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Lung Cancer Genome of Never-Smoker Lacks Hallmark Mutations of Adenocarcinoma

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By Monica Heger

As part of a pilot study that is aiming to use next-gen sequencing to help guide treatment for patients with rare cancer types, researchers have sequenced the whole genome and whole transcriptome of a non-smoker who nevertheless developed metastatic adenocarcinoma.

Researchers from the Translational Genomics Research Institute and the Virginia G Piper Cancer Center at Scottsdale Healthcare presented the results of the study this week at the International Association for the Study of Lung Cancer's annual conference in Amsterdam. The findings are also slated for publication in the Journal of Thoracic Oncology.

The goal of the project, which is slated to run around three years and enroll up to 10 patients, is to use next-gen sequencing for patients with rare or unusual types of cancer, as well as patients whose cancer has metastasized and who have already tried at least one line of chemotherapy, to try and identify alternative treatment strategies, said Glen Weiss, director of thoracic oncology at Virginia G. Piper Cancer Center Clinical Trials and lead author of the recent study.

The pilot study is being funded by the National Foundation for Cancer Research.

This specific patient was a 61-year old woman who had never smoked, yet still developed lung cancer, which then metastasized. Prior to sequencing, she had been treated with three types of chemotherapy, Weiss said.

The researchers sequenced the patient's whole tumor, matched normal genome, and normal and tumor transcriptomes on the Illumina HiSeq 2000 to around 32-fold coverage.

Typically, lung cancers are characterized by mutations to EGFR or KRAS, or an EML4/KRAS translocation. In fact, "the chance of having any one of these mutually exclusive events is 45 percent," said Weiss. However, this patient did not have any of those mutations. Instead, the team found a novel mutation in the known cancer gene TP53, as well as amplifications of the MYC gene, and numerous other mutations and translocations.

Weiss said that while none of the mutations they identified is directly druggable by any compounds on the market, there are agents in phase I trials targeting p53 and MYC that "might be an option for this patient."

Interestingly, Weiss said that while the TP53 mutation was found in only 29 percent of the tumor reads from the whole-genome sequencing data, looking at the transcriptome data, the mutation exhibited 100 percent expression, compared to no expression from the TP53 transcript in benign lung RNA.

Loss of heterozygosity was not observed, so "the observation suggests a mechanism other than LOH, and would not have been readily determined without the combined DNA and RNA integration approach," he added.

The mutation to TP53 could potentially explain why the patient developed lung cancer, despite not being a smoker. Mutations to that gene, which functions as a tumor suppressor, have been associated with the development of many different types of cancer, including lung.

Weiss said that the team plans to examine tumors from other never-smokers to see if they exhibit similar mutational patterns.

Additionally, as part of the National Foundation for Cancer Research project, they will sequence patients with other rare cancers.

Weiss added that while in this case, the sequencing was not done in a CLIA lab, "we hope to be able to offer this in the very near future."

While this particular patient will likely not immediately benefit from the sequencing, the researchers expect that sequencing of additional patients will identify druggable targets for commercial or investigational therapies. However, it will require follow up to ensure that these patients are able to "get to a treating center with access to the commercial drug or clinical trial with that investigational agent," said Weiss.

It is still early days for sequencing the tumor genomes of cancer patients, yet some groups have successfully used sequencing to help guide treatment.

For example, a team from TGen and the Mayo Clinic recently sequenced the genome of a patient with pancreatic cancer, uncovering mutations that could potentially be used to guide the patient's next course of treatment (IS 2/22/2011). The effort was done as part of a study to test the feasibility of sequencing the whole genomes of cancer patients.

In addition, researchers at the Genome Institute at Washington University sequenced the whole genome of a patient with a difficult to diagnose case of acute myeloid leukemia, the results of which changed the patient's course of treatment and enabled her to avoid having a bone marrow transplant (CSN 4/26/2011).

Other groups are aiming to incorporate sequencing into the regular treatment of cancer patients, such as the Fox Chase Cancer Center (CSN 6/15/2011), which will begin offering exome and transcriptome sequencing in an effort to identify potential treatment options.

While there have been some early successes, such as the Wash U AML case, others, like the most recent TGen case, have not yielded results that have been immediately beneficial to the patient.

Sequencing the genomes of cancer patients is "moving quite rapidly," said Weiss, but the "bottleneck is the huge amount of data and analyses" and translating that into a "feasible treatment option." For the time being, "because of costs and time to get from biopsy to full result, it should be considered research."


Have topics you'd like to see covered by Clinical Sequencing News? Contact the editor at mheger [at] genomeweb [.] com.

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