GENETICA E CANCRO

Patrizia Russo Dipartimento di Oncogenesi, S.C. Oncologia Sperimentale, Modulo Patologie Molecolari, Istituto Nazionale per la Ricerca sul Cancro, Genova-Italia

Cancer is a disease that develops slowly. For most solid human tumors, there is a 20-year interval from carcinogen exposure to clinical detection. During this time, cancer cells acquire the capacity to divide, invade, and metastasize.

Usual measurements of age-dependent cancer incidence have shown that the rate of tumour development is proportional to the fourth to sixth power of life time, suggesting that four to sixth independent genetic steps are necessary to complete tumorigenesis.

The best-studied case in human carcinogenesis is lung cancer associated with smoking. The analysis carried out by Cairns (PNAS 99:10567, 2002) indicates that the frequency of these tumours is proportional to the first or possibly second power of cigarettes per day and to the sith power of the duration of smoking.

Genetics Terminology.
Gene: (Mendelian Factor): the determinant of a characteristic of an organism. Genetic information is coded in the DNA, which is responsible for species and individual variation. A genes nucleotide sequence specifies a polypeptide or RNA and is subject to mutational analysis. Alleles: alternative form of a gene. Diploid: a eukaryotic cll or organism with two homologous sets of chromosomes. Genotype: the genetic constitutionof an organism. A diploid organism in which both alleles are the same at a given gene locus is said to be homozygous for that allele. Diploid organisms that have two different alleles at aspecific gene locus are said to be heterozygous. Haploid: a cell or an individual with one copy of each chromosome. Locus (gene locus, plural = loci): the specific placeon a chromosome where a gene is located. Phenotype: the physicl manifestation of a genetic trait that results from a specific genotype and its interaction with the environment. Oncogene: a gene whose action stimulates unregulated cellular proliferation. Cellular oncogenes are altered formsof cellular proto-oncogene. Suppressor gene: a gene that causes suppression of mutations in other genes.

Several ways for a normal cell to be transformed into a tumoral cell.

( a) Numerous genetic alterations in key genes

produced randomly (more than four to seven modifications). (b) A first mutation in a caretaker gene (such as DNA polymerase, DNA repair or DNA helicase genes) or in a gatekeeper gene (such as apoptosis or cell cycle regulation genes, tumour suppressor genes) followed by a second alteration on the other allele will significantly increase the genetic instability and therefore reduce the age of cancer appearance. (c) As in (b) but a germinal mutation in a gatekeeper gene predisposes to a given cancer following a sporadic modification of the corresponding wild type allele. A combination of (b) and (c) is possible and often found in XP skin tumours. (d) Same as (a) but the process of selection and clonal expansion should shorten the time for cancer appearance. (e) Pathways allowing a mutated cell to escape the carcinogenesis process, if no mutations occur in a gene implicated in the regulation of these pathways.

Acquired capabilities of Cancer

Hallmarks of cancer
abnormalities in selfsufficiency of growth signals; evading apoptosis; insensitivity to antigrowth signals; Limitless replicative potential; sustained angiogenesis; tissue invasion and metastases.

Tumours as Complex Tissues

The advances in molecular technologies are providing insight into the pathobiology of lung cancer development.
It is becoming apparent through candidate gene and genome wide approaches that clinically evident lung cancers have accumulated numerous (perhaps 20 or more) clonal genetic and epigenetic alterations as a multistep process. These alterations include the classical genetic abnormalities of tumour suppressor gene (TSG) inactivation and overactivity of growth promoting oncogenes. More recently, tumour acquired promoter hypermethylation has been recognised as a mechanism for the epigenetic inactivation of gene expression. The early clonal genetic lesions that occur in smoking damaged preneoplastic bronchial epithelium are being identified, as are the molecular differences between small cell lung cancer (SCLC) and nonsmall cell lung cancer (NSCLC), and between tumours with different clinical outcomes. These abnormalities lead to the

lung cancer".

"hallmarks of

Molecular studies are now performed in many research laboratories in an integrated approach with clinical investigators. These will lead to clinical applications with the potential to provide new avenues for early diagnosis, risk assessment, prevention, and treatment for this common and highly lethal condition.

Sequential molecular changes during the multistage pathogenesis of squamous cell lung carcinoma. Molecular changes occurring during lung pathogenesis may commence early (normal or slightly abnormal epithelium), at an intermediate (dysplasia) stage, or relatively late (carcinoma in situ, CIS, or invasive carcinoma).

Accumulation of mutations in lung carcinogenesis

tract. Upper panel, left, representative example of microdissection of hyperplastic lesion. Upper panel, right, representative example of cytology specimens. Lower panel, molecular analyses of microdissected invasive carcinoma (T), preneoplastic lesion (H, hyperplasia; D, dysplasia; CIS, carcinoma in situ) and sputum specimens (S). Normal lymphocytes (L) are used as source of constitutional DNA. Representative examples of loss of heterozygosity and genomic instability analyses; designed restriction fragment length polymorphism for K-RAS gene mutation analysis at codon 12; sequencing of TP53 gene showing mutation at exon 5, codon 177; and RARb promoter gene methylation in tumor and sputum specimens (UM, unmethylated; M, methylated).

Histopathologic and molecular changes during the pathogenesis of lung cancer. Sequential changes are involved in the development of NSCLC, squamous cell and adenocarcinoma (sequential theory of cancer development). SCLC may arise directly from histologically normal or from mildly abnormal epithelium, without passing through the entire histologic sequence (parallel theory of cancer development). CIS, carcinoma in situ; AAH, atypical adenomatous hyperplasia; BAC, bronchioalveolar carcinoma (non-invasive adenocarcinoma).