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FRA3B and other common fragile sites: the weakest links

Nature Reviews Cancer volume 1, pages 214–221 (2001)Cite this article

Key Points

  • Common fragile sites occur on every human chromosome and are frequently involved in chromosome rearrangements in cancer. There might be genes at these fragile sites that contribute to the development of cancer.

  • There are more than 80 common fragile sites, meaning that we all have these weak links in our chromosomes, although there might be variations in the degrees of fragility among individuals.

  • Common fragile sites can be damaged by exposure to carcinogens, such as those in tobacco smoke. The damage to at least one fragile site — FRA3B — also damages the FHIT gene, which encompasses FRA3B.

  • Damage to FHIT contributes to the growth of cancer cells in the lung, kidney, stomach, bladder and other cancers.

  • Mice that are missing one or both Fhit genes are very susceptible to carcinogen-induced cancers that can be prevented or delayed by treatment with viral vectors carrying the FHIT gene.

  • The WWOX gene at FRA16D is also susceptible to DNA damage, causing alteration of expression of WWOX. Alteration of WWOX expression probably contributes to growth of breast, ovarian and other cancers.

  • Genes at other common fragile sites might also contribute to cancer and should be isolated and studied to uncover their functions in neoplastic disease.

  • It is likely that carcinogen exposure can damage several fragile genes within a single cell, thereby activating one or more oncogenes and inactivating one or more tumour-suppressor genes simultaneously.

  • Deletions, amplifications and translocations at fragile sites are a result of delayed replication by carcinogens or other chemicals within the fragile regions, but there is still much to learn about the induction of fragility, repair or misrepair of the damage, and the consequences to the genes in fragile regions.

  • The functions of the fragile genes FRA3B and WWOX are largely unknown.

Abstract

In 1979, the first chromosome alteration associated with familial cancer was reported. Five years later, a fragile site was observed in the same chromosome region. The product of the fragile histidine triad (FHIT) gene, which encompasses this fragile site, is partially or entirely lost in most human cancers, indicating that it has a tumour-suppressor function. Inactivation of only one FHIT allele compromises this suppressor function, indicating that a 'one-hit' mechanism of tumorigenesis is operative. Are genes disrupted at other fragile sites? And, are these genes also tumour suppressors?

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Figure 1: The fragile site FRA3B is exquisitely sensitive to carcinogen damage, leading to FHIT loss.
Figure 2: The hydrolase reaction catalysed by FHIT.
Figure 3: FHIT gene therapy prevents tumour development in Fhit-deficient mice.

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Acknowledgements

We apologize to our colleagues whose relevant papers could not be cited owing to space limitations. We thank T. Glover, A. Paige, S. Ingvarsson and M. Aldaz for communicating unpublished results, J. Benovic for helpful comments on the manuscript, and H. Pace and C. Brenner for preparation of the figures. Supported by grants from the National Institutes of Health (USA) and a generous gift from G. Strawbridge.

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Authors and Affiliations

  1. Kimmel Cancer Center, Jefferson Medical College, Philadelphia, 19107, Pennsylvania, USA

    Kay Huebner & Carlo M. Croce

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DATABASES

CancerNet:

breast cancer

gastric cancer

oesophageal cancer

ovarian cancer

pancreatic cancer

renal cancers

 InterPro:

histidine triad

 LocusLink:

BCL2

BCL-XL

BRCA2

CAV1

CAV2

FHIT

Fhit

FRA3B

FRA7G

FRA7H

FRA16D

FRAXB

GS1

INK4A

KIP1

MSH2

NIT1

p53

STS

TES

TLR5a

tubulin

WAF1

Wox1

WWOX

OMIM

fragile X syndrome

FURTHER INFORMATION

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Glossary

GIEMSA-LIGHT BAND

If metaphase chromosome preparations on slides are treated with trypsin and then stained with the dye, Giemsa, the chromosomes show bands that are strongly or very lightly stained with the dye. The lightly stained bands are, in general, thought to be gene rich.

RECOMBINOGENIC DNA

Regions of genomes that participate in recombination reactions, such as chromosome translocations and DNA insertions or deletions, more frequently than surrounding DNA regions.

DNA POLYMERASE INHIBITOR

Chemical compound or agent that prevents the progression of DNA polymerization enzymes along the DNA during replication or repair of damage to DNA.

SOMATIC CELL HYBRID

Cell that is formed by fusion of a rodent and human cell, retaining all rodent chromosomes and one or more human chromosomes.

MATRIX ATTACHMENT REGION

Region where chromosomes are attached to the nuclear matrix, creating looped domains between attachment regions.

TRANSPOSON

Mobile DNA element that can move from one integration site to another in a genome.

KNUDSON'S TWO-HIT HYPOTHESIS

In 1971, Alfred Knudson proposed that two successive genetic 'hits' are required to turn a normal cell into a tumour cell and that, in familial cancers, one hit was inherited.

HISTIDINE TRIAD (HIT) PROTEIN

A protein superfamily with representatives in all branches of living organisms, defined by virtue of sequence alignment. All members of the superfamily contain the signature histidine triad motif, His-Ø-His-Ø-His-Ø-Ø (Ø is a hydrophobic amino acid).

CARCINOMA

A malignant tumour of the epithelium.

ADENOMA

A benign tumour arising from glandular epithelium.

SQUAMOUS PAPILLOMA

A benign tumour of the squamous epithelium.

FORESTOMACH

An extension of the distal oesophagus with an epithelial lining that is analogous to human distal oesophagus.

MUIR–TORRE SYNDROME

A familial cancer syndrome in which at least one skin tumour (of the sebaceous glands) and one internal tumour, usually colon cancer, occur in an individual who inherits a mutated mismatch-repair gene.

HEREDITARY NON-POLYPOSIS COLORECTAL CANCER

(HNPCC). An inherited predisposition to colorectal cancer, generally caused by germ-line mutation in a mismatch-repair gene.

BARRETT'S METAPLASIA OF THE OESOPHAGUS

Replacement of the squamous epithelium of the oesophagus by columnar epithelium similar to the glandular epithelium of the stomach, following chronic acid reflux.

ALLELIC ASYNCHRONY

Differences in replication time of adjacent segments of DNA.

WW DOMAIN

A motif that is involved in protein–protein interactions, consisting of two tryptophan residues (W) separated by ∼22 amino acids, with several other invariant amino acids.

OR DOMAIN

A domain typical of the oxidoreductase family of enzymes, which catalyses oxidation–reduction reactions.

LINE SEQUENCES

Long interspersed repetitive elements found in thousands of copies in the human and mouse genomes.

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Huebner, K., Croce, C. FRA3B and other common fragile sites: the weakest links. Nat Rev Cancer 1, 214–221 (2001). https://doi.org/10.1038/35106058

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