Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_4385_Библиотеки_им_академика_М_И_Перельмана

countries. When marijuana is smoked, a wide range of potential carcinogens are released and absorbed, with an overall risk of 2.6 compared to non-users.

HPV exists in many dierent serotypes and HPV 16, 18, 31, 33, 35 and 39 are associated with head and neck c ancer and HPV 16 and 18 are the most com mon types as sociated with squ amous cell carcinoma. e E6 and E7 open reading frames (ORFs) of the high-risk HPVs are impor­tant. ey bind to and inactivate tumour suppressor genes p53 and pRb, respectively, allowing uncontrolled cell proliferation, resulting in genomic instability and cellular transformation.

Hereditary information in eukaryotes is stored in the form of double-stranded deoxyri­bonucleic acid (DNA) and is referred to as the genome. DNA forms a double helix struc­ture bonding complementary pairs of nucleotides, such as adenine (A) with thymine (T) and cytosine (C) with guanine (G). Within the coding part of DNA nucleotides on each strand are grouped in triplets, known as codons. Each codon sequence determines a sin­gle specic amino acid. Some codons are ‘stop’ codons, constituting a signal for arrest of translation. e overwhelming majority of DNA (99.9%) exists in the cell nucleus as the nuclear genome and the remaining DNA forms the mitochondrial genome, encoding 37 genes.

A gene is a region of the chromosomal DNA that produces a functional ribonucleic acid molecule (RNA). It comprises regulatory DNA sequences that determine when and in which cell types that gene is expressed; exons are coding sequences and interspersed introns are non-coding DNA sequences.

Transcription is the intra-nuclear process driven by the RNA polymerase whereby one DNA strand acts as a template for the synthesis of an RNA strand (uracil replaces thymine in RNA). is primary RNA transcript then undergoes post-transcriptional processing, or splicing. e mature mRNA migrates into the cytoplasm where it acts as a template for the synthesis of a polypeptide during translation, via ribosomes. Successive amino acids are added creating a polypeptide chain from to the triplet code on the mRNA, resulting in protein synthesis.

DNA mutation may occur as a result of base substitutions, as well as nucleotide insertions and deletions. Insertions and deletions of nucleotides are very rare in coding DNA. Base substitution is a more common form of mutation in coding DNA, which may have a range of consequences on the function of the gene: a loss of function; a gain in function, oen due to stabilisation of the active protein or no net functional eect. An example of a silent substitu­tion yielding no functional eect is seen when an amino acid may be encoded by dierent codons (e.g. GUA, GAC, GUG and GUU all encode valine), so a substitution of the third base results in no change to the amino acid. At the other extreme is the nonsense mutation, whereby a base substitution results in an early stop codon, which leads to truncation of the polypeptide and a dramatic reduction in function.

A proto-oncogene may be converted into an oncogene by a point mutation or by a simple increase in the copy number of the gene (gene amplication) resulting in an overproduc­tion of protein. Loss of function of a tumour suppressor gene is also oncogenic, which can occur a number of ways, including a missense mutation causing loss of protein func­tion, an early stop codon and transcriptional silencing. e methylation status of CpG islands surrounding the promoter regions of genes determines whether a particular gene is expressed within a cell, such that methylation of a CpG island ‘switches o’ the gene that it is regulating. Many tumour suppressor genes are now recognised to be inactivated by hypermethylation of the promoter region in malignant tumours. With inactivation of a tumour suppressor gene, it must be considered there are two alleles, with the theory that both alleles must be non-functioning and known as Knudson’s ‘two-hit’ hypothesis. is is well explained by hereditary tumours, where an inherited mutation eliminates the function of one allele, the so-called loss of heterozygosity (LOH), with a second somatic mutation (‘hit’) required to facilitate the oncogenic potential of the mutations. It is now known that tumour suppressors do not all t this model, and they can be haploinsucient (gene only functions in the presence of two wild-type alleles), dominant negative (where one mutated allele has an eect that dominates over the eect of the wild-type allele) or gain of function.

bone marrow changes (Figure 53.2). PET-CT for staging, assessment of recurrence and evaluating the nasopharynx in