Is Cancer a Genetic Disease?

I recently had the opportunity to meet two charming young patients: One, a 32-year-old female with an extremely rare malignancy that arose in her kidney and the other a 33-year-old gentleman with widely metastatic sarcoma.

Both patients had obtained expert opinions from renowned cancer specialists and both had undergone aggressive multi-modality therapies including chemotherapy, radiation and surgery. Although they suffered significant toxicities, both of their diseases had progressed unabated. Each arrived at my laboratory seeking assistance for the selection of effective treatment.

With the profusion of genomic analyses available today at virtually every medical center, it came as no surprise that both patients had undergone genetic profiling. What struck me were the results. The young woman had “no measurable genetic aberrancies” from a panoply of 370 cancer-causing exomes, while the young man’s tumor revealed no somatic mutations and only two germ-line SNV’s (single nucleotide variants) from a 50 gene NextGen sequence, neither of which had any clinical or therapeutic significance.

What are we to make of these findings? By conventional wisdom, cancer is a genetic disease. Yet, neither of these patients carried detectable “driver” mutations. Are we to conclude that the tumors that invaded the cervical vertebra of the young woman, requiring an emergency spinal fusion, or the large mass in the lung of the young man are not “cancers”? It would seem that if we apply contemporary dogma, these patients do not have a cancer at all. But nothing could be further from the truth.

Cancer as a disease is not a genomic phenomenon. It is a phenotypic one. As such, it is extremely likely that these patients’ tumors are successfully exploiting normal genes in abnormal ways. The small interfering RNAs or methylations or acetylation or non-coding DNA’s that conspired to create these monstrous problems are too deeply encrypted to be easily deciphered by our DNA methodologies. These changes are effectively gumming up the works of the cancer cell’s biology without leaving a fingerprint.  

I have long recognized that cellular studies like the EVA-PCD platform provide the answers, through functional profiling, that genetic analyses can only hope to detect. The assay did identify drugs active in these patients’ tumor, which will offer meaningful benefit, despite the utter lack of genetic targets. Once again, we are educated by cellular biology in the absence of genomic insights. This leaves us with a question however – is cancer a genetic disease?

The Molecular Origins of Lung Cancer

I had the luxury of attending the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; Biology, Therapy and Personalized Medicine held in San Diego earlier this month. I say luxury, for as my schedule closes in on me and I sometimes find myself working 13-hour days, it can be difficult to take even a couple of days away to attend meetings. But this conference was too good to pass up (hats off to Marge Foti and all the AACR staff for all their great work).

This symposium organized by David Carbone and Roy Herbst, brought together a broad spectrum of sophisticated scientists and international investigators, as well as community members and fundraising organizations who had the opportunity to present a special session on patient advocacy.

The meeting began with a keynote address examining microRNAs and lung cancer presented by Frank Slack from Yale University. He examined the growing recognition that lung cancer arises not only from gene mutations but also from small fragments of RNA that can up- or down-regulate normal genes in abnormal ways. This was the topic of discussion for many subsequent presentations.

As an aside, many of the readers will know that I am generally underwhelmed by genomic analyses for the prediction of cancer response. The fact that normal genes can function abnormally under the control of these small RNA sequences is just one more example of the genotype–phenotype dichotomy that cannot be adequately examined on static contemporary genomic platforms.

Many presentations examined the molecular biology of lung cancer with important distinctions being drawn between adenocarcinoma and squamous cell carcinomas. While adenocarcinomas reveal a growing number of targets – EGFR, ALK, ROS, RAS, and others – all the subject of small molecule inhibitors; squamous cell carcinomas provide fewer opportunities for the use of these classes of drugs.

One of the interesting discussions was the frequent mutation of LKB1 in lung cancers. Work going back several years by John Minna, a pioneer in this field, identified changes in this metabolic regulator as a common finding in lung malignancies.

Additional presentations examined chemoprevention, molecular pathology, new mechanisms to categorize lung cancer subtypes, and a very interesting discussion of field cancerization. In a particularly interesting analysis, Ignacio Wistuba from M.D. Anderson, showed that molecular changes in the surface epithelium of the lung bronchioles recapitulated the molecular biology of the final tumor in a step-wise manner, inversely related to the distance to the tumor. That is, starting at the main bronchi, one or two mutational changes were detected. Moving closer to the site of the tumor, additional mutations were accumulated. Finally arriving at the site of the established malignancy, all of the constituent mutations associated with this particular cancer became manifest; a saltatory slide into cancer presumably associated with exposure to carcinogens.

Among the other exciting presentations were updates on redox-based approaches to cancer presented by Kenneth Tew and Garth Powis.

Jeff Engelman presented an update on a new class of agents that target the RAS pathway. This is ongoing work that he and his group have reported on over the last several years. We have been engaged in related work using an MEK/ERK inhibitor similar to the compound that Dr. Englemen reported on at this meeting. It is exciting indeed to see early clinical results with this class of compounds, for we have identified many patients who might benefit from this pathways’ inhibition. We wait with great anticipation for FDA approval of these compounds so that our patients currently being identified as candidates in the laboratory may soon receive these treatments.