Question

What would be good exosomatic examples of Lung adenocarcinoma and it's research. For example comparing SNP sequence and structural varience.   

Answer 1

Lung adenocarcinoma accounts for about 40% of all lung cancers. It tends to grow more slowly than other kinds of lung cancer.

There are numerous treatment options available to people affected by lung adenocarcinoma, and doctors are working hard to develop and improve these treatments.

Adenocarcinoma is a subtype of of non-small cell lung cancer (NSCLC). It tends to develop in smaller airways, such as bronchioles, and is usually located more along the outer edges of the lungs.

Adenocarcinoma is a cancer that begins in cells in the glands. Glandular cells are found in the lungs and some other internal organs. Most cancers of the breast, pancreas, prostate, and colon are also adenocarcinomas. Only adenocarcinoma that begins in the lungs is considered lung cancer.

Adenocarcinoma accounts for 40% of all lung cancers, is found more often in women, and tends to grow more slowly than other lung cancers. Most lung cancers in people who have never smoked are adenocarcinomas.

Research

This type of lung cancer may be diagnosed in many different ways. In addition, doctors have come up with very specific modes of categorizing lung cancer to help treat them better. Understanding the ways that doctors categorize lung cancers may help you understand your diagnosis.

How is Lung Adenocarcinoma Diagnosed?

Many different tests are used to diagnose lung cancer and determine whether it has spread to other parts of the body. Some can also help to decide which treatments might work best. The steps and tests used in diagnosing lung adenocarcinoma include:

• Imaging tests
• Laboratory tests
• Biopsies

Not all of these will be used for every person. The approaches used for an individual will depend on your medical history and condition, symptoms, location of the nodule(s), and other test results.

Read the Diagnosing Lung Cancer section to learn about the different steps and tests for making a lung cancer diagnosis.

Stages of Lung Cancer

Staging is a way of describing where the cancer is located, if or where it has spread, and whether it is affecting other parts of the body. Doctors use diagnostics to determine the cancer’s stage, so staging may not be complete until all of the tests are finished. Knowing the stage helps the doctor to recommend a treatment plan. Although lung cancer is treatable at any stage, only certain stages of lung cancer can be cured.

The Lung Cancer Staging section provides more information about this way of understanding lung adenocarcinoma.

Biomarker Profile

Lung cancer describes many different types of cancer that start in the lung or related structures. There are two different ways of describing what kind of lung cancer a person has:

• Histology—what the cells look like under a microscope. Adenocarcinoma is a histological subtype of non-small cell lung cancer. Other subtypes of non-small cell lung cancer include squamous cell lung cancer, large cell lung cancer, and some rarer types. Small cell lung cancer (SCLC)is the other major type of lung cancer.

• Biomarker profile (also called molecular profile, genomic profile, or signature profile)—the mutations, or characteristics, as well as any other unique biomarkers, found in a person’s cancer that allowed the cancer to grow.

A person’s lung cancer may or may not have one of the many known driver mutations that cause cancer. Researchers are making progress in understanding mutations in adenocarcinoma. Several therapies targeting these mutations are approved for use as first-line treatment and subsequent treatments in adenocarcinoma, and others are being studied in clinical trials.3

The decision to test for mutations (via biomarker testing) should be made together by you and your doctor.

Below are the driver mutations that have been identified for lung adenocarcinoma at this time:4

More information about driver mutations, and how and when testing for them is performed, can be found here (see “What is a driver mutation?,” “How is biomarker testing performed?,” and “Who should have their tumor tested, and when?”).

More About recent work in Adenocarcinoma

There are a number of treatment options for lung adenocarcinoma. Which ones are used to treat a specific patient’s lung cancer will depend on the stage of the cancer and the patient’s overall health and preferences.

Treatment options fall into two categories:

• Those that are approved by the FDA
• Those that are being studied in clinical trials

What are Currently Approved Treatment Options?

Approved treatment options for lung adenocarcinoma include:

• Surgery
• Radiation therapy
• Chemotherapy
• Targeted therapy
• Angiogenesis inhibitors
• Immunotherapy

Note that a patient’s age alone does not predict whether that patient will benefit from treatment, and should not be the only factor when deciding what treatment is best. Other factors, such as how fit a patient is othrwise and what other medical problems exist, also need to be considered.5

Surgery

Lung cancer that is only in one lung and that has not spread to other organs is often treated with surgery, if the patient can tolerate it. Read more about different surgical options and what to expect after surgery in the Treatment Options: Surgery section.

Radiation Therapy

Radiation therapy is a type of cancer treatment that uses high-powered energy beams to kill cancer cells. Depending on the individual patient’s situation, radiation therapy may be used when trying to cure cancer, control cancer growth, or relieve symptoms caused by the tumor, such as pain.

Radiation therapy can be given as the main treatment in early-stage lung adenocarcinoma if surgery is not possible. In that case, it may be given either with or without chemotherapy.

Read more about radiation treatment, including how it works, how and when it is given, the different kinds, and common side effects, in the Treatment Options: Radiation Therapy section.

Chemotherapy

Patients whose lung cancer has spread beyond the lung to local lymph nodes are often given chemotherapy and radiation therapy. As with other types of non-small cell lung cancer, patients with lung adenocarcinoma are often given two chemotherapy agents as first-line therapy. Which drugs are chosen will depend in part on the patient’s overall health and ability to tolerate different possible side effects.

For patients with lung adenocarcinoma, most often one of the platinum drugs cisplatin or carboplatin is combined with another chemotherapy drug, such as pemetrexed or doctataxel.6,7

There are other drug therapy options, like targeted therapies, angiogenesis inhibitors, and immunotherapy. These are discussed in more detail below. Your doctor will help to select the best treatment based on your medical history and other factors. Read more about chemotherapy, including how it works, how and when it is given, and possible side effects and how to manage them, in the Treatment Options: Chemotherapy section.

Targeted Therapy

Targeted therapies are a type of therapy that aims to target cancer cells directly. They focus on specific parts of cells and the signals that cause cancer cells to grow uncontrollably and thrive. All of the targeted therapies that have been studied and FDA-approved belong to a class of drugs called tyrosine kinase inhibitors (TKIs).

As discussed earlier in this section, there are a number of known driver mutations in lung adenocarcinoma. TKIs are currently approved by the US Food and Drug Administration (FDA) for five of them: the anaplastic lymphoma kinase (ALK) gene rearrangement, the epidermal growth factor receptor (EGFR)mutation, the ROS1 gene rearrangement, the BRAF V600E mutation, and the NTRK1 gene fusion. Lung cancers with these mutations are called ALK-positive, EGFR-positive, ROS1-positive, BRAF-positive, and NTRK1-positive.

ALK gene rearrangements happen in a small proportion (about 7%) of patients with lung adenocarcinoma. The following ALK inhibitors are currently FDA-approved for patients with ALK-positive metastatic non-small cell lung cancer, including adenocarcinoma:

• Crizotinib (Xalkori®): as first-line and greater treatment8
• Ceritinib (Zykadia®): as first-line and greater treatment9
• Alectinib (Alecensa®): as first-line and greater treatment10
• Brigatinib (Alunbrig®): for patients whose cancer has grown while they were on crizotinib or are intolerant to crizotinib11
• Lorlatinib (Lorbrena®): for patients whose disease has progressed on crizotinib and at least one other ALK inhibitor for metastatic disease or whose disease has progressed on alectinib or ceritinib as first-line therapy for metastatic disease12

EGFR mutations occur in about 10% of lung adenocarcinoma tumors. There are currently four FDA-approved EGFR inhibitors approved for patients with metastatic EGFR-positive non-small cell lung cancer:

• Afatinib (Gilotrif®): as first-line treatment13
• Dacomitinib (Visimpro®): as first-line treatment14
• Erlotinib (Tarceva®): as first-line treatment, maintenance therapy , and second-line or greater treatment after progression following at least one chemotherapy regimen.15
• Gefitinib (Iressa®): as first-line treatment16
• Osimertinib (Tagrisso®): as second-line treatment for patients whose tumors are (EGFR) T790M-positive and whose disease has proressed on or after EGFR TKI therapy17,18

About 1% to 2% of patients with lung adenocarcinoma have tumors with a ROS1 mutation. There is currently one tyrosine kinase inhibitor that has been approved for patients with metastatic NSCLC whose tumors are ROS1-positive. This is crizotinib (Xalkori®), a TKI that is also used for patients with ALK-positive tumors.8 Other ROS1 inhibitors are currently being studied in clinical trials.

The BRAF V600E mutation is found in 1%-3% of lung adenocarcinoma patients. There is currently one FDA-approved combination inhibitor treatment for patients with metastatic NSCLC with the BRAF V600E mutation: dabrafenib (Tafinlar®) and trametinib (Mekinist®).19

The NTRK1 gene fusion is found in about 3% of lung adenocarcinoma patients.20 There is currently one FDA-approved tyrosine kinase inhibitor, larotrectinib (Vitrakvi®), that has been approved for the treatment of patients whose solid tumors (e.g., lung, thyroid, colon):

• have an NTRK gene fusion (including the NTRK1 gene fusion among lung adenocarcinoma patients) without a known acquired resistance mutation,
• are metastatic or where surgical resection is likely to result in severe morbidity, and
• have no satisfactory alternative treatments or have progressed following treatment.21

The biggest challenge of TKIs is that all patients with lung cancer who initially benefit from them eventually develop resistance, known as acquired resistance. Doctors and researchers are working to overcome resistance in tumors and to keep TKIs effective against cancer for longer periods of time.

Read more about targeted herapy, including how it works, how and when it is given, possible side effects and how to manage them, and acquired resistance in the Treatment Options: Targeted Therapysection.

Angiogenesis Inhibitors

As the body develops and grows, it makes new blood vessels to supply all of the cells with blood. This process is called angiogenesis. When the new blood vessels provide oxygen and nutrients to cancer cells, they help the cancer cells grow and spread.

Angiogenesis inhibitors help stop or slow the growth or spread of tumors by stopping them from making new blood vessels. The tumors then die or stop growing because they cannot get the oxygen and nutrients they need. The way they do this is by blocking the cancer cells’ vascular endothelial growth factor (VEGF) receptors.22

Currently, two angiogenesis inhibitors are FDA-approved for patients with non-small cell lung cancer, including adenocarcinoma:

• Bevacizumab (Avastin®): In combination with carboplatin and paclitaxel for the first-line treatment of patients with unresectable, locally advanced, recurrent, or metastatic non-squamous adenocarcinoma23
• Ramucirumab (Cyramza®): In combination with docetaxel for the second-line treatment of patients with metastatic NSCLC whose disease has progessed on or after platinum-based chemotherapy24

Read more about how angiogenesis inhibitors work and common side effects, as well as questions to ask your healthcare team, in the Treatment Options: Angiogenesis Inhibitorssection.

Immunotherapy

Immunotherapy aims to strengthen the natural ability of the patient’s immune system to fight cancer. Instead of targeting the person’s cancer cells directly, immunotherapy trains a person’s natural immune system to recognize cancer cells and selectively target and kill them.25

Currently, there are four FDA-approved immunotherapy drugs for people with non-small cell lung cancer. These drugs belong to the type of immunotherapy called immune checkpoint inhibitors, which work by targeting and blocking the fail-safe mechanisms of the immune system. The goal is to block the immune system from limiting itself, so the immune system can target the cancer cells.

The four FDA-approved immunotherapy drugs are:

• Nivolumab (Opdivo®): For patients with metastatic NSCLC whose cancer has progressed after platinum-based chemotherapy. Patients with EGFR or ALK mutations should have disease progression on FDA-approved therapy for those mutations before they are treated with nivolumab.26
• Pembrolizumab (Keytruda®):
  • As first-line treatment for patients with EITHER stage III NSCLC who are not candidates for surgery or defnitive chemoradiation OR metastatic NSCLC, and whose tumors express PD-L1 (Tumor Proportion Score (TPS) greater than or equal to 1%) as determined by an FDA-approved test, with no EGFR or ALK mutations. (The Tumor Proportion Score (TPS) is the percentage of cancer cells that produce the PD-L1 proteins. The lung cancer tissue is stained with special dyes that mark PD-L1 positive tumor cells. A pathologist counts the number of cells that stain positive and determines the TPS.)
  • ​For first-line treatment of patients with metastatic NSCLC whose tumors have high PD-L1 expression as determined by an FDA-approved test, with no EGFR or ALK mutations
  • For patients with metastatic NSCLC whose tumors express PD-L1 as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. (Note: Platinum-based chemotherapies include carboplatin and cisplatin.) Patients with EGFR or ALK mutations should have disease progression on FDA-approved therapy for those mutations before they are treated with pembrolizumab
  • ​For first-line treatment of patients with metastatic non-squamous NSCLC, irrespective of PD-L1 expression, in combination with pemetrexed and carboplatin27
• Atezolizumab (Tecentriq®):
  • For first[line treatment of patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic mutations, in combination with bevacizumab, paclitaxel, and carboplatin
  • For patients with metastatic NSCLC who have disease progression during or following platinum-containing chemotherapy. Patients with EGFR or ALK mutations  should have disease progression on FDA-approved therapy for those mutations before they are treated with atezolizumab28
• Durvalumab (Imfinzi®): Approved for patients with stage III NSCLC whose tumors are not able to be surgically removed and whose cancer has not progressed after treatment with concurrent platinum-based chemotherapy and radiation therapy. (The purpose of this treatment is to reduce the risk of the lung cancer progressing

In addition to the approved treatments described above, there is a great deal of promising research going on now in clinical trials focused on people with lung adenocarcinoma.30 The following describe some, but by no means all, of the clinical trials available for people with lung adenocarcinoma.

Targeted Cancer Therapy

As shown earlier, a number of mutations have been found in lung adenocarcinoma in addition to EGFR, ALK, ROS1, BRAF V600E, and NTRK1. Among these are HER2, KRAS, MAP2K1, MET, NRAS, PIK3CA, and RET. Currently, researchers are working to develop drugs that target a number of these mutations.

Immunotherapy

Three main types of immunotherapy are currently being studied in clinical trials for people with all stages of non-small cell lung cancer:

• Immune checkpoint inhibitors by themselves or combined with other drugs
• Therapeutic cancer vaccines
• Adoptive T cell transfer

Immune checkpoint inhibitors, such as nivolumab (Opdivo®), pembrolizumab (Keytruda®), and atezolizumab (Tagrisso®) continue to be studied for treatment of earlier stages of lung cancer and in combination with other treatments.30

New Approaches to Existing Treatments

In addition to new treatments, doctors are also trying new approaches to existing treatments. Some examples include:

• Chemotherapy agents given in combination with radiation therapy, surgery, immunotherapy, and targeted cancer therapy
• Radiation therapy given in combination with chemotherapy and surgery
• Looking at whether using imaging procedures, such as PET and CT scans, can help doctors guide radiation therapy so that higher doses can be delivered directly to the tumor, causing less damage to healthy tissue

For Comparing SNP sequence and structural varience must see this article.

Recent studies using single-nucleotide polymorphism arrays have pinpointed novel oncogenes and tumor suppressors involved in specific types of human cancers.

One of the most daunting, though rewarding, challenges in cancer medicine is to determine how specific genetic alterations in tumors may affect the prognosis and lead to targeted therapies for the individual cancer patient. Current methods of gene-expression profiling have revealed that tumor types previously thought to be homogenous from histological criteria alone often have different underlying molecular signatures [1-3]. Complex mutational events seem to have a major impact on the expression of specific genes that contribute to the induction and progression of cancer, and, therefore, on the aggressiveness of the tumor and the clinical outcome of therapy [3-5]. The precise assessment of tumor-cell heterogeneity has thus become a central focus of cancer investigations. The ultimate goal of these efforts is to identify disease subtypes that are driven by altered signaling pathways whose genetic defects correlate well with prognosis and that offer attractive targets for molecular intervention [6-11].

The longest-established method of diagnosing and differentiating tumor types is the detection of chromosomal aberrations by cytogenetic analysis. Molecular cytogenetic techniques, such as spectral karyotyping, fluorescence in situ hybridization and chromosome-based comparative genomic hybridization (CGH), substantially improved resolution and genome coverage compared with conventional cytogenetics. But these techniques still did not offer the resolution and genome coverage of microarray gene-expression profiling. This can provide clinically significant insights into the heterogeneity of tumor cells and has been used to subclassify various human tumors [1-3,12], but it can sometimes be difficult to identify the truly relevant genes among the multiplicity of differences in gene expression recorded. Genomic methods that identify mutations directly and cover the whole genome at a similarly high resolution are required to help resolve such problems.

One attempt to improve the detection of structurally altered genomic regions combines classic CGH with the microarray platform, generating the array CGH technique, which relies on competitive hybridization of fragmented, labeled tumor DNA together with fragmented, but differentially labeled control DNA [13,14]. The microarray platform facilitates higher-resolution mapping of genomic regions that contain copy-number aberrations, such as amplifications and deletions, and the interpretation of data from array CGH studies is much more straightforward than that of conventional CGH. Another new microarray-based cytogenetic technique, high-resolution single-nucleotide polymorphism (SNP) array analysis, perhaps holds even greater promise for detailed structural examination of the cancer genome. SNP arrays allow the high resolution detection of loss of heterozygosity, a common event in tumorigenesis, in addition to the identification of DNA copy-number aberrations at a resolution similar to that of array CGH. A recent study of childhood acute lymphoblastic leukemia (ALL) by Mullighan et al. [15] illustrates the strength of SNP arrays for the identification of key genetic abnormalities in cancer.

Advantages of SNP array analysis

A SNP is defined as a DNA sequence variation at one specific position in the genome that occurs in at least 1% of the human population. Almost all SNPs have only two alleles, and so the heterozygous genotype and the two types of homozygous genotypes can generally be unambiguously determined. On current microarray platforms, 300,000 to 500,000 SNPs can be genotyped simultaneously. Ideally, the tumor sample is analyzed in parallel with a normal - or 'germline' - sample from the same patient; if such a control sample is unavailable, algorithms can be used instead [16]. However, with this approach, the resolution will be lowered, and the data interpretation could be hampered due to the extensive somatic variation in copy number within human populations (so-called copy number variation, or CNV) [17]. As the signal obtained for each position on the array is quantitative, DNA copy number can be determined from it. At the same time, a discrete genotype designation is generated that can be used to detect regions of loss of heterozygosity by comparison with the patient's germline DNA. Loss of heterozygosity means the loss of one allele at a given position (or positions); it is classically associated with tumorigenesis when a 'good' copy of a tumor suppressor gene is physically lost as a result of the deletion of a chromosome or a chromosomal region, leaving the cancer cell with only one (usually defective) allele.

Copy-number analysis by comparison to a matched normal DNA control for each patient's tumor will rapidly detect gene amplification, low-copy gain and deletion with a high degree of confidence, even at the level of a single-copy gain or loss (Figure ​(Figure1).1). To identify regions of loss of heterozygosity, one must infer genotype calls from a string of adjacent heterozygous SNPs, because homozygous germline genotypes are noninformative.

Figure 1

Illustration of SNP array analysis by example of matched neuroblastoma samples using the dChip software [25,26]. Normal (N) and tumor (T) DNA of five selected patients were hybridized to 10K Affymetrix SNP arrays (data kindly provided by R George [22]). ...

Most commonly, the loss of heterozygosity in tumor cells is a result of deletion of a region of a chromosome or of a whole chromosome, and SNP arrays identify these deleted regions as having loss of heterozygosity combined with a copy-number reduction. Loss of heterozygosity can, however, appear without a copy-number change - copy-neutral loss of heterozygosity. For example, a mutated tumor suppressor allele and its surrounding DNA can be copied and replace the other allele by somatic homologous recombination during the development of the neoplastic clone, resulting in a tumor cell that is homozygous for the mutated tumor suppressor allele and has a growth or survival advantage. This type of mutational event is known as uniparental disomy (UPD) and represents an important but largely overlooked mechanism for generating loss of heterozygosity. One of the advantages of SNP microarrays is that they are unique among genomic analysis methods in being able to identify UPD.

The study by Mullighan et al. [15] nicely illustrates the advantages of SNP arrays. The authors analyzed 192 cases of pediatric B-cell-progenitor acute lymphoblastic leukemia (B-ALL), 94% of which had a matched control sample from a time when the patient's leukemia was in remission. Recurrent chromosomal abnormalities are a hallmark of early B-ALL and the karyotype is, therefore, used to classify subtypes of the disease [18]. Copy-number analysis of the B-ALL cases by Mullighan et al. [15] revealed an overall prevalence of deletions in all subgroups except the hyperdiploid cases (cases with more than 50 chromosomes in the leukemic clone), in which gains dominated.

The highest frequency of deletions was found in hypodiploid cases (cases with less than 45 chromosomes in the leukemic clone), and in cases in which the ETV6 gene (on chromosome 12) and the RUNX1 gene (on chromosome 21; both genes encode transcription factors) were fused as the result of a translocation. A deletion involving ETV6 was detected in 33 of 46 cases also harboring this translocation between chromosomes 12 and 21. By contrast, cases with rearrangements affecting the MLL gene had a very low frequency of deletions and almost no amplifications. Altogether, the study identified more than 40 regions that were recurrently deleted in different patients, with three focal segments of chromosome 9 showing the highest overall frequency of deletions. At 9p21.3, a third of all cases had deletions in the tumor suppressor locus CDKN2A (encoding both p14-ARF and p16-INK4A), often occuring in the context of a region of UPD. A fifth of cases had a deleted MLL translocation partner gene MLLT3 (AF9), located on 9p21. More than a quarter of the cases (56 of 192) showed a deletion at 9p13.2, a locus not previously identified as being involved in B-ALL.

Some informative cases had very focused deletions that pinpointed the PAX5 gene as the likely target on chromosome band 9p13.2 [15]. Indeed, sequencing and functional studies by Mullighan et al. [15] led to the identification of PAX5 as a highly tumor type-specific tumor suppressor gene in early B-cell lineage ALL. PAX5 encodes a transcription factor that drives the differentiation of progenitor B cells by repressing self-renewal programs and activating genes specific for the B-cell lineage [19]. Mullighan et al. [15] found that haploinsufficiency rather than total loss of PAX5 function predominated; the deletions were accompanied by mutation of the remaining allele in only a minority of cases and two cases were identified that had a heterozygous mutation without a deletion. Other genes involved in B-cell development were found to be deleted in some cases, including EBF1, a transcription factor obligatory for B-progenitor cell differentiation. Six of eight cases showed very focused deletions that affected only the EBF1 locus and, therefore, were not detectable by conventional cytogenetic analysis.

The identification of PAX5 and EBF1 as new mutational targets in early B-lineage leukemogenesis shows the value of SNP array studies for selecting genes for detailed analysis. Like PAX5, the EBF1 gene retained one wild-type allele in the majority of the cases, supporting the idea that haploinsufficiency is an inherent property of some tumor suppressors [20,21]. In cases with defects in such genes, it may be possible to increase gene expression from the remaining allele.

Other work has also shown the power of SNP array analysis to identify the loss of functional tumor suppressors even in cases lacking chromosomal deletions, or gain of regions containing potential oncogenes. We have performed a matched control study by SNP array of 22 neuroblastoma patients [22] and identified chromosomal aberrations that had been previously implicated in neuroblastoma by more laborious analysis of loss of heterozygosity at individual loci. A subset of four cases showed loss of heterozygosity of 11p solely as a result of UPD, indicating that cells might not tolerate the haploinsufficiency generated by large deletions of some chromosomal regions. A matched control study of 14 basal cell carcinomas by Teh et al. [23] revealed that, in almost all cases, the region on chromosome 9q harboring the tumor suppressor gene PTCH1 has undergone loss of heterozygosity. More than a third of these cases resulted from UPD, implying the duplication of a mutated allele.

Sellers and colleagues [24] have taken a different approach to exploiting the information provided by SNP arrays. To uncover novel signaling pathways in human cancers, they first examined the structural genomic aberrations of a cell line panel by SNP array copy-number analysis. Clustering of the cell lines according to their copy-number aberrations identified subgroups that showed amplifications and deletions in shared regions. One cluster, comprising six out of nine melanoma cell lines, showed a copy-number gain in a defined region of chromosome 3p. Comparison of the gene-expression profiles of the six melanoma cell lines with the other lines identified a small set of genes as highly expressed, only one of which, that encoding transcription factor MITF, was located within the chromosome 3p region. Additional studies established that MITF is a survival factor with oncogenic properties in melanoma.

Thus, SNP array technology can provide a global analysis of DNA copy-number alterations in human cancers while revealing important loss of heterozygosity due to UPD, which would be entirely missed by conventional cytogenetic analysis or array CGH. Identification of UPD in tumor cells allows genetically similar cases to be classified together for prognostic and therapeutic purposes in the absence of a cytogenetically apparent deletion. In addition, the finding of a UPD implies that a significant mutational or heritable epigenetic event has occurred within the duplicated region, thus providing a good reason for further detailed analysis at the DNA sequence level.

A cross comparison of all cases included in a SNP array study makes it possible to define shared regions of copy-number change, loss of heterozygosity and UPD and to delineate both minimally deleted and minimally amplified regions. Thus, SNP array studies can pinpoint critical structurally altered regions within the genome of a particular type of cancer and contribute to the discovery of novel oncogenes or tumor suppressors, as shown by the study of Mullighan et al. [15]. The potential oncogenic function of genes located in amplified regions that are also overexpressed in the tumor cells can be tested functionally in animal models.

Ultimately, SNP array analysis should provide a way to reliably subclassify tumors on the basis of shared genetic abnormalities, so that patients can be assigned to the most appropriate therapies. This technology also seems especially promising as a way of implicating oncogenic pathways and initiating the search for targets that could be exploited in the development of molecular therapeutics. For a protein to be a useful therapeutic target within the cancer cell, it must have a driving role in a pathway controlling tumor initiation, the maintenance of the malignant phenotype or metastatic behaviors. Tumors acquire multiple critical genetic aberrations before they become clinically apparent, and, by the use of powerful technologies, such as SNP analysis and eventually whole genome resequencing, it should then be possible to target several of these defects to reverse tumor growth.