Large mutations in normal-appearing cells that neighbor tumors

Go to the profile of Yasminka A Jakubek
Nov 05, 2019
0
0
Figure 1

Clonal mosaicism, multiple genetically distinct cell populations in a single organism, is the result of post-zygotic mutations followed by clonal expansions (Figure 1). Studies of tissues from healthy donors have uncovered acquired mutations in genes, such as TP53 and KRAS, that are recurrently mutated in cancers, and demonstrate that individuals with clonal mosaicism in blood are at elevated risk of incident hematological cancers [1-3]. Ideally, we would like to know which mutations in otherwise healthy individuals are most likely to lead to cancer. This underscores the importance of studying acquired mutations in non-cancer tissues, including normal-appearing adjacent-to-tumor (NAT) tissues. These tissues and the neighboring tumor can share somatic mutations and extracellular/environmental exposures.

Our group had previously worked on detection of somatic mutations in NAT tissues from lung cancer patients, and had shown that we could detect large chromosomal alterations (gain, loss, and copy neutral loss of heterozygosity) present at modest mutant cell fractions by using SNP array data and haplotype information [4 & 5]. This work demonstrated the presence of mutations, including large copy number alterations, in the airway field of cancerization and motivated us to expand upon this work. The TCGA data provided us with a unique opportunity to survey mosaicism across NAT tissues from 27 cancer sites. We found that NAT tissues from specific sites had recurrent megabase-scale alterations in particular chromosome arms; these included 1q in breast, 9p in bladder, 9q in head and neck, chromosome 20 in stomach, and chromosome X in kidney. Therefore, although they have a much lower copy number alteration burden relative to tumors, NAT also have distinct patterns of copy number changes.

For NAT tissues from head and neck, we jointly analyzed acquired point mutation and chromosomal alterations, and discovered an association with mutations in head and neck cancer driver genes and the presence of chromosomal alterations. This result suggests that chromosomal alterations may, in some cases, indicate that a clone is further along the path towards malignancy. This idea is supported by the previously reported positive association between a higher burden of chromosomal alterations in oral premalignant lesions and progression to invasive disease [6]. The alterations themselves may contribute to this progression and/or signal defects in cellular pathways responsible for genomic integrity.

Somatic chromosomal alterations are large mutational events that simultaneously impact many genes. Therefore, relative to point mutations, it is more difficult to understand the molecular effects of SCNAs. Although challenging, understanding if and how these chromosomal alterations with tissue-specific patterns of enrichment are related to clonal expansions, cancer and other diseases could help advance early detection and prevention. If some of the identified chromosomal alterations are indicative of an increased risk of cancer, could we detect these clonal expansions with biomarkers and stratify individuals for more intensive screening regimens? Can we identify chemo-preventive agents or life-style changes that would eliminate or halt expansion of these cells? These are challenging and open questions, but we are optimistic about the research community’s ability to tackle them through innovation and interdisciplinary collaboration.


References

1.         Machiela, M.J. & Chanock, S.J. The ageing genome, clonal mosaicism and chronic disease. Curr Opin Genet Dev 42, 8-13 (2017).

2.         Martincorena, I. et al. Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin. Science 348, 880-886 (2015).

3.         Yizhak, K. et al. RNA sequence analysis reveals macroscopic somatic clonal expansion across normal tissues. Science 364 (2019).

4.         Jakubek, Y. et al. Genomic Landscape Established by Allelic Imbalance in the Cancerization Field of a Normal Appearing Airway. Cancer Res 76, 3676-3683 (2016).

5.         Kadara, H. et al. Driver Mutations in Normal Airway Epithelium Elucidate Spatiotemporal Resolution of Lung Cancer. Am J Respir Crit Care Med (2019).

6.         Garnis, C. et al. Genomic imbalances in precancerous tissues signal oral cancer risk. Molecular cancer 8, 50 (2009).


Go to the profile of Yasminka A Jakubek

Yasminka A Jakubek

Instructor, MD Anderson

No comments yet.