A new study published on 7 June in Science contradicts the prevailing idea that all genes in the human body are identical copies of each other (1). Instead, even ‘normal’ tissues accumulate genetic mutations over time resulting in something called mosaicism.
The findings suggest mutations can — and often do — exist in nearly all individuals and across many ‘normal’ human tissues. And many of them are found in so-called ‘cancer hotspots’, as some of the earliest precancerous changes that may go on to eventually become cancer.
The fact that mosaicism exists in tissues is not a new concept. Previous studies found high levels of mosaicism in the skin, oesophagus, and blood. However, the study is the largest of its kind to date. And the major discovery here is that mosaicism is present across a huge range of tissues.
The researchers from the Broad Institute of MIT and Harvard in the US collected and analysed 6700 samples — from 29 major tissue groups including the brain, bladder, and lungs — of around 500 people to look for mutations. And found a lot more than expected.
This time, the use of RNA data allowed scientists to examine mutations on a much larger scale. The body uses DNA as a template for making RNA sequences, so mutations in DNA are sometimes reflected in RNA.
More specifically, they used something called RNA sequencing to look for groups of cells with the same mutations based on RNA-sequence data from the Genotype-Tissue Expression (GTEx) project, a resource for researchers to study how inherited changes in genes lead to common diseases. Although the study is not without limitations since not all DNA mutations arise in RNA sequences.
Nonetheless, and interestingly, instead of every tissue containing the same genome, the large-scale analysis uncovered a mosaic of mutations throughout the different tissues of the body. And many of the mutations they found are known to drive cancer.
In particular, skin, lung, and oesophagus cells and tissues contain the largest numbers of mutations, which is expected, according to the authors. The environment plays an important role in generating genetic mutations. For example, exposure to cigarette and sunlight are known to cause DNA changes.
Apart from tissue type, the researchers also discovered a connection between the number of mutations and age — samples from older individuals had a greater number of mutations.
While genome analyses of cancerous tissues allow researchers to learn about the genetic make-up of tumours, they don’t provide much information on the genetic background of the tissue that led to the formation of the tumour.
Thus, new information on mutations found in normal cells and tissues and whether they eventually develop into cancerous ones could improve our understanding of the origins and progression of cancers. And possibly help develop new methods for the early detection of cancer.
So, the next step will be deciphering how to tell which cells do eventually lead to cancer and which cells remain normal — which could be the key to detecting cancers much earlier and possibly even preventing them.
(1) Yizhak, K. et al. RNA sequence analysis reveals macroscopic somatic clonal expansion across normal tissues. Science (2019). DOI: 10.1126/science.aaw0726