Shared inheritance reveals landscape of somatic and germline cancer risk in TP53.

Loss of function of the TP53 tumour suppressor gene, with variants detected in blood arising either from the germline or from somatic clonal expansions of haematopoiesis.

Apparently pathogenic TP53 variants found in blood may come from the germline or from somatic clonal expansions, which complicates risk interpretation. Using blood-derived whole-exome data from 469,391 UK Biobank participants, the authors combined variant allele fraction (VAF) with haplotype-sharing analysis to separate germline from somatic TP53 variants. Germline variants clustered at sites linked to partial loss of p53 function and lower penetrance, whereas classic Li-Fraumeni alleles appeared to be predominantly somatically acquired. Classic alleles at high VAF carried a markedly increased risk of haematological malignancy but not of solid tumours, reflecting the contribution of large TP53-mutant clonal expansions. The prevalence of clonal expansion correlated with missense variant pathogenicity, so somatic activity provides an informative in vivo proxy for functional impact.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The practical message for the cancer genetics clinic is that a TP53 variant found in blood DNA should not be reported as germline without a careful look at the allele fraction: mistaking clonal haematopoiesis for a constitutional variant commits a family to Li-Fraumeni-type surveillance, cascade testing and needless anxiety, while a low-penetrance germline variant may equally be overcalled. The trade-off is that the study population consists of unselected middle-aged adults, precisely where clonal haematopoiesis weighs most heavily, so these proportions do not transfer directly to a family referred for a suggestive cancer history, and no confirmation on non-haematopoietic tissue is provided. In practice it argues for weighing VAF, age and family context together and, whenever there is doubt, testing a non-blood sample before diagnosing Li-Fraumeni syndrome.

Analysis by Dr Thibaut Benquey