A genetic model for colorectal tumorigenesis

Because most colorectal carcinomas appear to arise from adenomas, studies of different stages of colorectal neoplasia may shed light on the genetic alterations involved in tumor progression. We looked for four genetic alterations (ras-gene mutations and allelic deletions of chromosomes 5, 17, and 18) in 172 colorectal-tumor specimens representing various stages of neoplastic development. The specimens consisted of 40 predominantly early-stage adenomas from 7 patients with familial adenomatous polyposis, 40 adenomas (19 without associated foci of carcinoma and 21 with such foci) from 33 patients without familial polyposis, and 92 carcinomas resected from 89 patients. We found that ras-gene mutations occurred in 58 percent of adenomas larger than 1 cm and in 47 percent of carcinomas. However, ras mutations were found in only 9 percent of adenomas under 1 cm in size. Sequences on chromosome 5 that are linked to the gene for familial adenomatous polyposis were not lost in adenomas from the patients with polyposis but were lost in 29 to 35 percent of adenomas and carcinomas, respectively, from other patients. A specific region of chromosome 18 was deleted frequently in carcinomas (73 percent) and in advanced adenomas (47 percent) but only occasionally in earlier-stage adenomas (11 to 13 percent). Chromosome 17p sequences were usually lost only in carcinomas (75 percent). The four molecular alterations accumulated in a fashion that paralleled the clinical progression of tumors. These results are consistent with a model of colorectal tumorigenesis in which the steps required for the development of cancer often involve the mutational activation of an oncogene coupled with the loss of several genes that normally suppress tumorigenesis.

Genetic alterations during colorectal-tumor development.

Uncontrolled cell proliferation is the hallmark of cancer, and tumor cells have typically acquired damage to genes that directly regulate their cell cycles. Genetic alterations affecting p16(INK4a) and cyclin D1, proteins that govern phosphorylation of the retinoblastoma protein (RB) and control exit from the G1 phase of the cell cycle, are so frequent in human cancers that inactivation of this pathway may well be necessary for tumor development. Like the tumor suppressor protein p53, components of this "RB pathway," although not essential for the cell cycle per se, may participate in checkpoint functions that regulate homeostatic tissue renewal throughout life.

http://science.sciencemag.org/content/sci/274/5293/1672.full.pdf

Cancer Cell Cycles

Patterns of DNA methylation and chromatin structure are profoundly altered in neoplasia and include genome-wide losses of, and regional gains in, DNA methylation. The recent explosion in our knowledge of how chromatin organization modulates gene transcription has further highlighted the importance of epigenetic mechanisms in the initiation and progression of human cancer. These epigenetic changes -- in particular, aberrant promoter hypermethylation that is associated with inappropriate gene silencing -- affect virtually every step in tumour progression. In this review, we discuss these epigenetic events and the molecular alterations that might cause them and/or underlie altered gene expression in cancer.

The fundamental role of epigenetic events in cancer

Lessons from Hereditary Colorectal Cancer

The past 60 years surely constitute a Golden Age for biomedical science, and for medical genetics in particular. A personal experience began with an encounter with inborn errors of metabolism, selection, and the incidences of hereditary diseases, and peaked with molecular biology, virology, and cytogenetics, finally focusing all three on the problem of cancer.

https://www.annualreviews.org/doi/pdf/10.1146/annurev.genom.6.080604.162320

A personal sixty-year tour of genetics and medicine

Laboratory. Clinical interface

Study of hereditary cancer in humans has revealed new mechanisms in carcinogenesis. In particular, a new class of cancer gene, recessive in oncogenesis, accounts for dominantly transmitted predisposition to some cancers, and may play a primary role in the nonhereditary forms of most cancers. Comparison of polymorphic markers in lymphocytes and tumors has permitted the in vivo observation of somatic events that lead to genetic recombination. The tissue specificities of these recessive cancer genes suggest that their normal alleles, like those of oncogenes, play important roles in normal development.

Genetics of human cancer.

Summary and recommendations of the workshop held at the first international conference on molecular and clinical genetics of childhood renal tumors, Albuquerque, New Mexico, May 14–16, 1992

// Suraj Peri 1 , Elena Caretti 2 , Rossella Tricarico 2 , Karthik Devarajan 1 , Mitchell Cheung 3 , Eleonora Sementino 3 , Craig W. Menges 3 , Emmanuelle Nicolas 3 , Lisa A. Vanderveer 4 , Sharon Howard 5 , Peggy Conrad 6 , James A. Crowell 7 , Kerry S. Campbell 5 , Eric A. Ross 1 , Andrew K. Godwin 8 , Anthony T. Yeung 4 , Margie L. Clapper 4 , Robert G. Uzzo 3,9 , Elizabeth P. Henske 10 , Christopher J. Ricketts 11 , Cathy D. Vocke 11 , W. Marston Linehan 11 , Joseph R. Testa 3,9 , Alfonso Bellacosa 2 , Levy Kopelovich 12 and Alfred G. Knudson 3 1 Department of Biostatistics and Bioinformatics, Fox Chase Cancer Center, Philadelphia, PA, USA 2 Cancer Epigenetics, Fox Chase Cancer Center, Philadelphia, PA, USA 3 Cancer Biology, Fox Chase Cancer Center, Philadelphia, PA, USA 4 Cancer Prevention and Control, Fox Chase Cancer Center, Philadelphia, PA, USA 5 Blood Cell Development and Function, Fox Chase Cancer Center, Philadelphia, PA, USA 6 University of California San Francisco, San Francisco, CA, USA 7 Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, NCI, Rockville, MD, USA 8 Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA 9 Kidney Cancer Programs, Fox Chase Cancer Center, Philadelphia, PA, USA 10 Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, NCI, Bethesda, MD, USA 11 Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute Bethesda, MD, USA 12 Department of Medicine, Weill Cornell Medical College, New York, NY, USA Correspondence to: Alfonso Bellacosa, email: // Joseph R. Testa, email: // Levy Kopelovich, email: // Keywords : VHL, TSC1, TSC2, transcriptomics, primary kidney epithelial cells Received : August 31, 2016 Accepted : September 07, 2016 Published : September 22, 2016 Abstract Tumor suppressor genes and their effector pathways have been identified for many dominantly heritable cancers, enabling efforts to intervene early in the course of disease. Our approach on the subject of early intervention was to investigate gene expression patterns of morphologically normal “one-hit” cells before they become hemizygous or homozygous for the inherited mutant gene which is usually required for tumor formation. Here, we studied histologically non-transformed renal epithelial cells from patients with inherited disorders that predispose to renal tumors, including von Hippel-Lindau (VHL) disease and Tuberous Sclerosis (TSC). As controls, we studied histologically normal cells from non-cancerous renal epithelium of patients with sporadic clear cell renal cell carcinoma (ccRCC). Gene expression analyses of VHL mut/wt or TSC1 / 2 mut/wt versus wild-type (WT) cells revealed transcriptomic alterations previously implicated in the transition to precancerous renal lesions. For example, the gene expression changes in VHL mut/wt cells were consistent with activation of the hypoxia response, associated, in part, with the “Warburg effect”. Knockdown of any remaining VHL mRNA using shRNA induced secondary expression changes, such as activation of NFκB and interferon pathways, that are fundamentally important in the development of RCC. We posit that this is a general pattern of hereditary cancer predisposition, wherein haploinsufficiency for VHL or TSC1 /2, or potentially other tumor susceptibility genes, is sufficient to promote development of early lesions, while cancer results from inactivation of the remaining normal allele. The gene expression changes identified here are related to the metabolic basis of renal cancer and may constitute suitable targets for early intervention.

/pdf/haploinsufficiency-in-tumor-predisposition-syndromes-altered-53w39cu6za.pdf

Haploinsufficiency in tumor predisposition syndromes: altered genomic transcription in morphologically normal cells heterozygous for VHL or TSC mutation.

Alfred G. Knudson

Papers

A personal sixty-year tour of genetics and medicine

Laboratory. Clinical interface

Genetics of human cancer.

Summary and recommendations of the workshop held at the first international conference on molecular and clinical genetics of childhood renal tumors, Albuquerque, New Mexico, May 14–16, 1992

Haploinsufficiency in tumor predisposition syndromes: altered genomic transcription in morphologically normal cells heterozygous for VHL or TSC mutation.