Does Lifestyle Matter to Prevent Cancer or Is It Just All “Bad Luck”?

By Andre Goy, MD
Published: Friday, Feb 12, 2016
Andre Goy, MD, MS

Andre Goy, MD

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.

Timing of Somatic Mutations

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.

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Online CME Activities
TitleExpiration DateCME Credits
Community Practice Connections™: 18th Annual International Lung Cancer Congress®Oct 31, 20181.5
Clinical Interchange™: Translating Research to Inform Changing Paradigms: Assessment of Emerging Immuno-Oncology Strategies and Combinations across Lung, Head and Neck, and Bladder CancersOct 31, 20182.0
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