Lung Cancer Genes Reveal Risks of Smoking

Why is lung cancer so tough to beat? And why do many people relapse after surgery to remove lung tumors? Recent research published in the journal Science focused on these two questions. Lung cancer will kill 159,000 people this year alone, according to the American Cancer Society.

Elza C. de Bruin and the team at Cancer Research UK in London pinpointed genetic mutations in separate regions of single lung tumors. They used that information to paint a picture of the tumor’s history. The scientists found that tumors had different mutations in various locations at different times, which explains why antitumor drugs only work for so long — they can only destroy a portion of an ever-evolving tumor.

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The scientists looked at the genes in 25 regions of seven different non-small cell lung cancers. They found that the areas often showed distinct mutations. Tumors in long-term smokers revealed that mutations due to smoking were less common as the disease developed. Tumors in people who had once smoked but quit, on the other hand, suggested that the damage was done long ago, and a quiet period of tumor latency had come before their cancer diagnosis.

Lung Cancer Can Go Undetected for Decades

Lung cancer can essentially lie dormant for more than 20 years before it becomes an aggressive disease that can lead to death. The so-called faults that cause each tumor to grow create genetically unique sections, the researchers found. 

Why don’t treatments work as well as we think they should? Going after a particular genetic mistake shown in a biopsy will only be effective against those parts of the tumor with that particular fault, which means that other areas can continue to grow.

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Many of those faults are triggered by smoking, the scientists say. However, as the disease progresses, these become less important. Most of the faults in later stage lung cancer are caused by a new process, controlled by a protein called APOBEC. 

“The work shows that even in heavy smokers, later in the cancer evolution a new process called APOBEC becomes apparent that mutates DNA in addition to the tobacco carcinogens,” said study author Charles Swanton, Ph.D., of Cancer Research UK's London Research Institute and the University College London Cancer Institute. “This new mutational process seems to provide the fuel for the selection of new cancer gene mutations that further drive cancer growth.” 

The researchers say their work shows the need for earlier detection tests. About two-thirds of people are diagnosed with lung cancer when the disease is at an advanced stage — and when treatments are less likely to work.

Why Do Patients Relapse?

A separate study by Jianjun Zhang, Ph.D., and colleagues from the MD Anderson Cancer Center at the University of Texas used whole-genome sequencing to map 11 lung tumors.

The team discovered that about 76 percent of all mutations (and 20 out of 21 known cancer gene mutations) were present in all of the tumors.

Survival from lung cancer remains devastatingly low ... By understanding how it develops we've opened up the disease's evolutionary rule book in the hope that we can start to predict its next steps.
Charles Swanton, Ph.D., Cancer Research UK

When the team tested three lung cancer patients who had relapsed 21 months after surgery to remove tumors, they found that they all had many more mutations in their tumors than patients who were still living cancer-free. That means that a larger number of mutations may be linked to a greater risk of relapsing. 

“Even early stage lung cancers can be diverse, with drivers of disease progression present in one biopsy but not another,” said Swanton, who was not involved in Zhang's study.

“Survival from lung cancer remains devastatingly low, with many new targeted treatments making a limited impact on the disease,” Swanton added. “By understanding how it develops we've opened up the disease's evolutionary rule book in the hope that we can start to predict its next steps.” 

Nic Jones, Ph.D., Cancer Research UK's chief scientist, agrees. “If we can nip the disease in the bud and treat it before it has started traveling down different evolutionary routes we could make a real difference in helping more people survive the disease,” Jones said in a press release.

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