Diagnosis of patients with Lynch syndrome lacking the Amsterdam II or Bethesda criteria

Abstract

Background Lynch Syndrome (LS) is an autosomal dominant inheritance disorder characterized by genetic predisposition to develop cancer, caused by pathogenic variants in the genes of the mismatch repair system. Cases are detected by implementing the Amsterdam II and the revised Bethesda criteria, which are based on family history. Main body Patients who meet the criteria undergo posterior tests, such as germline DNA sequencing, to confirm the diagnosis. However, these criteria have poor sensitivity, as more than one-quarter of patients with LS do not meet the criteria. It is very likely that the lack of sensitivity of the criteria is due to the incomplete penetrance of this syndrome. The penetrance and risk of developing a particular type of cancer are highly dependent on the affected gene and probably of the variant. Patients with variants in low-penetrance genes have a lower risk of developing a cancer associated with LS, leading to families with unaffected generations and showing fewer clear patterns. This study focuses on describing genetic aspects of LS cases that underlie the lack of sensitivity of the clinical criteria used for its diagnosis. Conclusion Universal screening could be an option to address the problem of underdiagnosis.

Optimizing mixed sample analysis as a step to comprehensive desease screening: a pilot study

“…These criteria undergo modifications in their models and strategies over time due to the recognition of their inadequacy based on practical experience [5]. Initially, individuals eligible for genetic testing for LS were identified based on their fulfillment of the Amsterdam criteria or Bethesda guidelines [6]. However, it has been established that these criteria are insufficient for effectively screening for Lynch syndrome because they can miss 23-50% of cases [3,7,8].…”

“…These criteria undergo modifications in their models and strategies over time due to the recognition of their inadequacy based on practical experience [5]. Initially, individuals eligible for genetic testing for LS were identified based on their fulfillment of the Amsterdam criteria or Bethesda guidelines [6].…”