Clonal status of actionable driver events and the timing of mutational processes in cancer evolution

Abstract

Deciphering whether actionable driver mutations are found in all or a subset of tumor cells will likely be required to improve drug development and precision medicine strategies. We analyzed nine cancer types to determine the subclonal frequencies of driver events, to time mutational processes during cancer evolution, and to identify drivers of subclonal expansions. Although Table S1. Driver genes within each cancer type (provided as a separate Excel file). Table S2. Mutational spectra of cancer genes (provided as a separate Excel file). Table S3. Cancer genes identified through clonality and temporal dissection analysis (provided as a separate Excel file). Table S4. Genes linked with targeted therapeutics (provided as a separate Excel file). Competing interests: C.S. sits on the Roche/Genentech clinical trial steering committee. All other authors declare that they have no competing interests.Data and materials availability: Data and code are available online at https://bitbucket.org/nmcgranahan/pancancerclonality/ downloads/McGranahan_data.zip. Europe PMC Funders Group Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts mutations in known driver genes typically occurred early in cancer evolution, we also identified later subclonal "actionable" mutations, including BRAF(V600E), IDH1(R132H), PIK3CA(E545K), EGFR(L858R), and KRAS(G12D), which may compromise the efficacy of targeted therapy approaches. More than 20% of IDH1 mutations in glioblastomas, and 15% of mutations in genes in the PI3K(phosphatidylinositol 3-kinase)-AKT-mTOR (mammalian target of rapamycin) signaling axis across all tumor types were subclonal. Mutations in the RAS-MEK (mitogen-activated protein kinase kinase) signaling axis were less likely to be subclonal than mutations in genes associated with PI3K-AKT-mTORsignaling. Analysis of late mutations revealed a link between APOBEC-mediated mutagenesis and the acquisition of subclonal driver mutations and uncovered putative cancer genes involved in subclonal expansions, including CTNNA2 and ATXN1. Our results provide a pan-cancer census of driver events within the context of intratumor heterogeneity and reveal patterns of tumor evolution across cancers. The frequent presence of subclonal driver mutations suggests the need to stratify targeted therapy response according to the proportion of tumor cells in which the driver is identified.

Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future

“…Subclonal mutations in PIK3CA have been found in, among other cancer types, lung (de Bruin et al, 2014), breast (Yates et al, 2015), colorectal (Uchi et al, 2016), melanoma (Harbst et al, 2016), esophageal squamous cell carcinoma (Hao et al, 2016), ccRCC (Gerlinger et al, 2014a) and ovarian cancers (Bashashati et al, 2013). In keeping with these results, across 9 cancer types, mutations in the PI3K-AKT-mTOR pathway were found to harbor a higher proportion of subclonal mutations compared to genes associated with RAS-MAPK pathway (McGranahan et al, 2015). However, other driver mutations exhibit a tendency to be clonal in certain cancer types but not others.…”

“…Studies exploring ITH within solid tumors have demonstrated a tendency for established cancer genes to harbor clonal mutations (McGranahan et al, 2015). However, despite this tendency, even mutations in cancer genes can be present in only a subset of cancer cells within a tumor.…”

“…The observation that multiple different diversity measures in Barrett's esophagus predict progression to esophageal adenocarcinoma (Maley et al, 2006;Merlo et al, 2010) is indicative that diversity may lead to selection of aggressive subclones, even without therapeutic selection pressures. Relatedly, the fact that cancer genes can harbor a statistically significant enrichment of subclonal mutations suggests a signal of selection can be present throughout tumor evolution (McGranahan et al, 2015). It remains an open question whether distinct clinical behaviors can be observed depending on the mode of tumor evolution, or whether the occurrence of neutral evolution and drift may limit the ability to predict a tumor's next step (Lipinski et al, 2016).…”

“…Predominantly this likely reflects the fact that distinct mutational processes may operate at different times in tumor evolution (de Bruin et al, 2014;McGranahan et al, 2015;Nik-Zainal et al, 2012). Indeed, the most notable outliers with regard to high subclonal mutational burden, but low clonal burden, are low-grade gliomas that recur as glioblastomas after treatment with the alkylating agent temozolomide Kim et al, 2015).…”

“…In other cancer types, such as non-small cell lung cancer (NSCLC) and bladder cancer, the presence of a large subclonal mutation burden can be attributed to the action of the APOBEC family of cytidine deaminases (de Bruin et al, 2014;McGranahan et al, 2015;Zhang et al, 2014). In colorectal and prostate cancers, alterations to mismatch repair or proofreading machinery can occasionally play a key role in generating both clonal and subclonal mutations (Kumar et al, 2016;Uchi et al, 2016).…”