Overcome tumor heterogeneity-imposed therapeutic barriers through convergent genomic biomarker discovery: A braided cancer river model of kidney cancer

Abstract

Tumor heterogeneity, encompassing genetic, epigenetic, and microenvironmental variables, is extremely complex and presents challenges to cancer diagnosis and therapy. Genomic efforts on genetic intratumor heterogeneity (G-ITH) confirm branched evolution, support the trunk-branch cancer model, and present a seemingly insurmountable obstacle to conquering cancers. G-ITH is conspicuous in clear cell renal cell carcinoma (ccRCC), where its presence complicates identification and validation of biomarkers and thwarts efforts in advancing precision cancer therapeutics. However, long-term clinical benefits on targeted therapy are not uncommon in metastatic ccRCC patients, implicating that there are underlying constraints during ccRCC evolution, which in turn force a nonrandom sequence of parallel gene/pathway/function/phenotype convergence within individual tumors. Accordingly, we proposed a “braided cancer river model” depicting ccRCC evolution, which deduces cancer development based on multiregion tumor genomics of exceptional mTOR inhibitor (mTORi) responders. Furthermore, we employ an outlier case to explore the river model and highlight the importance of “Five NGS Matters: Number, Frequency, Position, Site and Time” in assessing cancer genomics for precision medicine. This mutable cancer river model may capture clinically significant phenotype-convergent events, predict vulnerability/resistance mechanisms, and guide effective therapeutic strategies. Our model originates from studying exceptional responders in ccRCC, which warrants further refinement and future validation concerning its applicability to other cancer types. The goal of this review is employing kidney cancer as an example to illustrate critical issues concerning tumor heterogeneity.

Genomic landscape and evolution of metastatic chromophobe renal cell carcinoma

“…Among the 451 upregulated genes in ICD (+) chRCC, 401 (89%) were up in WGD (+) ccRCC compared with WGD (-) ccRCC, and among the 525 downregulated genes in ICD (+) chRCC, 415 (79%) were down (χ 2 test, P < 1 × 10 -30 ) ( Figure 6A). Hence, the molecular signature conferred by ICD in chRCC is highly concordant with that by WGD in ccRCC, implying a shared pathway convergent evolution between 2 kidney cancer subtypes (28,36).…”

“…In patients 2 and 3, TP53 mutation was absent in the primary tumor but present in the metastatic lymph nodes. In patient 4, the same TP53 N310Tfs mutation was present in primary and metastatic lymph node samples, whereas 5 different PTEN mutations were detected and distributed among samples, demonstrating convergent mutation evolution of PTEN (28,31,32). In patient 5, both TP53 and PTEN mutations were detected in the dominant clone and hence present in both primary and metastatic liver samples.…”

“…TP53 and PTEN mutations appear to be more frequent in the primary tumors of M-chRCC than nonmetastatic ID-chRCC patients, implying their roles in metastatic progression of chRCC. Of note, more than 1 TP53 mutation was detected in the primary tumors of 6 M-chRCC and 3 ID-chRCC cases (Figure 2A), reminiscent of the convergent mutation evolution of 3p tumor suppressors and the resulting intratumor heterogeneity in ccRCC (28).…”

Renal cell carcinoma

“…Indeed, owing to the predominance of clear cell histology in metastatic disease (83–88%) 12,13 , tumours with non-clear cell histology have been grouped as ‘nccRCC’ (Table 1) for feasibility in conducting clinical trials 14–16 . Furthermore, recent cancer genomic studies have revealed an overt complexity of intra-tumour 17–19 and inter-tumour 7,20 heterogeneity in ccRCC, which could contribute to the heterogeneous clinical outcomes observed 21–23 .…”

Long-Term Effects of Metabolic Stress on Human Malignant Melanoma Cell Line

“…It is now a known fact that a tumour is not a homogenous tissue and in recent years, many researchers have focused on the heterogeneity of the tumour tissue. [14][15][16][17][18] The outer layers of a tumour can proliferate easily. These cells have enough space to proliferate, and sufficient access to blood as a source of oxygen and nutrition and a readily accessible stream for getting rid of all the metabolic wastes.…”