Intratumor Heterogeneity
Definition
Intratumor heterogeneity (ITH) is the presence of genetically and phenotypically distinct subclonal populations within a single tumor. It provides the substrate upon which Darwinian selection acts during clonal-evolution and is a fundamental property of human cancers (McGranahan & Swanton, 2017).
Prevalence
ITH has been documented across virtually all cancer types. The degree of ITH is highly variable — between 0 and over 8,000 coding mutations have been found to be heterogeneous within primary tumors or between primary and metastatic sites (McGranahan & Swanton, 2017). Certain tumor types, such as melanoma and lung cancer, harbor a significantly larger clonal mutational burden than others, largely due to powerful exogenous mutagens (UV light, tobacco carcinogens).
A large clonal burden does not equate to a large subclonal burden, and vice versa. The clonal and subclonal landscapes reflect both the timing and intensity of mutational processes and the strength of selective pressures over time (McGranahan & Swanton, 2017).
Sources
ITH arises from ongoing mutation during tumor growth. Key sources include:
- Point mutations from endogenous and exogenous mutational processes, including APOBEC-mutagenesis
- chromosomal-instability producing aneuploidy and copy-number-alterations
- whole-genome-duplication events that create tetraploid intermediates
- chromothripsis and chromoplexy — catastrophic genomic rearrangements
- Epigenetic variation, which occurs at rates orders of magnitude higher than genetic change (Greaves & Maley, 2012)
Clinical Significance
ITH is a critical determinant of therapy failure. As McGranahan & Swanton (2017) argue, ITH “provides the substrate for adaptation under selective pressures (including therapy and immune surveillance), making it a critical determinant of drug resistance, metastasis, and patient outcome” (p. 613).
Truncal (clonal) mutations present in all tumor cells, including canonical driver events in EGFR, KRAS, TP53, and KEAP1, represent more homogeneous therapeutic targets. In contrast, branch (subclonal) mutations are restricted to subsets of the tumor and targeting them leaves resistant subpopulations untouched.
Clonal diversity as a biomarker. The level of ITH has prognostic value. In Barrett’s esophagus, genetic clonal diversity independently predicted progression to esophageal adenocarcinoma (Maley et al., 2006, cited in Greaves & Maley, 2012). In TRACERx Renal, subclonal diversification of somatic CNAs and mutational drivers was independently associated with reduced progression-free and overall survival (Turajlic et al., 2019).
Immunotherapy. Subclonal neo-antigens do not stimulate an adequate immune response. McGranahan et al. (2016, cited in McGranahan & Swanton, 2017) showed reduced sensitivity to checkpoint blockade in melanoma and NSCLC tumors with a significant burden of subclonal mutations. clonal-neoantigens derived from truncal mutations, expressed homogeneously, are superior immunotherapy targets.