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

2.50
Hdl Handle:
http://hdl.handle.net/10541/90781
Title:
Heritability of cellular radiosensitivity: a marker of low-penetrance predisposition genes in breast cancer?
Authors:
Roberts, Stephen A; Spreadborough, Anne R; Bulman, Barbara; Barber, James B P; Evans, D Gareth R; Scott, David
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.
Affiliation:
Cancer Research Campaign Biomathematics and Computing Unit, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester M20 4BX, United Kingdom. sroberts@picr.man.ac.uk
Citation:
Heritability of cellular radiosensitivity: a marker of low-penetrance predisposition genes in breast cancer? 1999, 65 (3):784-94 Am. J. Hum. Genet.
Journal:
American Journal of Human Genetics
Issue Date:
Sep-1999
URI:
http://hdl.handle.net/10541/90781
DOI:
10.1086/302544
PubMed ID:
10441587
Type:
Article
Language:
en
ISSN:
0002-9297
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorRoberts, Stephen Aen
dc.contributor.authorSpreadborough, Anne Ren
dc.contributor.authorBulman, Barbaraen
dc.contributor.authorBarber, James B Pen
dc.contributor.authorEvans, D Gareth Ren
dc.contributor.authorScott, Daviden
dc.date.accessioned2010-01-28T10:11:49Z-
dc.date.available2010-01-28T10:11:49Z-
dc.date.issued1999-09-
dc.identifier.citationHeritability of cellular radiosensitivity: a marker of low-penetrance predisposition genes in breast cancer? 1999, 65 (3):784-94 Am. J. Hum. Genet.en
dc.identifier.issn0002-9297-
dc.identifier.pmid10441587-
dc.identifier.doi10.1086/302544-
dc.identifier.urihttp://hdl.handle.net/10541/90781-
dc.description.abstractMany 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.en
dc.language.isoenen
dc.subjectBreast Canceren
dc.subject.meshAlleles-
dc.subject.meshBreast Neoplasms-
dc.subject.meshChromosome Aberrations-
dc.subject.meshFemale-
dc.subject.meshGenetic Predisposition to Disease-
dc.subject.meshGenetic Variation-
dc.subject.meshGenotype-
dc.subject.meshHumans-
dc.subject.meshLikelihood Functions-
dc.subject.meshLymphocytes-
dc.subject.meshMale-
dc.subject.meshModels, Genetic-
dc.subject.meshMultifactorial Inheritance-
dc.subject.meshPedigree-
dc.subject.meshPenetrance-
dc.subject.meshPhenotype-
dc.subject.meshQuantitative Trait, Heritable-
dc.subject.meshRadiation Tolerance-
dc.subject.meshReproducibility of Results-
dc.subject.meshStatistical Distributions-
dc.titleHeritability of cellular radiosensitivity: a marker of low-penetrance predisposition genes in breast cancer?en
dc.typeArticleen
dc.contributor.departmentCancer Research Campaign Biomathematics and Computing Unit, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester M20 4BX, United Kingdom. sroberts@picr.man.ac.uken
dc.identifier.journalAmerican Journal of Human Geneticsen

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