (CRC). Some CRC patients develop mismatch repair deficiency without germline pathogenic mutation, known as Lynch-like syndrome (LLS). We compared the risk of CRC in first-degree relatives (FDRs) in LLS and LS patients. LLS was diagnosed when tumors showed immunohistochemical loss of MSH2, MSH6, and PMS2; or loss of MLH1 with BRAF wild type; and/or no MLH1 methylation and absence of pathogenic mutation in these genes. CRC and other LS-related neoplasms were followed in patients diagnosed with LS and LLS and among their FDRs. Standardized incidence ratios (SIRs) were calculated for CRC and other neoplasms associated with LS among FDRs of LS and LLS patients. In total, 205 LS (1205 FDRs) and 131 LLS families (698 FDRs) had complete pedigrees. FDRs of patients with LLS had a high incidence of CRC (SIR, 2.08; 95% confidence interval (CI), 1.56–2.71), which was significantly lower than that in FDRs of patients with LS (SIR, 4.25; 95% CI, 3.67–4.90; p < 0.001). The risk of developing other neoplasms associated with LS also increased among FDR of LLS patients (SIR, 2.04; 95% CI, 1.44–2.80) but was lower than that among FDR of patients with LS (SIR, 5.01, 95% CI, 4.26–5.84; p < 0.001). FDRs with LLS have an increased risk of developing CRC as well as LS-related neoplasms, although this risk is lower than that of families with LS. Thus, their management should take into account this increased risk.

Highlights

Lynch syndrome (LS) is the most frequent cause of hereditary colorectal cancer (CRC) [1]
We considered as LS-related tumors those from the endometrium, ovaries, urinary tract, stomach, small intestine, pancreas, biliary tract, skin, and brain
Through July 2019, we included 160 patients diagnosed with CRC who met the diagnostic criteria of Lynch-like syndrome (LLS) and 286 patients diagnosed with CRC and LS

Summary

Introduction

Lynch syndrome (LS) is the most frequent cause of hereditary colorectal cancer (CRC) [1] It is characterized by the presence of pathogenic mutations in DNA mismatch (MMR) repair genes (MLH1, MSH2, MSH6, PMS2) or EpCAM (epithelial cell adhesion molecule), with an autosomal dominant inheritance [2]. LS but has revealed a large number of patients (~30%) who present with tumor microsatellite instability (MSI) or loss-of-expression MMR proteins but without evidence of germline pathogenic mutation in these genes [4]. This condition is known as Lynch-like syndrome (LLS). Classified VUS in MMR genes could be a cause of LLS

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