1. The promise of cancer genetics
Dr Daniel A Haber, MD, Eric R Fearon, MD 
The Lancet 
Volume 351, Pages SII1-SII8 (May 1998)
DOI: /S (98)
Copyright © 1998 Elsevier Ltd Terms and Conditions

2. Figure 1
Mutations in retinoblastoma tumour-suppressor gene (RB1) contribute to inherited and sporadic cancers
Figure illustrates contribution of cell context to effects of RB1 mutations. In individuals who harbour germline mutation in one RB1 allele, inactivation of remaining normal allele by somatic mutation is rate-limiting event in development of retinoblastoma (ie, RR1 mutation is “early” or initiating defect). More than 90% of patients with germline RB1 mutation develop one or more retinoblastomas. Sporadic retinoblastomas are rare and arise after development of somatic mutations in both RB1 alleles within retinoblast. By contrast, individuals with germline mutation in RB1 do not have increased risk of lung cancer, despite fact that RB1 inactivation is frequently observed in sporadic lung cancer. These and other observations Imply that RB1 mutations contribute to tumour progression, rather than tumour initiation, in lung cancers. Possible explanation is that inactivation of both RB1 alleles before development of mutations in other genes (eg, TP53) may lead to apoptosis rather than neoplastic transformation in cell types other than retinoblasts. RB1 mutation may thus be considered “late” genetic event in lung cancer and most common tumours.
The Lancet  , SII1-SII8DOI: ( /S (98) )
Copyright © 1998 Elsevier Ltd Terms and Conditions

3. Figure 2
Mutations in tumour-suppressor genes and oncogenes affect conserved genetic pathways
Tumour. Suppressor proteins are indicated in red and oncogene products in green. (a) RB1 protein (p105–RB) is regulated during cell-cycle progression by phosphorylation (P); hyperphosphorylated forms of p105–RB are inactive. Whilst mutations in RB1 are frequent in some cancer types (eg, small-cell lung cancer), in many other cancer types, RB1 mutations are not found, Instead, overexpression of proto-oncogene proteins, such as cyclin D1 (CYC D1) or the cyclin dependent kinase 4 (CDK4), results in inappropriate phosphorylation of p105–RB and its functional inactivation. Inactivation of p16 CDK inhibitor also results in inappropriate phosphorylation and inactivation of p105–RB. Net consequence of these defects in CYC Dl, CDK4, or p16 is inability of p105–RB to block expression of cellular genes that are regulated by the E2F and DP families of transcription factors. (b) Mutations in APC gene are present in germline of persons with familial polyposis, as well as in about 70% of sporadic colorectal adenomas and carcinomas. Critical function of APC protein appears to be regulation of β-catenin (β-cat) protein levels. β -cat is abundant cell protein, and mostly complexed with cytoplasmic domain of E-cadherin (E-cad) cell-cell adhesion protein and β-catenin (β-cat). Inactivation of APC in colorectal and other cancer cells results in accumulation of β-cat, increased binding of β-cat to Tcf-4, and increased transcriptional activation of Tcf-4 target genes. In some colorectal adenomas and carcinomas that lack APC mutations, point mutations and small deletions render S-cat oncogenic, because mutant β-cat proteins are resistant to effects of APC. As result, Tcf-4 target genes are deregulated. (c) Germline mutations in Patched (PTCH) gene are responsible for Gorlin and hereditary nevoid basal-cell cancer syndromes, in which affected individuals develop large numbers of basal-cell cancers, as well as medulloblastomas. The Ptch protein inhibits activity of smoothened (Smo) protein, and Ptch itself can be inhibited by soluble factor known as sonic hedgehog (Shh). Inhibition of Ptch function or its mutational inactivation results in increased expression of Gli transcription factor. Both Smo and Gli are proto-oncogenes. Activating point mutations in Smo have been seen in some basal-cell cancers, and amplification of Gligene has been observed in some brain tumours and sarcomas.
The Lancet  , SII1-SII8DOI: ( /S (98) )
Copyright © 1998 Elsevier Ltd Terms and Conditions