We now have a better understanding of the sequence of events, particularly regarding the timing of these mutations, their impact, and some of the factors involved that might cause them.
Chairman and Director Lymphoma Division Chief John Theurer Cancer Center at HackensackUMC Chief Science Officer and Director Research and Innovation Regional Cancer Care Associates Professor, Medicine Georgetown University
The impressive progress in understanding cancer cell biology as well as access to human genome sequencing (now feasible on routine samples) has profoundly transformed oncology. Numerous novel therapies have emerged as a result, particularly small molecules often referred to as “biologicals” or “targeted therapies,” which not only show activity in chemorefractory patients, but may also replace standard chemotherapy in some situations in the future. Similarly, the ability to look at the broad genetic landscape of many types of cancer has shed light on the huge molecular diversity of the disease, both among patients and even within one individual (through baseline clonal heterogeneity and/or clonal evolution).
Every tumor harbors thousands of genetic (and epigenetic) alterations that are not present in the patient’s germline DNA. The molecular complexity of cancer is daunting (over 3 million somatic mutations reported) making it difficult to “read the culprit.” It is clear nowadays though that all mutations are not equal. Only a very small fraction of these alterations are in “driver genes,” which when mutated lead to growth advantage over surrounding cells.
Meanwhile, numerous somatic mutations, which accumulate during the long process of tumorigenesis, appear “neutral” and are therefore referred to as “passenger” mutations. Comprehensive studies have shown that only about 200 genes (out of 20,000 in the human genome) can function as drivers when mutated. These driver genes are involved in 12 signaling pathways, which understandably regulate core cellular processes: cell fate and survival, proliferation and genome maintenance. A typical tumor contains 2 to 8 of these “driver genes,” the rest being all passenger mutations.
The original theory over 30 years ago was that cancer was just the result of the random accumulation of successive mutations leading to cancer phenotype. We now have a better understanding of the sequence of events, particularly regarding the timing of these mutations, their impact, and some of the factors involved that might cause them.Tumors evolve with a multistep process—from benign to malignant lesions—which has been particularly well studied in colorectal cancers. The first, or, “gatekeeping,” mutation provides a selective growth advantage to a normal epithelial cell, allowing it to outgrow its surrounding cells and become a microscopic clone.
The “founding” or “breakthrough” mutations in colon cancer most often affect the adenomatous polyposis coli (APC) pathway, particularly the APC gene and lead to the classical polyp or adenoma (seen in routine colonoscopies). The next step occurs when a second mutation in another gene—often KRAS—unleashes a second round of clonal expansion. This process of mutation/clonal expansion continues, with additional mutations in several other key genes, eventually generating a malignant tumor that becomes invasive and can metastasize to lymph nodes and distant organs, such as the liver, consistent with the picture of advanced stage colon cancer as we know in the clinic.
This process takes decades with each driver mutation providing only a small selective growth advantage; however, this slight increase, repeated once or twice per week, can result in a large mass, containing billions of cells. The multistep process is the same across all cancers, though the number of mutations varies with age and tissue type.
In organs with significant self-renewal compartment (to continuously replenish gastrointestinal lining, for example), the number of mutations observed is much higher compared with pancreatic or brain tumors. Also a colon cancer in a 90-year-old patient has twice as many mutations as a morphologically identical colorectal cancer in a 45-year-old patient (making them likely more resistant to treatment). In summary, the driver mutations process typically starts decades before the diagnosis with accumulation of a “sufficient” number of driver mutations and a highly variable (based on tissue and age) number of passenger mutations along the way.Researchers at Johns Hopkins, in their effort to understand why some cancers are more likely to occur than others, concluded that in about two-thirds of cancer tissue types investigated, the development of cancer could be largely explained by the “bad luck” of random mutations that arise during DNA replication in normal nonmalignant stem cells of a given organ. According to this theory, cancer arises when stem cells go out of control and are not due to external factors. Needless to say, Tomasetti and Vogelstein’s paper published last year in Science (2015;347:78-81), generated instant reaction and even some criticism due to the concern their theory might dismiss important cancer prevention efforts.
However, a new study just out in Nature (2016;529:43-47) might contradict the “bad luck” theory of cancer. Researchers at Stony Brook University in New York took another look at the data used by Tomasetti and Vogelstein. They noted that even taking into account the total number of stem cell divisions, some cancers were still more likely to occur than others. They found that for many cancers, including some of the most common ones, about 10% of the risk was traceable to random copying errors. More common cancers, they inferred, must have some additional external causes, such as the environment or lifestyle-related factors. Extensive epidemiological data support the role of the environment in cancer from carcinogens, to excess UV exposure or smoking. For example, lung cancers in smokers have 10 times as many somatic mutations as those from nonsmokers. Obesity and BMI definitely affect cancer incidence across many cancer subtypes, through complex mechanisms linked to chronic inflammation, cytokines, hormonal disturbances, and insulin resistance.
The benefit of physical exercise on the outcome of cancer patients has been shown in both solid tumors and blood cancers, including in some studies an improvement of overall survival. In our center, an exercise plan is now part of standard care recommendation. The mechanisms involved in the protective effects of exercise and nonsedentary lifestyles are definitely beyond this column but are well recognized by the medical community.
Though opposed, the two theories discussed above are actually complementary. There is no question that there is a minority of drivers in cancer, and those happen early on and over decades. The current ability to focus on such driver mutations and the pathways they control has rendered complex genome landscapes intelligible and exploitable. This provides an opportunity to develop relevant usable “profiles” for targeted therapy combinations (aiming at cancer vulnerabilities/ Achilles’ heels) and true precision medicine. I also believe a promising future strategy in cancer will be through very early detection based on the presence of clones (liquid biopsies) with enough potential “drivers” to intervene either with small molecules or more likely immunotherapy to prevent progression to a true or clinically patent cancer. While chance has a role in determining who gets cancer and who does not, it’s very clear that lifestyle and environmental factors together within the context of our genes can change the odds considerably.