A pathogenic mosaic TP53 mutation in two germ layers detected by next generation sequencing.

Area of Science:

• Genetics
• Oncology
• Developmental Biology

Background:

• Li-Fraumeni syndrome is linked to germline TP53 mutations, increasing cancer risk.
• Pathogenic TP53 mosaic mutations are infrequently documented.

Observation:

• A 2-year-old presented with three distinct cancers within six months, including soft tissue tumors and neuroblastoma.
• Standard genetic testing for TP53, ALK, and SDH mutations in blood DNA was negative.

Findings:

• Whole exome sequencing revealed a TP53 mutation (c.743 G>A, p.Arg248Gln) in 3-20% of the patient's blood DNA, undetectable by Sanger sequencing.
• This TP53 mutation was homozygous in all tumors and confirmed as germline mosaicism via newborn blood spot analysis.
• The mutation's presence in tumors from different germ layers suggests an early embryonic origin, pre-dating gastrulation.

Implications:

• This case highlights the utility of next-generation sequencing in detecting low-level mosaic mutations.
• Early embryogenesis TP53 mosaicism can lead to diverse and aggressive cancers.
• Understanding early-acting mosaic mutations is crucial for diagnosing and managing rare cancer predisposition syndromes.