Mutations In Normal Tissues Research Articles

Patterns of Somatically Acquired Amplifications and Deletions in Apparently Normal Tissues of Ovarian Cancer Patients

Little is understood about the occurrence of somatic genomic alterations in normal tissues and their significance in the context of disease. Here, we identified potential somatic copy number alterations (pSCNAs) in apparently normal ovarian tissue and peripheral blood of 423 ovarian cancer patients. There were, on average, two to four pSCNAs per sample detectable at a tissue-level resolution, although some individuals had orders of magnitude more. Accordingly, we estimated the lower bound of the rate of pSCNAs per cell division. Older individuals and BRCA mutation carriers had more pSCNAs than others. pSCNAs significantly overlapped with Alu and G-quadruplexes, and the affected genes were enriched for signaling and regulation. Some of the amplification/deletion hotspots in pan-cancer genomes were hot spots of pSCNAs in normal tissues as well, suggesting that those regions might be inherently unstable. Prevalence of pSCNA in peripheral blood predicted survival, implying that mutations in normal tissues might have consequences for cancer patients.

Uncovering the Profile of Somatic mtDNA Mutations in Chinese Colorectal Cancer Patients

In the past decade, a high incidence of somatic mitochondrial DNA (mtDNA) mutations has been observed, mostly based on a fraction of the molecule, in various cancerous tissues; nevertheless, some of them were queried due to problems in data quality. Obviously, without a comprehensive understanding of mtDNA mutational profile in the cancerous tissue of a specific patient, it is unlikely to disclose the genuine relationship between somatic mtDNA mutations and tumorigenesis. To achieve this objective, the most straightforward way is to directly compare the whole mtDNA genome variation among three tissues (namely, cancerous tissue, para-cancerous tissue, and distant normal tissue) from the same patient. Considering the fact that most of the previous studies on the role of mtDNA in colorectal tumor focused merely on the D-loop or partial segment of the molecule, in the current study we have collected three tissues (cancerous, para-cancerous and normal tissues) respectively recruited from 20 patients with colorectal tumor and completely sequenced the mitochondrial genome of each tissue. Our results reveal a relatively lower incidence of somatic mutations in these patients; intriguingly, all somatic mutations are in heteroplasmic status. Surprisingly, the observed somatic mutations are not restricted to cancer tissues, for the para-cancer tissues and distant normal tissues also harbor somatic mtDNA mutations with a lower frequency than cancerous tissues but higher than that observed in the general population. Our results suggest that somatic mtDNA mutations in cancerous tissues could not be simply explained as a consequence of tumorigenesis; meanwhile, the somatic mtDNA mutations in normal tissues might reflect an altered physiological environment in cancer patients.

Mutations in normal breast tissue and breast tumours.

The accumulation of mutations is a feature of all normal cells. The probability of any individual gene in any cell acquiring a mutation is, however, low. Cancer is therefore a rare disease in comparison with the number of susceptible cells. Mutations in normal tissue are stochastic, vary widely among cells and are therefore difficult to detect using standard methods because each change is so rare. If, however, a tissue such as the breast undergoes considerable clonal expansion, particularly if relatively late in life, normal tissue may have accumulated many thousands of detectable mutations. Since breast cancers are clonal and have almost certainly undergone many more cell divisions than normal cells, each tumour may have many millions of mutations, most of which are entirely innocent and some of which have accumulated in the cell of origin prior to tumorigenesis. Despite some claims to the contrary, even at normal mutation rates, clonal expansion within a tumour is quite sufficient to account for the mutations of five or six genes that are generally supposed necessary for carcinogenesis to occur. Hypermutability does, however, contribute to the pathogenesis of many cancers and, although evidence is indirect in breast cancer, may take forms such as karyotypic instability via centrosome amplification.