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An Analysis of Genetic Heterogeneity in Untreated Cancers

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An Analysis of Genetic Heterogeneity in Untreated Cancers ANALYSIS An analysis of genetic heterogeneity in untreated cancers Johannes G. Reiter 1*, Marina Baretti 2, Jeffrey M. Gerold3, Alvin P. Makohon- Moore4, Adil Daud 5, Christine A. Iacobuzio- Donahue 4,6, Nilofer S. Azad2, Kenneth W. Kinzler2,7,8, Martin A. Nowak 3,9,10* and Bert Vogelstein 2,7,8,11* Abstract | Genetic intratumoural heterogeneity is a natural consequence of imperfect DNA replication. Any two randomly selected cells, whether normal or cancerous, are therefore genetically different. Here, we review the different forms of genetic heterogeneity in cancer and re-analyse the extent of genetic heterogeneity within seven types of untreated epithelial cancers, with particular regard to its clinical relevance. We find that the homogeneity of predicted functional mutations in driver genes is the rule rather than the exception. In primary tumours with multiple samples, 97% of driver- gene mutations in 38 patients were homogeneous. Moreover, among metastases from the same primary tumour, 100% of the driver mutations in 17 patients were homogeneous. With a single biopsy of a primary tumour in 14 patients, the likelihood of missing a functional driver-gene mutation that was present in all metastases was 2.6%. Furthermore, all functional driver-gene mutations detected in these 14 primary tumours were present among all their metastases. Finally , we found that individual metastatic lesions responded concordantly to targeted therapies in 91% of 44 patients. These analyses indicate that the cells within the primary tumours that gave rise to metastases are genetically homogeneous with respect to functional driver-gene mutations, and we suggest that future efforts to develop combination therapies have the potential to be curative. Subclonal Tumours develop through an evolutionary process that In this Analysis article, we review the different forms of Mutations present in only a usually spans multiple decades. During the expansion genetic tumour heterogeneity and re-evaluate sequencing subset of the tumour’s cells. of cell populations, intratumoural heterogeneity arises data in the literature with particular regard to the clini- They are sometimes described as a natural consequence of imperfect DNA replica- cal relevance of intratumoural heterogeneity. As a result as ‘branched’ because they 1–4 occur on a branch of the tion . Whenever a cell divides, a few mutations across of the different forms of tumour heterogeneity and the 5 tree when the evolutionary the whole genome are acquired . In a tumour composed recent focus on subclonal heterogeneity, some discrepan- trajectory of the tumour of billions of cells, every conceivable point mutation cies have arisen between the interpretations of observed is assessed. is expected to be present in at least a few cells. At the heterogeneity and its clinical implications2,12. Other dis- genetic level, not only is every cancer type different but crepancies arise from loose distinctions between func- also every tumour of the same type and every cell of the tional driver- gene mutations and passenger mutations, same tumour are different. This extensive heterogeneity because not every mutation within a bona fide driver has been considered a major barrier to drug develop- gene actually drives tumorigenesis2,13–15. When these fac- ment and long- term disease control6–11. However, the tors are taken into account, the sequencing data are in success (even if short-lived) of several forms of targeted harmony with clinical experience. Homogeneity of true therapies suggests that intratumoural heterogeneity does driver- gene mutations emerges as the rule rather than not preclude initial therapeutic response. For example, in the exception in treatment-naive cancers. patients with metastases — who represent the majority of patients treated with therapeutic agents — it would be Mutated driver genes in tumour evolution difficult to observe an objective response if some meta- Before we delve into a quantitative description of tumour *e- mail: johannes.reiter@ static lesions did not harbour the targeted driver- gene heterogeneity at the genetic level, we review some of stanford.edu; martin_ 7 [email protected]; mutation in the vast majority of their cells . How can the basic principles underlying the genetic determi- [email protected] the successful responses to targeted therapies be recon- nants of cancer. Solid tumours typically require alter- https://doi.org/10.1038/ ciled with the intratumoural heterogeneity that has been ations of three driver genes to convert a normal cell s41568-019-0185-x observed in next-generation sequencing studies? into a cancer cell2,16–21, although this number can vary NATURE REVIEWS | CANCER ANALYSIS Clonal among cancer types and individual patients. Each of suggests that one of these mutations is usually intra- Mutations present in virtually these alterations promotes tumorigenesis by providing genic (producing a stop codon, for example), while the all cells of the tumour. They are a selective growth advantage to the cells within their other is often a large deletion that inactivates the other also called ‘truncal’ because microenvironment. In other words, driver-gene muta- allele39,40. It is important to note that some driver genes they are in the trunk of the tumour evolutionary tree. tions result in an increase in cell division or a decrease (for example, NOTCH1 or CDH1) can act as oncogenes in cell death, resulting in a net cell gain overall. Relatively in one cancer type but as tumour suppressor genes in Clonal sweep small changes in the cell birth rate, b, or in the death rate, other cancer types2,36, reflecting the different signalling A mechanism through which a d, can dramatically alter the net growth rate, given by circuitries that define organogenesis; as such, not all subpopulation sweeps through r = b − d (REFS22–27). For example, assume that a tumour driver genes follow the typical mutational patterns. a tumour and drives all other competing subpopulations grows exponentially, with a volume doubling time of In the case of three mutated driver genes, the first 28 to extinction. 150 days . The growth rate is then r = ln(2)/150 ≈ 0.5% driver- gene mutation usually allows the formation of per day. If the cells within the tumour divide every a small clonal expansion, creating a benign lesion18,41,42. 4 days5,29, then b = 1/4 = 0.25 per day, and the death rate These lesions typically grow to a size of a few million is d = b − r = 0.245 per day according to the formula cells and are usually undetectable clinically. The second given above. Suppose that a driver- gene mutation then driver- gene mutation results in a second wave of local occurs in one cell of this tumour. A driver- gene muta- clonal expansion, often leading to a clinically detectable, tion causes an increase in the birth rate of on average although still benign, tumour20,43–45. The third mutation 0.4%22, although some driver-gene mutations can confer endows the tumour cell not only with a further selective much stronger or weaker selective advantages30,31. A typi- growth advantage but also with the ability to expand cal new birth rate is then b' = b(1 + 0.004) = 0.251 per in its environment by invading through the basement day. If the death rate is unchanged, then the new growth membrane20,45, thereby defining malignancy (that is, rate of this cell is r' = b' − d = 0.6% per day. The new cancer). Furthermore, advanced tumours typically con- mutation therefore increases the net growth rate by 20% tain frequent gains and losses of focal genomic regions, per day (= 0.6%/0.5%). The number of these mutated chromosome arms and whole chromosomes40,46,47. cells will then double every ~120 days (= ln(2)/0.006), Depending on the cancer type, whole- genome dupli- as compared with the 150 days of the cells without this cation occurs in 10–80% of cancers, which could lead additional driver- gene mutation. Over many months to to subsequent chromosomal alterations39,48. To date, it years, this difference is sufficient for cells with this has been impossible to determine whether the rate of driver- gene mutation to progressively outgrow the cells chromosome gains and losses (chromosome instabil- without this additional mutation in the tumour22,32–35. ity) increases during tumour progression. However, Driver genes can be classified into well- defined sig- a new approach employing organoids should make this nalling pathways, and their effects depend on the tis- determination possible in the future49. Despite intense sue origin of the cells. A few dozens of driver genes are efforts, no genetic alterations have been identified that recurrently mutated across many cancer types, but most unambiguously endow the cell with the ability to meta- driver genes are recurrently mutated only in a few tis- stasize50. The process of metastasis seems stochastic; sues and cancer types36,37. The functional consequences once a cancer has developed (that is, once a tumour has of mutated driver genes complement each other, result- acquired invasive growth capability), it may only be a ing in patterns of co-occurrence and mutual exclusivity matter of time before a cell invades a vessel and seeds among driver- gene mutations37,38. In the case of onco- a distant metastasis14. genes, a single missense mutation generally represents Although three driver- gene mutations appear to be the genetic alteration responsible for activating it. In the sufficient for the development of most malignant solid case of tumour suppressor genes, inactivation typically tumours, more than three mutated driver genes can be requires two separate mutations. Preliminary evidence observed in tumours, because the evolutionary process never stops. These additional mutations can be clonal, but are more likely to be subclonal, compared with the Author addresses mutations driving the disease. 1Canary Center for Cancer Early Detection, Department of Radiology, Stanford University Heterogeneity among driver- gene mutations in School of Medicine, Palo Alto, CA, USA.
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