Cancer Subclonal Genetic Architecture as a Key to Personalized Medicine

Abstract

The future of personalized oncological therapy will likely rely on evidence-based medicine to integrate all of the available evidence to delineate the most efficacious treatment option for the patient. To undertake evidence-based medicine through use of targeted therapy regimens, identification of the specific underlying causative mutation(s) driving growth and progression of a patient's tumor is imperative. Although molecular subtyping is important for planning and treatment, intraclonal genetic diversity has been recently highlighted as having significant implications for biopsy-based prognosis. Overall, delineation of the clonal architecture of a patient's cancer and how this will impact on the selection of the most efficacious therapy remain a topic of intense interest.

Introduction

In the early 1600s, Miguel de Cervantes wrote the book titled Don Quixote during the historical period known as the Spanish Golden Age. In the book, the protagonist Alonso Quijano, an older gentleman with waning mental facilities, dons a suit of armor and renames himself “Don Quixote de la Mancha.”Early one morning at dawn, Don Quixote rides off on his trusted horse “Rocinante”along with his neighbor Sancho Panza whom he asked to be his squire. Together, they experience a series of (mis)adventures. In one particularly famous episode described in the novel, they came on a vast plain dotted with a myriad of windmills wherein Don Quixote, on seeing them, said to his squire, “Fortune is guiding our affairs better than we ourselves could have wished. Do you see over yonder, friend Sancho, thirty or forty hulking giants? I intend to do battle with them and slay them. With their spoils we shall begin to be rich for this is a righteous war and the removal of so foul a brood from off the face of the earth is a service God will bless.”Sancho Panza replied to his trusted master, “What giants?”“Those you see over there,”replied his master, “with their long arms. Some of them have arms well-nigh two leagues in length.”Don Quixote imagined the windmills to be giants with large arms in the distance and proceeded to fight the giants to rid humanity of their scourge.

The imagery provided by Cervantes is quite interesting and relevant for cancer researchers as Don Quixote consistently misinterpreted his adversaries and actions of his allies. Misinterpretation of the enemy targets resulted in consequences that expended resources that were not productive in achieving the overarching goal. Viewed as an allegory for cancer research, one can envision the hub of the windmill as the original mutation within an individual cell and each of the windmill blades as multiple cancers emerging of this initiating event due to genetic heterogeneity. This process results in a diverse set of cell populations emanating out from the “hub”of the original cell mutation. Thus, each patient may have a completely different set of cancers (blades on the windmill) due to the overall chaotic processes.

This past year, technological advances in measuring intratumor cancer diversity revealed significant differences between cancerous cells within a patient [Potter NE, Ermini L, Papaemmanuil E, Cazzaniga G, Vijayaraghavan G, Titley I, Ford A, Campbell P, Kearney L, Greaves M (2013). Single-cell mutational profiling and clonal phylogeny in cancer. Genome Res 23(12), 2115–2125]. Investigators at the Institute of Cancer Research quantified cancer diversity within five different patients with leukemia. When the mutations were compared in individual tumor cells against a known database, it was determined that patients had not 1 but between 2 and 10 genetically distinct leukemias. Thus, each of the patients was found to not have a single cancer but multiple cancers much like the windmill analogy with multiple blades. In fact, it appears that treatment of patients with cancer will require that their disease be considered as multiple cancers each needing its own unique intervention. In other words, not only will the hub need to be treated but also each of the “blades” emanating out from the initiating cell will also need to be targeted to have a lasting cure. In fact, although it is currently unclear how many different cancers a solid tumor may have, it could increase many-fold, and each patient will likely have a different number that will require treatment. Advances in technology are beginning to transform our understanding and capabilities by providing an opportunity to undertake a comprehensive interrogation of the complex genomics within a tumor using single-cell analysis. Whole-genome amplification of single cells obtained from the tumor of a patient allowing for subclonal information to be derived will likely be proven as a significant advance in our quest for if not an outright cure, then at least significantly prolonged survival with a good quality of life.

Summary

The overall economic burden of cancer is huge and was recently assessed across the European Union using a population-based cost analysis (Luengo-Fernandez et al., Lancet Oncology, 14(12):1165–74, 2013). The overall cancer cost was estimated to be in the $170 billion range annually. These numbers clearly indicate that we cannot afford to continue to charge at windmills but need to begin to carefully assess how best to focus our attention and resources. Areas might include targeting tumor vasculature, stimulation of the immune system, or early diagnosis or a combination. It seems clear that, likely, each patient has a unique and complex array of diverse mutations, each of which must be treated to gain optimal therapeutic control. In this regard, improving our understanding of cancer biology in the context of genotypic and phenotypic diversity is required to positively impact outcomes of patients with cancer. The mission of the journal Neoplasia is to provide peer-reviewed information related to advancing knowledge and clinical care of oncology patients. In this regard, we have published a diverse array of articles on topics related to tumor biology, genetics, experimental therapeutics, clinical investigations, and cancer imaging (Table 1). The dissemination of this broad-based information will assist researchers with their efforts in adding continuously to the progressing story. Neoplasia provides rapid access to all articles to the worldwide clinical cancer research community, which is a key feature of this journal. As the Editor along with my esteemed members of the Editorial Board, together we are very pleased with the success that this effort has had in serving the cancer research community and look forward to continued progress in improving the outcome of patients diagnosed with cancer.

Table 1.

Summary of Published Articles.

Subject	2011	2012	2013
Cancer genetics	[17,31,33,37,40,54,57,73,98,99,103]	[127,128,131,135,136,148,156,159,161,166,167,170,171,176,181,183,188,195,196,201,205,206,225,228]	[230,233,243,245,261,264,267,269,283,287,291,294,300,309,316,319,324,328,348,349]
Cell and tumor biology	[1–3,9–11,18,24,26–30,35,39,45,46,48–50,55,61,64,66,67,69,74,75,82,85–90,92,94,101,102,104–108,110]	[111–115,117,119,122,123,129,130,132–134,138,142,146,147,154,155,158,160,165,169,173,177,180,182,185,189–192,194,197,203,204,207–209,217–220]	[231,236,237,241,242,246,247,249,253,255,259,260,262,268,271,272,274,278,279,281,282,288,293,296,299,301,303,304,307,311,312,314,317,318,322,326,329,330,333–336,338,339,341,342,344,345,347,350]
Experimental therapeutics	[6,8,13–16,21,23,32,34,36,41–43,51,52,56,60,65,68,77–79,81,83,84,95–97,100,109]	[116,120,121,126,137,140,144,151,152,157,164,168,172,174,178,179,186,187,193,198,199,202,211–213,216,226,227,229]	[232,234,239,240,244,250,254,256–258,263,275–277,280,285,286,297,298,302,305,306,320,321,323,325,337,340,351–353]
Tumor immunology	[4,7,53,59,63,71,72,80,91,93]	[124,125,143,149,175,184,210,214,222]	[235,238,273,331]
Epidemiology and prevention			[266,289,292,295,310,313]
Cancer imaging	[12,22,25,44,47,58,76]	[145,150,153,162,163,200]	[270,308,327,343,354]
Clinical investigations	[19,62]	[118,141]	[248,332]
Animal models	[5,20,38,70]	[139,215]	[251,252,265,284,290,315]