Author(s): Saad F Idris 1 , Saif S Ahmad 1 , Michael A Scott 1 , George S Vassiliou 2 , James Hadfield [*] 3
array CGH; cancer; cancer genomics; next-generation sequencing; oncology; personalized medicine; pyrosequencing; SNP-CGH; targeted therapy
Genomic alterations in cancer
A small number of hereditary cancer syndromes are directly caused by germline mutations and heritable genetic variation may also play a role in many sporadic cancers. However, the great majority of human cancers are driven by somatic mutations within the cancer-cell genome that occur during life. Understanding the diversity and function of these somatic mutations is the cornerstone of current cancer research and detecting known mutations of clinical significance reliably is increasingly forming an important part of clinical practice. The major impetus for elucidating the nature and function of somatic mutations in cancer genomes is the potential for the development of effective targeted anticancer therapies, the archetypal example being the tyrosine kinase inhibitor imatinib, which directly inhibits the BCR -ABL fusion gene product arising from the translocation t(9;22) in chronic myeloid leukemia, and which has revolutionized the treatment and outcome of this previously devastating disease  .
Nucleotide substitutions are the most common genomic alterations in tumors - usually at a stated rate of one substitution per million nucleotides  . Insertion and deletions are ten-times less common. The rate of mutation varies significantly. For example, skin melanomas occurring as a result of UV radiation exposure, display substantially more mutations than hematopoietic tumors [3-5] . Even small point mutations or microdeletions can be vitally important to detect, as they may have major relevance to the patient's prognosis and future treatment  . Much larger acquired chromosomal translocations are a well-characterized feature of hematological malignancy but have also been demonstrated in solid-organ tumors [7,8] . Smaller copy-number variations (CNVs) in tumor genomes can also result in the amplification of oncogenes and/or inactivation of tumor-suppressor genes contributing directly to tumor pathogenesis. Additionally, loss of heterozygosity (LOH) of tumor suppressor genes is increasingly being recognized as an important genomic alteration contributing to tumor initiation and progression  . After an inactivating mutation of the first allele, LOH occurs either as a result of loss of function of the remaining normal allele or as a result of uniparental disomy where the mutant allele is duplicated and the remaining normal allele lost. Reliable detection of all of these types of mutation within cancer genomes of individual patients is necessary if we are to offer truly personalized cancer care to our patients.
The mainstay of current cancer diagnosis is histological examination of tumor cells with immunohistochemical analysis. These methods are relatively blunt instruments that fail to distinguish between molecularly distinct subtypes of tumors, which may have individual tumor biology, prognosis and treatment. In a variety of cancers, especially hematological, more specific molecular tests are now widely employed to provide more detailed information about individual patients' disease. It is routine practice, for example, to examine bone marrow samples from patients with acute leukemia using flow cytometry, in order to identify...