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Heritability of cellular radiosensitivity: a marker of low-penetrance predisposition genes in breast cancer?

Roberts, S A; Spreadborough, A R; Bulman, B; Barber, J B; Evans, D G; Scott, D

American journal of human genetics. 1999;65(3):784-94.

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Abstract

Many inherited cancer-prone conditions show an elevated sensitivity to the induction of chromosome damage in cells exposed to ionizing radiation, indicative of defects in the processing of DNA damage. We earlier found that 40% of patients with breast cancer and 5%-10% of controls showed evidence of enhanced chromosomal radiosensitivity and that this sensitivity was not age related. We suggested that this could be a marker of cancer-predisposing genes of low penetrance. To further test this hypothesis, we have studied the heritability of radiosensitivity in families of patients with breast cancer. Of 37 first-degree relatives of 16 sensitive patients, 23 (62%) were themselves sensitive, compared with 1 (7%) of 15 first-degree relatives of four patients with normal responses. The distribution of radiosensitivities among the family members showed a trimodal distribution, suggesting the presence of a limited number of major genes determining radiosensitivity. Segregation analysis of 95 family members showed clear evidence of heritability of radiosensitivity, with a single major gene accounting for 82% of the variance between family members. The two alleles combine in an additive (codominant) manner, giving complete heterozygote expression. A better fit was obtained to a model that includes a second, rarer gene with a similar, additive effect on radiosensitivity, but the data are clearly consistent with a range of models. Novel genes involved in predisposition to breast cancer can now be sought through linkage studies using this quantitative trait.

Bibliographic metadata

Type of resource:
Content type:
Publication type:
Published date:
Abbreviated journal title:
ISSN:
Place of publication:
UNITED STATES
Volume:
65
Issue:
3
Pagination:
784-94
Digital Object Identifier:
10.1086/302544
Pubmed Identifier:
10441587
Pii Identifier:
S0002-9297(07)62332-5
Access state:
Active

Institutional metadata

University researcher(s):

Record metadata

Manchester eScholar ID:
uk-ac-man-scw:210849
Created by:
Evans, Gareth
Created:
12th October, 2013, 14:23:54
Last modified by:
Evans, Gareth
Last modified:
12th October, 2013, 14:23:54

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