Alu element insertion in the MLH1 exon 6 coding sequence as a mutation predisposing to Lynch syndrome

Area of Science:

• Genetics
• Molecular Biology
• Oncology

Background:

• Lynch syndrome (LS) is a primary cause of hereditary colorectal cancer.
• Lynch-like syndrome (LLS) describes patients with LS phenotypes but no identified causal germline mutations.
• Mobile DNA sequences, such as Alu retrotransposons, are implicated in cancer development.

Purpose of the Study:

• To investigate the genetic basis of Lynch-like syndrome in a family.
• To identify novel mechanisms contributing to hereditary colorectal cancer.
• To explore the role of retroelement insertions in cancer genetics.

Main Methods:

• Initial Sanger sequencing analysis classified the family as LLS.
• Next-generation sequencing (NGS) was employed for deeper genetic analysis.
• Analysis focused on identifying insertions and their impact on gene splicing.

Main Results:

• NGS identified an AluY5a insertion in the MLH1 gene (exon 6).
• This insertion caused MLH1 exon skipping, leading to a pathogenic frameshift.
• The identified genetic alteration was present in affected family members with colorectal adenocarcinomas.

Conclusions:

• Retroelement insertions, specifically Alu elements, represent an underappreciated cause of hereditary cancer.
• AluY5a insertion in MLH1 can induce splicing alterations leading to colorectal cancer.
• Systematic screening for retroelement insertions is recommended for LLS patients to refine risk assessment and surveillance.