Biomedical Engineering Reference
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cells but do not provide survival advantage of cancer. The identification and
characterization of driver mutations and the cancer genes represent a central aim
of cancer research [ 7 , 8 , 30 ]. With the advancement of technologies to sequence
multiple cancer genomes and the accumulation of cancer biology knowledge,
somatic mutations were identified in about 447 (~2 %) of the ~22,000 human
protein-coding genes (COSMIC database, version 3/15/2012) [ 24 ].
12.2.1 Genomics
Single nucleotide polymorphisms . The somatic mutations in a cancer cell genome
can encompass several distinct classes of DNA sequence change. The most common
mutation is the substitutions of one base by another, known as single nucleotide
polymorphism (SNP). Some of these SNPs will cause changes in the amino acids
(building blocks of proteins) and ultimately alter the function of the encoded
proteins. These changes, known as non-synonymous mutations, are critical and
may provide insights into mechanisms of oncogenes driving the development of
cancer. Some of the cancer cells might acquire non-synonymous mutations to confer
resistance to targeted therapies. Other SNPs that do not cause changes at the amino
acids are known as synonymous mutations (or “silent mutations”), which may or
may not have a functional impact on the survival advantage of the cancer cell.
Insertions or deletions . The second class of somatic mutations is the insertions
or deletions of small or large segments of DNA. Similar to SNPs, insertions or
deletions in DNA sequence may cause changes in amino acids sequence, therefore,
leading to gain or loss of function of the encoded proteins. Insertion of exogeneous
DNA into normal cell genome is a common mechanism in virus-associated cancers.
For example, integration of the human papillomavirus (HPV) E6 and E7 oncogenes
into human genome, which bind and enhance degradation of p53 and RB tumor
suppressor genes, respectively, is a predominant mechanism for HPV-induced head
and neck cancer [ 91 ].
Chromosomal rearrangement . Another class of somatic mutations in cancer cell
genome is chromosomal rearrangement. These are large structural alterations in the
genome in which DNA has been broken and then rejoined to a DNA segment from
elsewhere in the genome. Molecular consequence of these rearrangements is the
generation of new fusions genes that drive cancer development. Examples of these
are BCR-ABL in CML [ 65 ], ALK-EML4 in non-small cell lung cancer [ 73 ], and
TMPRSS2-ETS family in prostate cancer [ 83 ].
Amplifications and deletions . Other common mutations in the cancer cell genome
are chromosomal amplifications and deletions. For chromosomal amplification,
copy number of a DNA segment or even the whole chromosome can increase
from the two copies present in the normal diploid genome to sometimes several
hundred copies (known as gene amplification)
in the cancer cell genome.
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