Prevalence of mismatch repair deficiency and Lynch syndrome in a cohort of unselected small bowel adenocarcinomas

Abstract

AimsPrevious estimates of the prevalence of mismatch repair (MMR) deficiency and Lynch syndrome in small bowel cancer have varied widely. The aim of this study was to establish the prevalence of MMR deficiency and Lynch syndrome in a large group of small bowel adenocarcinomas.MethodsTo this end, a total of 400 small bowel adenocarcinomas (332 resections, 68 biopsies) were collected through the Dutch nationwide registry of histopathology and cytopathology (Pathologisch-Anatomisch Landelijk Geautomatiseerd Archief (PALGA)). No preselection criteria, such as family history, were applied, thus avoiding (ascertainment) bias. MMR deficiency status was determined by immunohistochemical staining of MMR proteins, supplemented by MLH1 promoter hypermethylation analysis and next generation sequencing of the MMR genes.ResultsMMR deficiency was observed in 22.3% of resected and 4.4% of biopsied small bowel carcinomas. Prevalence of Lynch syndrome was 6.2% in resections and 0.0% in biopsy samples. Patients with Lynch syndrome-associated small bowel cancer were significantly younger at the time of diagnosis than patients with MMR-proficient and sporadic MMR-deficient cancers (mean age of 54.6 years vs 66.6 years and 68.8 years, respectively, p<0.000).ConclusionsThe prevalence of MMR deficiency and Lynch syndrome in resected small bowel adenocarcinomas is at least comparable to prevalence in colorectal cancers, a finding relevant both for treatment (immunotherapy) and family management. We recommend that all small bowel adenocarcinomas should be screened for MMR deficiency.

Mismatch repair deficiency in early‐onset duodenal, ampullary, and pancreatic carcinomas is a strong indicator for a hereditary defect

“…The high dMMR yield in our cohort could be explained by preselection on the basis of young age, resulting in an increased number of patients with hereditary predisposition. Our findings are consistent with significantly lower age at diagnosis of LS-related SBCs (mean age: 54.6 years) compared to sporadic dMMR (68.8 years) and pMMR (66.6 years) SBCs [14]. Indeed, we identified LS solely in the earlyonset group, where it was the most common molecular background in dMMR tumours (5/11).…”

“…Because of rarity, large studies on DC are either missing or include DC in cohorts of periampullary or other small bowel carcinomas (SBCs). The observed dMMR frequency in early-onset DCs is more than two-fold higher compared to 13-23% dMMR in unselected DCs [13,14]. The high dMMR yield in our cohort could be explained by preselection on the basis of young age, resulting in an increased number of patients with hereditary predisposition.…”

“…For instance, in a consecutive unselected cohort of 400 SBCs (22.3 and 4.4% dMMR in resected and biopsy SBCs, respectively), MLH1 promoter hypermethylation was the most common cause of the dMMR phenotype, explaining 40.5% of dMMR resections and 66.7% of dMMR biopsy specimens. This is potentially related to an overrepresentation of patients with coeliac disease, known to be associated with dMMR, particularly in the context of MLH1 promoter hypermethylation [14]. The mean age at diagnosis in the reported cohort was significantly higher in sporadic dMMR SBCs (68.8 years) compared to LS-associated SBCs (54.6 years) [14].…”

“…This is potentially related to an overrepresentation of patients with coeliac disease, known to be associated with dMMR, particularly in the context of MLH1 promoter hypermethylation [14]. The mean age at diagnosis in the reported cohort was significantly higher in sporadic dMMR SBCs (68.8 years) compared to LS-associated SBCs (54.6 years) [14].…”

How Should We Test for Lynch Syndrome? A Review of Current Guidelines and Future Strategies

“…For example, 92.9% (13/14) of sporadic MMR-deficient GCs had MLH1 promoter methylation [ 236 ], whereas 0.0% (0/14) of MLH1-deficient LS CNS tumours and UCs had MLH1 promoter methylation [ 28 ]. In addition, MLH1 promoter methylation testing has been shown to increase the specificity of LS screening in OCs [ 237 ] and in SBCs [ 171 ]. However, additional research into the efficacy of MLH1 promoter methylation testing in each tumour type is needed, as are analyses of cost-effectiveness before expansion of screening guidance to include MMR deficiency testing of all Lynch-spectrum tumours is considered.…”