Cancer Genome Atlas

Lung Ca and Ethnicity: Why Genomics Needs to Step Up

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Research reveals insufficient samples from racial minorities to detect moderately common genomic alterations

The current ethnic demography of the U.S. gives truth to the melting pot metaphor: 61.3% white, 17.8% Hispanic, 13.3% black, 5.7% Asian, and 1.5% Native peoples. Cancer researchers have begun evaluating this demographic breakdown against the available genomic data for carcinomas.

For instance, there’s The Cancer Genome Atlas (TCGA), a collaboration between the National Cancer Institute and the National Human Genome Research Institute (NHGRI) to create multi-dimensional maps of the key genomic changes in 33 types of cancer.

More than 11,000 cancer patients have contributed biospecimens for genomic sequencing and analysis to TCGA, with upwards of 500 samples analyzed for each tumor type, including lung cancer. These large datasets are needed to provide statistical power to produce a comprehensive genomic profile of each cancer. A large sample size is also necessary to provide the power to detect mutations against the background rate.

“TCGA project has uncovered numerous uncommon subtypes and mutations across multiple cancer types, and these results are being used to develop new therapies and ultimately improve outcomes for patients with cancer,” noted Joseph Osborne, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York City, and colleagues.

But there is a weakness of the data used to study cancer genomics, and that’s an imbalance in the representation of the various ethnic groups.

Alex Adjei, MD, PhD, editor-in-chief of the Journal of Thoracic Oncology, noted: “The genomic revolution has led to the sequencing of lung cancer specimens in large consortia such as TCGA in the United States, that have provided useful genomic information to drive therapeutic as well as other research in lung cancer. However, tumors from under-represented minorities in the United States such as blacks and Hispanics were under-represented in these samples. This has meant that the mutational profiles of lung cancer from these populations are not accurately documented.”

Researchers have tackled this disparity by taking a closer look at how databases like TCGA and others can increase the sample size to better represent the population. As Osborne’s group remarked, “Without adequate representation of racial minorities within massive sequencing efforts, healthcare disparities may inadvertently be increased, because race-specific mutational patterns are unable to be appreciated.”

‘Avoid Widening the Gap’

“It is probable, but poorly understood, that ethnic diversity is related to the pathogenesis of cancer, and may have an impact on the generalizability of findings from TCGA to racial minorities,” Osborne et al continued. “Despite the important benefits that continue to be gained from genomic sequencing, dedicated efforts are needed to avoid widening the already pervasive gap in healthcare disparities.”

The team reviewed ethnic data in TCGA from 5,729 samples in 10 of the 33 available tumor types, including lung adenocarcinoma and lung squamous cell carcinoma. They used the estimated median somatic mutational frequency for each tumor type by racial ethnicity to calculate the samples needed beyond TCGA to detect a 5% and 10% mutational frequency over the background somatic mutation frequency.

For patients of white ethnicity, TCGA is very powerful, the authors said. All tumor types from white patients contained enough samples to detect a 10% mutational frequency. Of the 5,729 samples analyzed by the team 77% (4,389) came from white patients — an overrepresentation of white patients compared with their percentage of the U.S. population, they pointed out.

“This is in contrast to all other racial ethnicities, for which group-specific mutations with 10% frequency would be detectable only for black patients with breast cancer. Group-specific mutations with 5% frequency would be undetectable in any racial minority, but detectable in white patients for all cancer types except lung (adenocarcinoma and squamous cell carcinoma) and colon cancer.”

The median somatic mutation frequency (per Mb) was 8.1 for lung adenocarcinoma and 9.9 for lung squamous cell carcinoma.

Black ethnicity comprised 12% (660) of patients, Asian were 3% (173), Hispanic made up 3% (149), and less than 0.5% combined were from Native Peoples of the 5,729 TCGA samples analyzed.

“As we demonstrate, despite the approximately proportional relative sample size of many demographic minorities within TCGA when compared with the U.S. population, the absolute sample size of these minorities is inadequate to capture even relatively common somatic mutations that are specific to those groups,” the authors wrote. “Still, TCGA can be commended for their enrollment of racial minorities that has been far more successful than many clinical trial efforts.”

The investigators cited non-small cell lung cancer (NSCLC) and the epidermal growth factor receptor (EGFR) mutation as an example of a carcinoma where ethnicity-specific data made a difference. The phase III ISEL trial failed to show a benefit of treatment with gefitinib (Iressa) in a predominantly white cohort. But there was a significant overall survival benefit in Asian patients.

“These observations are explained by the PIONEER study, a multinational epidemiologic prospective study that demonstrated that EGFR mutations are present in 51.4% of stage IIIB or IV lung adenocarcinomas among Asian patients, in contrast to approximately 20% in white and African-American patients,” the researchers said. “Given the potential for disparate tumor biology by race, we must critically evaluate the generalizability of new discoveries to all patients.”

NSCLC and Hispanics

Giuseppe Giaccone, MD, PhD, co-leader of the Experimental Therapeutics Program at the Lombardi Comprehensive Cancer Center of Georgetown University Medical Center in Washington, D.C., and colleagues sought to narrow the Hispanic cancer genomic knowledge gap by assessing EGFR mutations (exons 18-21) among NSCLC patients at seven institutions in the U.S. and Latin America.

Samples were obtained from 642 patients; 75% (480) of the samples had EGFR mutation analysis successfully performed. The ethnic breakdown of the samples was:

  • 66% (318) non-Latino whites
  • 19% (90) Latino
  • 7% (35) non-Latino Asians
  • 6% (30) non-Latino blacks
  • 2% other races/ethnicities

EGFR mutations were found in 23% (21) of the Latino cohort, with varying frequencies according to the country of origin. Latinos from Peru demonstrated the highest frequency at 37%, followed by the U.S. at 23%, Mexico at 18%, Venezuela at 10%, and Bolivia at 8%.

The researchers found a significant difference in the frequency of EGFR mutations among the different racial and ethnic subgroups analyzed (P < 0.001), with non-Latino Asians having the highest frequency at 57%, followed by Latinos at 23%, non-Latino whites at 19%, and non-Latino blacks at 10%. Patients from Peru had an overall higher frequency of mutations (37%) than all other Latinos (17%), but this difference exhibited only a trend toward significance (P = 0.058).

There were two significant study limitations, the authors said: First, Latino patient enrollment in the U.S. was low (30 patients, 7%) despite a study protocol specifically targeted toward Latino enrollment. In addition, although several large Latin American cancer centers participated, they also had low Latino enrollment.

“This problem highlights the significant difficulties of research collaborations with developing countries in which resource constraints, logistic, and legal challenges may significantly affect enrollment,” the authors stated.

Second, the study did not account for the significant racial and genetic differences within the Latino population. The authors did not collect information on race in the Latino population, nor did they perform genetic ancestry analyses or germline ancestry informative markers that could characterize genetic origin within admixed populations.

“It is possible that we may have primarily sampled a subset of Latino patients with NSCLC, such as the Latino white population. Because this population is similar, in terms of genetic ancestry, to the non-Latino white population in the U.S., this may have obscured a potential difference in EGFR mutation frequency between the two groups.”

The authors acknowledged that Latinos with Native peoples ancestry are of special interest, given that they represent the majority population in Mexico, Central America, and parts of South America (such as Peru), and Latinos from these geographic areas comprise the largest subgroup of Latinos in the U.S.

Citing the high frequency (37%) of EGFR mutations found in Peru, the investigators said they believe this may be an indication there may be a higher EGFR mutation frequency among Latinos defined by a high Native Peoples ancestry. Or, it may be related to a sampling of the Peruvian population of Chinese and Japanese descent, which is among the largest in Latin America.

“Although we did not observe a difference in the frequency of EGFR mutations between Latinos and non-Latinos, our results should be interpreted with caution, given the significant limitations of the study,” the researchers wrote.

Latino Lung Registry

In an effort to address the lack of genomic data from Hispanic/Latino patients with lung cancer, the Latino Lung Cancer Registry was recently established. It is a multinational effort among the University of South Florida in Tampa; Ponce Health Sciences University in Ponce, Puerto Rico; and Universidad Peruana Cayetano Heredia in Lima, Peru.

The registry currently has NSCLC tumor samples from 163 Hispanic/Latino patients. The ethnic background of the Hispanic/Latino patients in the registry is reported as 67% European, 21% Native peoples, and 12% African. Patients are clustered into ancestral groups on the basis of ancestry informative marker analyses.

In another study, Nicholas Gimbrone, of Lee Moffitt Cancer Center and Research Institute in Tampa, FL, and colleagues from the Latino Lung Cancer Registry performed targeted exome sequencing of the registry samples to determine how ethnicity may affect the genetic aberrations found in NSCLC. The mutation frequencies were compared with those in a similar cohort of non-Hispanic white (NHW) patients. The adenocarcinomas (120) in the Hispanic/Latino group had EGFR mutations in 31% versus 17% in the NHW group (P<0.001).

“Our data suggest that the increase in EGFR mutations within our [Hispanic/Latino] cohort is driven by females, with 48% having EGFR mutations,” the authors wrote.

In addition, they said, the data suggests that relative to European ancestry, Native peoples ancestry correlates with low rates of tumor protein p53 (TP53) and serine/threonine kinase 11 (STK11) mutations and high rates of EGFR mutations and that African ancestry correlates to low rates of KRAS mutations.

“This observation may point to a connection to a genetic component from Asia-Pacific migration, because it is known that the EGFR mutation rate is high among Asian patients,” the authors stated.

Study limitations were the various tissue sources and sequencing technologies utilized by the participating institutions; the incomplete clinical data for several samples; and the lack of age, tumor stage, and outcome data for all patients. “Substantial variation in the distribution of sex, smoking history, and ancestry is evident between the three Latino cohorts included in the registry, indicating the potential complexity in untangling the factors contributing to driver mutation frequencies,” stated Ann Schwartz, PhD, and Donovan Watza, both from the Barbara Ann Karmanos Cancer Institute in Detroit, in an accompanying editorial.

They noted that the formation of the Latino Lung Cancer Registry represents progress in addressing the dearth of genomic cancer data in the Hispanic/Latino population, but cautioned that additional funding, enrollment, and data collection will be necessary for this registry to reach maturity.

Treatable cancer subtype found.

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Australian researchers have identified a potentially treatable subtype of pancreatic cancer, which accounts for about 2% of new cases. This subtype expresses high levels of the HER2 gene. HER2-amplified breast and gastric cancers are currently treated with Herceptin.

Pancreatic cancer is the fourth leading cause of cancer death in Western societies, with a 5-year survival rate of less than 5%. It is a molecularly diverse disease, meaning that each tumour will respond only to specific treatments that target its unique molecular make-up.

Sebastian_Kaulitzki_PancreaticCancer_shutterstock

A new study, published in Genome Medicine, used a combination of modern genetics and traditional pathology to estimate the prevalence of HER2-amplified pancreatic cancer. Pancreatic surgeon Professor Andrew Biankin, from Sydney’s Garvan Institute of Medical Research and the Wolfson Wohl Cancer Research Centre at the University of Glasgow, worked with pathologist Dr Angela Chou and bioinformatician Dr Mark Cowley from Garvan, as well as cancer genomics specialist Dr Nicola Waddell from the Queensland Centre for Medical Genomics at the University of Queensland.

Using data sourced from the Australian Pancreatic Cancer Genome Initiative1 (APGI), the team identified a patient with high-level HER2 amplification. Using whole genome DNA sequencing of the tumour, Dr Nicola Waddell pinpointed the specific region of the genome that contains HER2.

Dr Angela Chou then performed detailed histopathological characterisation of HER2 protein in tissue samples taken in the past from 469 pancreatic cancer patients. This produced a set of standardised laboratory testing guidelines for testing HER2 in pancreatic cancer, and showed the frequency of HER2 amplified pancreatic cancer of 2.1%. 

Dr Chou also found that – like HER2-amplified breast cancer patients – the cancers of those with HER2-amplification in the pancreas tended to spread to the brain and lung, rather than the norm, which is the liver.

Dr Mark Cowley analysed all the data generated by the project and compared it to other sequences from many cancer types produced by the International Cancer Genome Consortium and The Cancer Genome Atlas project. “HER2 amplification was prevalent at just over 2% frequency in 11 different cancers,” he observed.

“We make the case that if HER2 is such a strong molecular feature of several cancers, then perhaps recruiting patients to clinical trials on the basis of the molecular features rather than the anatomical region of their cancer could have a significant impact on patient outcomes, and still make economic sense for pharmaceutical companies.”

“Such ‘Basket trials’ as they are sometimes called, may advance treatment options for those with less common cancer types.”

In Australia, 2,000 people are diagnosed with pancreatic cancer each year, and so 40 are likely to have the HER2 amplified form. 

While Herceptin is available through the Pharmaceutical Benefits Scheme for treating breast and gastric cancer, it is not available for treating HER2-amplified pancreatic cancer as no clinical trial has yet been conducted to determine the drug’s efficacy in that case.

The Garvan Institute in collaboration with the Australasian Gastro-Intestinal Trials Group, is recruiting pancreatic cancer patients through the APGI for a pilot clinical trial, known as ‘IMPaCT’2, to test personalised medicine strategies. 

Potential patients will be screened for specific genetic characteristics, including high levels of HER2, based on their biological material sequenced as part of the APGI study. Once these characteristics are confirmed, patients will be randomised to receive standard therapy or a personalised therapy based on their unique genetic make-up.

 

Study reveals how inherited risk factors in ‘junk DNA’ affect breast cancer predisposition.

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Novel method provides insights in biology of breast cancer

In light of recent large population studies, it’s known that some people carry inherited DNA changes that increase their lifetime risk of diseases, including breast and prostate cancer. To the surprise of scientists, scores of these “risk alleles” have been found in vast regions of the genome – sometimes called “junk DNA” or “dark matter” – that don’t carry the genetic code for proteins, so how they influence an individual’s cancer risk isn’t known.

In a new study, scientists at Dana-Farber Cancer Institute have shown that several such alleles affect DNA segments known as “enhancers” and turn on or off genes involved in breast cancer. Interestingly, four of the genes the research team pinpointed hadn’t previously been implicated in breast cancer. The scientists, led by Matthew Freedman, MD, PhD, reported their findings in the Jan. 31 issue of Cell.

“We can use this tool to show that the DNA variation that influences risk controls the expression of a nearby gene involved in cancer,” said Freedman, of Dana-Farber’s Center for Cancer Genome Discovery and Center Functional Cancer Epigenetics and the Broad Institute. Freedman explained that knowing this link gives scientists new insights into the biology of breast cancer. “If you can identify which pathway or gene is involved in the risk of developing cancer, primary cancer prevention efforts can be more rationally designed.”

In the past several years, investigations called genome-wide association studies (GWAS) have helped define the genetic root causes of many diseases, including cancer. These studies have identified large numbers of relatively common polymorphisms, or places in the human genome where the genetic code differs among individuals, that are associated with inherited, increased risks of cancer.

About 70 such variants – also known as single-nucleotide polymorphisms, or SNPs – have been identified in prostate cancer and an equal number in breast cancer. Although these risk alleles are common in the population, each one increases cancer risk by only a modest amount, according to Freedman. Some individuals may inherit enough risk variants, however, to make a significant difference that someday might prompt physicians to recommend preventive measures.

Freedman said that because the segments of DNA containing the variants lie in uncharted regions of the genome, “it has been a challenge to connect these variants to genes that influence cancer risk.” Clues to their function came in 2012, when reports based on a public database called ENCODE suggested that many of these SNPs are located within regions that regulate the activity of genes.

The Dana-Farber scientists tapped this information and another large publicly funded database, The Cancer Genome Atlas, which contains thoroughly analyzed samples of tumors and the corresponding normal tissue from cancer patients. They studied data on increased gene activity in tumor samples from 407 breast cancer patients. At the same time, they examined data on normal blood samples from those same patients, which revealed the number of breast cancer risk alleles the patients had been born with.

Sophisticated computational methods then linked the risk alleles’ promoter functions to six overactive genes within the breast cancers: two of the genes had already been implicated in breast cancer, but four were identified for the first time, the scientists reported. “Our data showed that the expression of these genes was under genetic control [of the DNA variants],” Freedman said.

He said that this study, the largest of its kind, “is just the beginning” of further work to understand how these variants affect the biology of breast cancer development.

First author of the report is Qiyuan Li, PhD, a postdoctoral fellow in the Freedman lab.

The research was supported in part by grants from the National Institutes of Health (U19CA148537 and R01 CA131341), the Mayer Foundation, the H.L. Snyder Medical Foundation, the Kohlberg Foundation, and the A. David Mazzone Awards Program.

At Dana-Farber/Brigham and Women’s Cancer Center, breast cancer is treated through the Susan F. Smith Center for Women’s Cancers Breast Oncology Program.

Source: Dana-Farber Cancer Institute.

 

New Tools Enhance Molecular Portraits of Breast Cancers.

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Using a combination of analytical tools, investigators with The Cancer Genome Atlas (TCGA) Research Network have completed a molecular study of breast tumors from 825 women. The results, recently reported in Nature, confirm the existence of four major subtypes of breast cancer and add new details about the biological changes underlying these diseases.

The researchers used up to six different technologies to characterize subsets of the tumors. In addition to sequencing DNA and RNA, the investigators profiled patterns of DNA methylation and counted the number of copies of genes in tumors. This was also the first TCGA study to report protein expression patterns in tumor samples.

The integration of these results has given researchers a catalog of the genetic and epigenetic abnormalities in each subtype of breast cancer, underscoring the idea that these tumors are, in many respects, distinct diseases.

“This paper and five others [describing breast cancer genomes] published this year in Nature provide a new roadmap for translational and basic research on breast cancer,” said co-lead investigator Dr. Matthew Ellis of the Washington University School of Medicine in St. Louis. Researchers could spend a decade following up on these results, he added. (See the sidebar for links to the study abstracts.)

Previous studies had hinted that one of the subtypes, basal-like breast cancer, was genetically similar to a form of ovarian cancer. The TCGA study confirmed this idea and suggested that treatments currently being tested for some ovarian cancers could be tested against these breast cancers.

“This finding really stood out,” said Dr. Ellis. “And it led to discussions [among the study authors] about the most appropriate types of chemotherapy for patients with breast cancer.” The other subtypes are known as luminal A, luminal B, and HER2-enriched breast cancers.

Making Use of Multiple Technologies

Speaking at a press briefing on cancer research last week, NCI Director Dr. Harold Varmus acknowledged that the four breast cancer subtypes have been known for years. What’s new, he explained, is that, for each subtype, TCGA investigators used multiple technologies to describe the “landscape of genetic abnormalities” in greater detail than in the past.

The Six Nature Studies

“We haven’t had a storehouse of so much valuable information about each of these categories of cancer, with the same tumors analyzed for a wide variety of properties,” he said. “It’s the repository that is so important.”

Because the study included hundreds of tumors, the researchers were able to detect uncommon but recurring mutations. Some of these mutations indicated that the tumors might respond to existing drugs. “Repurposing drugs will be important for treating this disease,” said Dr. Ellis.

Even if a particular mutation occurs in only 2 percent of patients, Dr. Ellis continued, breast cancer is common enough that researchers should be able to enroll enough women in clinical trials to test existing drugs that target these mutations.

About 20 percent of the patients with basal-like tumors might be candidates for drugs known as PARP inhibitors based on analyses of the genes BRCA1 and BRCA2 in their tumors, the researchers said. The group of basal-like tumors includes triple-negative breast cancers, which are difficult to treat and disproportionately affect younger women and African Americans.

The Translation Phase

Only three genes—TP53, PIK3CA, and GATA3—were mutated in more than 10 percent of the patients’ tumors. Drugs that target changes resulting from defects in PIK3CA are in development and could be tested in selected patients with breast cancer. However, designing and implementing large clinical trials can take years, the researchers cautioned.

“People always want to know when this kind of research is going to affect clinical care,” said Dr. Charles Perou of the Lineberger Comprehensive Cancer Center at the University of North Carolina, another study leader. “Now that we’ve made these discoveries, we’re in the translation phase.”

Many of the new discoveries can now be tested in the context of clinical trials. For instance, the study suggested there may be at least two groups of patients with HER2-positive tumors, and these groups may have different responses to treatment.

“We had a hint of this from past gene-expression studies,” said Dr. Perou. But the integrated results of the TCGA analysis, which included proteomics, are “far more convincing and suggestive than results based on any one technology alone.”

Dr. Perou co-authored one of the first studies to use genomics to distinguish subtypes of cancer. The study, published in 2000, used what was then a new tool—DNA microarrays—to profile the expression of 8,000 genes in breast tumors from 42 women.

More than a decade later, the technological advances in genomics have been “astonishing,” noted Dr. Ellis. The missing component right now is information about proteins and the biochemistry of cancer cells, he observed.

“Over the next 10 years, we need to study proteins in the same way that we have just studied DNA and RNA over the last decade,” said Dr. Ellis. Only then, he added, “will we develop a complete picture of the biochemistry of cancer cells.”

Source: NCI

 

 

Lung Cancer Genome Surveys Find Many Potential Drug Targets.

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Five new studies have identified genetic and epigenetic alterations in hundreds of lung tumors, including many changes that could be targeted by drugs that are already available or in clinical testing.

The reports, all published this month, included genomic information on more than 400 lung tumors. In addition to confirming genetic alterations previously tied to lung cancer, the studies identified other changes that may play a role in the disease. (Links to the study abstracts appear in the sidebar below.)

“These five papers are the first major salvo of genome-wide studies using all of the newest technologies to analyze a large number of lung cancers,” said Dr. John Minna, a clinician and lung cancer researcher at the University of Texas Southwestern Medical Center, who co-authored one of the studies.

Collectively, the studies covered the main forms of the disease—lung adenocarcinomas, squamous cell cancers of the lung, and small cell lung cancers.

Although preliminary, the findings could be used to develop molecular markers for identifying patients who are candidates for certain targeted drugs. At the same time, researchers in the lab can now evaluate the newly discovered changes to identify novel potential therapeutic targets.

“All of these studies say that lung cancers are genomically complex and genomically diverse,” said Dr. Matthew Meyerson of Harvard Medical School and the Dana-Farber Cancer Institute, who co-led several of the studies, including a large-scale analysis of squamous cell lung cancer by The Cancer Genome Atlas (TCGA) Research Network.

Some genes, Dr. Meyerson noted, were inactivated through different mechanisms in different tumors. He cautioned that little is known about alterations in DNA sequences that do not encode genes, which is most of the human genome.

Squamous Cell Tumors

The TCGA investigators sequenced the genomes or exomes (the protein-coding regions of DNA) of tumor samples from 178 patients with squamous cell lung cancer. In more than half of the tumors examined, the researchers found a change to a gene or a signaling pathway that is targeted by a drug that exists or is in development. The findings were reported in Nature on September 9.

“This gives us an enormous opportunity for progress in this disease,” said Dr. Meyerson.

The TCGA model integrates genomic data for squamous cell lung cancers with clinical information, when available, and with other tumor characteristics, such as gene expression, epigenetic changes to cells, and alterations in the number of gene copies.

“The framework for these five studies was built on a convergence of new technologies and the need to better understand the biology of lung cancers as it relates to new therapies for our patients,” said Dr. Paul Paik, who treats patients with lung cancer at Memorial Sloan-Kettering Cancer Center and was part of the clinical team involved in TCGA.

Small studies (for example, here and here) have provided hints that certain signaling pathways are important in squamous cell lung cancers, leading to new trials of targeted drugs. “Now, with the publication of the TCGA study, we know that squamous cell lung cancers have a myriad of potentially targetable changes,” Dr. Paik noted.

An unexpected finding was the presence of mutations in the EGFR gene in about 1 percent of squamous cell tumors. These tumors might respond to available drugs that block signals through the EGFR pathway.

The researchers also found evidence of genetic changes that may help lung cancer cells evade surveillance by the immune system.

The Five Studies

Testing Lung Tumors

Any therapeutic targets to emerge from the new reports would need to be incorporated into molecular tests that can identify candidates for certain drugs. A leader in this work is the Lung Cancer Mutation Consortium, which has been building knowledge of the mutations associated with the disease and testing for these changes.

Many patients with lung adenocarcinomas have benefited from targeted drugs. Crizotinib (Xalkori), for instance, has elicited some dramatic responses in patients whose tumors harbor a particular gene fusion. Some medical centers now routinely test tumors before selecting treatment for patients with lung adenocarcinomas.

“If you look at lung cancer as a whole, the big therapeutic targets were first identified in adenocarcinomas,” Dr. Minna explained. “Now there are new targeted therapies that could make an impact on squamous cell lung cancer.”

At Memorial Sloan-Kettering, all patients with squamous cell lung cancer have their tumors tested for drug targets using various techniques, including DNA sequencing. Among 28 of these patients evaluated recently, more than 60 percent had tumors that contained a potential target.

Dr. Paik noted that his group will use the TCGA results to expand their testing. “In a sense, the future potential of this new work is being realized now,” he said. “That’s pretty exciting.”

Small Cell Lung Cancer

Two new reports describe genetic changes in small cell lung cancers, which tend to be aggressive and about which little has been known. The research teams conducted exome or whole-genome sequencing on a total of 82 samples of such tumors.

“This study gave us a host of new targets to explore,” said Dr. Charles Rudin of the Johns Hopkins Kimmel Cancer Center, who led one study. The next steps will be to validate which targets are driving the growth of tumors and are “druggable,” he added.

The researchers found that a gene called SOX2, which plays a role in normal development, may contribute to some small cell lung cancers, as well as other cancers, and could be targeted.

Small cell lung cancers have been challenging to study because most are not treated surgically, so tumor samples are rare. What’s more, these tumors have high rates of genetic mutations due to tobacco smoke, yet only some mutations are driving the disease, noted Dr. Roman Thomas of the University of Cologne in Germany, who led the other study.

Using statistical “filters,” his group found that genes involved in modifying histone proteins, which help package DNA within a cell, were frequently mutated in the disease.

“These cancers are extraordinarily complex, so as researchers our steps forward are incremental—but, still, they are steps,” Dr. Thomas noted. “No one would have imagined that lung cancer would be the prototypical disease for targeted medicine.”

Comparing Tumors in Smokers and Nonsmokers

Non-small cell lung cancers were the focus of two additional studies, which appeared in Cell. One group sequenced the exomes or genomes of 183 tumor samples, and the other conducted whole-genome sequencing of tumor tissues from 17 smokers and nonsmokers.

“We found a substantially lower number of mutations in the genomes of tumors from nonsmokers compared to the smokers,” said Dr. Ramaswamy Govindan of the Washington University School of Medicine in St. Louis, MO, who led the study. Five study participants who had never smoked had a mutation that could be targeted by an existing drug.

All these studies show how diverse and how complicated the cancer genome is. But we now have a panoramic view of the genomic landscape, and this is important for moving forward in this disease.

—Dr. Ramaswamy Govindan

In all, the study authors found 54 genes with potentially targetable alterations in the 17 patients.

“The days of large clinical trials for lung cancer are over,” Dr. Govindan said, noting that patients need to be selected for specific treatments based on the characteristics of their tumors. “We also need to develop clinical trials that move targeted therapies to earlier stages of lung cancer, where we have a better chance of a cure.”

Future clinical trials, he predicted, would look for relatively large effects of drugs in selected patients. Dr. Minna agreed, saying, “If the effects are not there, we will move on to the next target and the next drug.”

The new results are really a teaser for what’s coming. TCGA plans to sequence a total of 500 adenocarcinomas and 500 squamous cells tumors. These results could help shed light on issues such as epigenetic changes in lung cancer, mechanisms of drug resistance, and how tumors are influenced by the surrounding tumor microenvironment.

“All these studies published back to back show how diverse and how complicated the cancer genome is,” Dr. Govindan said. “But we now have a panoramic view of the genomic landscape, and this is important for moving forward in this disease.”

Dr. Minna added, “After treating thousands of patients with lung cancer and not doing too well, I am very excited about the new results.”

Source: NCI

Researchers Use Gene Deletions to Find Cancer Treatment Targets.

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Chromosomal damage that can transform healthy cells into cancer cells may also create weaknesses that can be exploited to kill the cancer cells, a new study suggests. The idea, called “collateral vulnerability,” could be used to identify new targets for drug therapy in multiple cancers, according to researchers from the Dana-Farber Cancer Institute and the University of Texas MD Anderson Cancer Center. The study was published August 16 in Nature.

Directly targeting genetic mutations that drive cancer with drugs is difficult, particularly in the case of mutations that delete tumor suppressor genes. Using data on the brain cancer glioblastoma multiforme (GBM) from The Cancer Genome Atlas (TCGA) initiative, the research team identified a number of “collateral” or “passenger” gene deletions that occurred during chromosomal damage that resulted in the loss of tumor suppressor genes.

The researchers next looked for passenger gene deletions that met two criteria: the deleted genes were involved in functions vital to cell survival, and the deleted genes were closely related to existing genes that perform similar functions. This loss of redundancy caused by passenger gene deletions can potentially be exploited to selectively kill tumor cells, the authors explained.

One gene that met these criteria is ENO1. ENO1 produces enolase 1, an enzyme that plays a central role in a process cells use to make energy. Human cells have a closely related gene (ENO2) that produces the enzyme enolase 2, which acts as a back-up for enolase 1 in brain tissue. Brain cells normally have a high level of enolase 1 activity and a small amount of enolase 2 activity. In some patients with GBM, however, the tumor cells lack enolase 1 activity because ENO1 was deleted when a tumor suppressor gene was deleted. This lack of enolase 1 activity could make these tumor cells more vulnerable to enolase inhibition.

This idea was tested using two targeting strategies. First, in GBM cell lines that lacked ENO1, the investigators showed that silencing ENO2 gene expression with a short hairpin RNA (a short RNA sequence that blocks the production of enolase 2 protein from ENO2 messenger RNA) sharply reduced cell growth, and tumors failed to form in mice injected with the treated cells.

The second approach involved a drug that targets the enolase 1 and enolase 2 proteins. Treatment of GBM cell lines lacking ENO1 with the drug caused the cancer cells to die because of the low overall enolase levels in these cells. But drug treatment had little effect on normal brain cells or GBM cells that had ENO1, since these cells have high levels of ENO1 gene expression and are, therefore, less sensitive to the drug.

The collateral vulnerability concept is similar in some respects to the idea of synthetic lethality, which uses genetic mutations in cancer-associated genes to identify other potential cellular vulnerabilities, explained the study’s co-lead author, Dr. Florian Muller of MD Anderson.

There are many more passenger gene deletions than tumor suppressor gene deletions, “and some of these passenger-deleted genes perform functions critical for cell survival,” Dr. Muller continued. “So, by expanding the concept to passenger genes, we vastly expand the possibility of finding these relationships, and, in the case of essential-redundant gene pairs like ENO1 and ENO2, we also provide a rational, knowledge-based method of drug-target discovery.”

The researchers are extending their work to other passenger gene deletions in GBM, Dr. Muller said.

This research was supported in part by the National Institutes of Health (CA95616-10 and CA009361).

Also in the Journals: Youth Tobacco Use Dropped between 2000 and 2011

Tobacco use and cigarette smoking fell among middle and high school students between 2000 and 2011, according to data from the National Youth Tobacco Survey, a school-based, self-administered questionnaire given to students in grades 6 through 12. Researchers from the Centers for Disease Control and Prevention published the findings last month in Morbidity and Mortality Weekly Report.

Percentage of U.S. Middle and High School Students Using Tobacco

Middle School Students

High School Students

2000

2011

2000

2011

Current Tobacco Use

14.9

7.1

34.4

23.2

Current Smoked Tobacco Use

14.0

6.3

33.1

21.0

Current Cigarette Use

10.7

4.3

27.9

15.8

Source: NCI