Germline mutation in ATR in autosomal- dominant oropharyngeal cancer syndrome

Area of Science:

• Genetics and Molecular Biology
• Human Disease and Cancer Biology

Background:

• The ATR (ataxia telangiectasia and Rad3 related) gene is crucial for maintaining genome integrity and coordinating DNA replication and repair.
• Autosomal-recessive loss-of-function mutations in ATR are associated with Seckel syndrome, a developmental disorder.
• The role of ATR in autosomal-dominant inherited diseases was previously unexplored.

Purpose of the Study:

• To investigate a novel autosomal-dominant inherited disorder characterized by oropharyngeal cancer and skin telangiectases.
• To identify the genetic basis of this new disease and its association with ATR.
• To understand the molecular mechanisms linking ATR dysfunction to cancer susceptibility.

Main Methods:

• Pedigree analysis of 24 affected individuals across five generations.
• Genetic mapping to chromosomal region 3q22-24.
• Sequencing of candidate genes, including ATR, to identify causative mutations.
• Functional studies using cultured fibroblasts to assess p53 levels after ATR activation.
• Analysis of tumor tissue for loss of heterozygosity at the ATR locus.

Main Results:

• A heterozygous missense mutation (c.6431A>G [p.Gln2144Arg]) in the ATR gene was identified and segregated with the disease.
• The mutation is located in the FAT domain of ATR, which is involved in p53 activation.
• Fibroblasts from affected individuals showed reduced p53 levels after ATR activation.
• Loss of heterozygosity for the ATR locus was observed in oropharyngeal tumor tissues.

Conclusions:

• The findings implicate a germline mutation in ATR as a cause of a novel autosomal-dominant cancer syndrome.
• This ATR mutation compromises its function, leading to increased susceptibility to malignancy.
• The study expands the known spectrum of ATR-related disorders and highlights its role in inherited cancer predisposition.