Somatic mutant clones colonize the human esophagus with age

Abstract

The extent to which cells in normal tissues accumulate mutations throughout life is poorly understood. Some mutant cells expand into clones that can be detected by genome sequencing. We mapped mutant clones in normal esophageal epithelium from nine donors (age range 20 to 75 years). Somatic mutations accumulated with age and were mainly caused by intrinsic mutational processes. We found strong positive selection of clones carrying mutations in 14 cancer genes, with tens to hundreds of clones per square centimeter. In middle-aged and elderly donors, clones with cancer-associated mutations covered much of the epithelium, with NOTCH1 and TP53 mutations affecting 12 to 80% and 2 to 37% of cells, respectively. Unexpectedly, the prevalence of NOTCH1 mutations in normal esophagus was several times higher than in esophageal cancers. These findings have implications for our understanding of cancer and ageing.

Oncogenic mutations in histologically normal endometrium: the new normal?

“…Accumulation of somatic alteration with increasing age has previously been suggested even in the context of normal tissues . To assess the relationship between age and presence of somatic cancer‐driver alterations, we generated a logistic regression model based on the sequencing and IHC findings for the 25 women in the Hx cohort and 85 women in the Bx cohort (Figure ).…”

“…Somatic mutations have been previously described to increase in prevalence with increasing age in a variety of noncancerous tissues and thus we sought to determine the relationship between age and prevalence of somatic mutation in the normal endometrium. Overall, we found that the prevalence of oncogenic mutations in normal endometrium indeed increases by age; the risk of harboring such a mutation increases by approximately 5% per year.…”

“…However, the emergence and refinement of next generation sequencing techniques has markedly improved the resolution of mutation detection down to around 1% for single nucleotide polymorphisms . Subsequently, clonal subpopulations of cells harboring somatic driver mutations have been observed in several normal tissues including the skin , blood , peritoneal washings , and the esophageal epithelium , thereby shining light on early somatic events that predate malignant transformation (or even the appearance of precancerous lesions) and the nature of seemingly age‐related accumulation of mutations.…”

KRAS mutations in implant‐associated peripheral giant cell granuloma

“…Taken together, our data and the literature available, we can hypothesize that the inflammatory environment of the peri‐implant tissue could trigger KRAS mutations and MAPK/ERK activation, which can contribute to IA‐PGCG development. Despite the increasing number of reports of pathogenic mutations in normal and inflammatory tissues (Lac et al, ; Martincorena et al, ), there are no data regarding peri‐implant inflammatory tissues. Thus, further studies are necessary to test these assumptions.…”

Early detection and therapeutics

“…This is especially important in view of recent data showing that typical driver mutations can occur in healthy cells throughout life, which does not necessarily alter the cell behaviour. For example, a study analysing the oesophageal epithelium from healthy donor samples showed the presence of TP53 mutations in 5-10% across all nine donors, with the oldest donor (75 years old) having TP53 mutations in 20-35% of cells (Martincorena et al, 2018). In another study, analysing the role of ctDNA in the early detection of small-cell lung cancer, the TP53 mutations were present in the plasma of 11% of the 225 non-cancer controls (Fernandez-Cuesta et al, 2016).…”