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X-Chromosome Genetics and Human Cancer

Nature Reviews Cancer volume 4, pages 617–629 (2004)Cite this article

Key Points

  • Although female mammals carry two copies of the X chromosome, both male and female mammalian cells carry a single active X chromosome, as in females one copy of the X chromosome is inactivated.

  • Both of the main types of genetic alterations that lead to cancer — tumour-suppressor inactivation and oncogene activation — act dominantly when they affect the single active copy of an X-linked gene. The same alterations remain silent when they affect the inactivated X chromosome in female cells.

  • Increased dosage of X-linked genes is thought to represent a key event in oncogenesis. Two principal mechanisms that achieve such change in gene dosage are commonly observed in tumours: gain of whole copies or regions of the active X chromosome and loss or skewing of the inactivation mechanism.

  • As for autosomal genes, the expression of X-linked genes can be altered by changes in methylation, in addition to classic genetic mutations. Increases and decreases in methylation of X-chromosome genes have been implicated in certain cancers.

  • Some genes that are located on the inactive X chromosome escape inactivation in normal cells and several of these are implicated in human cancer.

  • Translocations involving regions of the X chromosome have unique outcomes in relation to ability to cause cancer. Events involving relocation of regions of the inactive X chromosome to an autosome can result in the reactivation of previously silent X-linked genes, with potential oncogenic effects. Conversely, loss of expression of an autosomal tumour suppressor can result from translocation to the inactive X chromosome.

  • Defects in the X-chromosome inactivation process can lead to cancer. The BRCA1 tumour suppressor is thought to have a key role in X-chromosome inactivation, and it has been proposed that loss of this function contributes to the development of cancer when normal expression of this gene is lost.

Abstract

In mammals, the X chromosome is unique within the chromosome set. In contrast to the other chromosomes — for which two active copies are present — both male and female cells carry only one active X chromosome. This is because males have only one X chromosome and in females only one copy is active, a situation that leads to specific characteristics for genes located on this chromosome. How are the outcomes of genetic events involved in cancer — namely activation of oncogenes and inactivation of tumour suppressors — expected to be different when these genes are carried on the X chromosome rather than on autosomes?

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Figure 1: The process of X-chromosome inactivation.
Figure 2: The impact of X-chromosome genetics on cancer.
Figure 3: Tumorigenic effects of translocations involving the X chromosome.

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Acknowledgements

P. Dessen and A. Kauffmann are gratefully acknowledged for their help in illustrating the set of genes that escape X-chromosome inactivation. J.F. is supported by the 'Association pour la Recherche sur le Cancer' (ARC).

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Authors and Affiliations

  1. Institut Gustave-Roussy and UMR 8125 CNRS, Villejuif, 94805, France

    Alain Spatz, Christophe Borg & Jean Feunteun

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  1. Alain Spatz
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DATABASES

Cancer.gov

acute lymphoblastic leukaemia

acute myeloid leukaemia

anal cancer

female breast cancer

colorectal cancer

lung cancer

male breast cancer

malignant mesothelioma

melanoma

ovarian cancer

prostate cancer

renal-cell cancer

testicular cancer

Entrez Gene

XIST

XIC

TGCT1

ARAF1

ELK1

HPCX

TFE3

GPC3

GRPR

RB

AR

BRCA1

BRCA2

NEMO

Glossary

UNISOMY

The state of an individual or cell carrying only one member of a pair of homologous chromosomes.

MOSAICISM

The occurrence in an individual of two or more cell populations of different chromosomal constitutions derived from a single zygote.

HETEROCHROMATIN

Highly condensed region of the interphase nucleus consisting of nucleic acid and associated histone proteins packed into nucleosomes. Heterochromatin is transcriptionally inactive and becomes especially abundant in the nuclei of terminally differentiated cells, in which most formerly active genes are repressed.

LOSS OF HETEROZYGOSITY

Refers to a mutation or other genetic event that results in the loss of one allele.

KLINEFELTER'S SYNDROME

A syndrome affecting males, characterized by small testes, infertility and the development of breasts. Patients tend to be tall with long legs. The syndrome is typically associated with an XXY chromosome complement, although variants include XXYY, XXXY, XXXXY and several mosaic patterns.

XX MALE SYNDROME

A syndrome that occurs in males that is associated with the presence of two X chromosomes. The parts of the Y chromosome that are necessary for the male phenotype are thought to be located elsewhere in the genome as a result of translocation, at least in some cases.

IMPRINTING

Monoallelic gene expression or inactivation of either the maternal or paternal allele of a particular locus.

ENTEROCHROMAFFIN-LIKE CELL

A distinctive type of neuroendocrine cell present in gastric mucosa underlying epithelia; most prevalent in the acid-secreting regions of the stomach.

RETROTRANSPOSONS

Transposable elements (transposons) that, similar to retroviruses, require reverse transcription for their replication. The DNA element is transcribed into RNA, reverse-transcribed into DNA and then inserted at a new site in the genome.

ALLELOTYPING

A technique used to identify the paternal and maternal alleles of a given gene based on polymorphisms.

FANCONI ANAEMIA

A rare disorder that is characterized by developmental abnormalities of the skeleton and other organs, defects in skin pigmentation, progressive failure of the bone marrow to replenish platelets and red and white blood cells, and susceptibility to acute myeloid leukaemia and squamous-cell carcinoma.

SUPEROXIDE DISMUTASE

An enzyme that is present in all aerobic organisms. It catalyses the conversion of highly reactive and destructive superoxide anion radicals, which are generated by the metabolism of the cell, into hydrogen peroxide.

WISKOTT–ALDRICH SYNDROME

An X-linked genetic disorder that almost always affects males and is characterized by thrombocytopaenia, eczema, melena and susceptibility to bacterial infections because of severe immunodeficiency.

INCONTINENTIA PIGMENTI

An inherited hypopigmented skin lesion that shows a so-called 'marble-cake' pattern, which is variably associated with epidermal nevi, alopecia, and ocular, skeletal and neural abnormalities.

PENETRANCE

The frequency with which individuals who carry a given mutation show associated phenotypic manifestations. If the penetrance of a disease allele is 100%, then all individuals carrying that allele will express the associated phenotype.

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Spatz, A., Borg, C. & Feunteun, J. X-Chromosome Genetics and Human Cancer. Nat Rev Cancer 4, 617–629 (2004). https://doi.org/10.1038/nrc1413

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  • DOI: https://doi.org/10.1038/nrc1413

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