Genetic Epidemiology, Translational Neurogenomics, Psychiatric Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
11830610
TITLE
Dominant negative ATM mutations in breast cancer families.
ABSTRACT
BACKGROUND NlmCategory: BACKGROUND
The ATM gene encoding a putative protein kinase is mutated in ataxia-telangiectasia (A-T), an autosomal recessive disorder with a predisposition for cancer. Studies of A-T families suggest that female heterozygotes have an increased risk of breast cancer compared with noncarriers. However, neither linkage analyses nor mutation studies have provided supporting evidence for a role of ATM in breast cancer predisposition. Nevertheless, two recurrent ATM mutations, T7271G and IVS10-6T-->G, reportedly increase the risk of breast cancer. We examined these two ATM mutations in a population-based, case-control series of breast cancer families and multiple-case breast cancer families.
METHODS NlmCategory: METHODS
The ATM gene encoding a putative protein kinase is mutated in ataxia-telangiectasia (A-T), an autosomal recessive disorder with a predisposition for cancer. Studies of A-T families suggest that female heterozygotes have an increased risk of breast cancer compared with noncarriers. However, neither linkage analyses nor mutation studies have provided supporting evidence for a role of ATM in breast cancer predisposition. Nevertheless, two recurrent ATM mutations, T7271G and IVS10-6T-->G, reportedly increase the risk of breast cancer. We examined these two ATM mutations in a population-based, case-control series of breast cancer families and multiple-case breast cancer families. Five hundred twenty-five or 262 case patients with breast cancer and 381 or 68 control subjects, respectively, were genotyped for the T7271G and IVS10-6T-->G ATM mutations, as were index patients from 76 non-BRCA1/2 multiple-case breast cancer families. Linkage and penetrance were analyzed. ATM protein expression and kinase activity were analyzed in lymphoblastoid cell lines from mutation carriers. All statistical tests were two-sided.
RESULTS NlmCategory: RESULTS
The ATM gene encoding a putative protein kinase is mutated in ataxia-telangiectasia (A-T), an autosomal recessive disorder with a predisposition for cancer. Studies of A-T families suggest that female heterozygotes have an increased risk of breast cancer compared with noncarriers. However, neither linkage analyses nor mutation studies have provided supporting evidence for a role of ATM in breast cancer predisposition. Nevertheless, two recurrent ATM mutations, T7271G and IVS10-6T-->G, reportedly increase the risk of breast cancer. We examined these two ATM mutations in a population-based, case-control series of breast cancer families and multiple-case breast cancer families. Five hundred twenty-five or 262 case patients with breast cancer and 381 or 68 control subjects, respectively, were genotyped for the T7271G and IVS10-6T-->G ATM mutations, as were index patients from 76 non-BRCA1/2 multiple-case breast cancer families. Linkage and penetrance were analyzed. ATM protein expression and kinase activity were analyzed in lymphoblastoid cell lines from mutation carriers. All statistical tests were two-sided. In case and control subjects unselected for family history of breast cancer, one case patient had the T7271G mutation, and none had the IVS10-6T-->G mutation. In three multiple-case families, one of these two mutations segregated with breast cancer. The estimated average penetrance of the mutations was 60% (95% confidence interval [CI] = 32% to 90%) to age 70 years, equivalent to a 15.7-fold (95% CI = 6.4-fold to 38.0-fold) increased relative risk compared with that of the general population. Expression and activity analyses of ATM in heterozygous cell lines indicated that both mutations are dominant negative.
CONCLUSION NlmCategory: CONCLUSIONS
The ATM gene encoding a putative protein kinase is mutated in ataxia-telangiectasia (A-T), an autosomal recessive disorder with a predisposition for cancer. Studies of A-T families suggest that female heterozygotes have an increased risk of breast cancer compared with noncarriers. However, neither linkage analyses nor mutation studies have provided supporting evidence for a role of ATM in breast cancer predisposition. Nevertheless, two recurrent ATM mutations, T7271G and IVS10-6T-->G, reportedly increase the risk of breast cancer. We examined these two ATM mutations in a population-based, case-control series of breast cancer families and multiple-case breast cancer families. Five hundred twenty-five or 262 case patients with breast cancer and 381 or 68 control subjects, respectively, were genotyped for the T7271G and IVS10-6T-->G ATM mutations, as were index patients from 76 non-BRCA1/2 multiple-case breast cancer families. Linkage and penetrance were analyzed. ATM protein expression and kinase activity were analyzed in lymphoblastoid cell lines from mutation carriers. All statistical tests were two-sided. In case and control subjects unselected for family history of breast cancer, one case patient had the T7271G mutation, and none had the IVS10-6T-->G mutation. In three multiple-case families, one of these two mutations segregated with breast cancer. The estimated average penetrance of the mutations was 60% (95% confidence interval [CI] = 32% to 90%) to age 70 years, equivalent to a 15.7-fold (95% CI = 6.4-fold to 38.0-fold) increased relative risk compared with that of the general population. Expression and activity analyses of ATM in heterozygous cell lines indicated that both mutations are dominant negative. At least two ATM mutations are associated with a sufficiently high risk of breast cancer to be found in multiple-case breast cancer families. Full mutation analysis of the ATM gene in such families could help clarify the role of ATM in breast cancer susceptibility.
DATE PUBLISHED
2002 Feb 06
HISTORY
PUBSTATUS PUBSTATUSDATE
pubmed 2002/02/07 10:00
medline 2002/03/15 10:01
entrez 2002/02/07 10:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Chenevix-Trench G Chenevix-Trench Georgia G Queensland Institute of Medical Research, Brisbane, Australia. georgiaT@qimr.edu.au
Spurdle AB Spurdle Amanda B AB
Gatei M Gatei Magtouf M
Kelly H Kelly Helena H
Marsh A Marsh Anna A
Chen X Chen Xiaoqing X
Donn K Donn Karen K
Cummings M Cummings Margaret M
Nyholt D Nyholt Dale D
Jenkins MA Jenkins Mark A MA
Scott C Scott Clare C
Pupo GM Pupo Gulietta M GM
Dörk T Dörk Thilo T
Bendix R Bendix Regina R
Kirk J Kirk Judy J
Tucker K Tucker Katherine K
McCredie MR McCredie Margaret R E MR
Hopper JL Hopper John L JL
Sambrook J Sambrook Joseph J
Mann GJ Mann Graham J GJ
Khanna KK Khanna Kum Kum KK
INVESTIGATORS
JOURNAL
VOLUME: 94
ISSUE: 3
TITLE: Journal of the National Cancer Institute
ISOABBREVIATION: J Natl Cancer Inst
YEAR: 2002
MONTH: Feb
DAY: 06
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Print
ISSN: 0027-8874
ISSNTYPE: Print
MEDLINE JOURNAL
MEDLINETA: J Natl Cancer Inst
COUNTRY: United States
ISSNLINKING: 0027-8874
NLMUNIQUEID: 7503089
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
COMMENTS AND CORRECTIONS
REFTYPE REFSOURCE REFPMID NOTE
ErratumIn J Natl Cancer Inst 2002 Jun 19;94(12):952
CommentIn J Natl Cancer Inst. 2002 Jun 19;94(12):951-2; author reply 952 12072552
GRANTS
GRANTID AGENCY COUNTRY
CA69638 NCI NIH HHS United States
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Ataxia Telangiectasia Mutated Proteins
Blotting, Western
Breast Neoplasms pathology
Cell Cycle Proteins pathology
Chromosome Mapping pathology
DNA Mutational Analysis pathology
DNA-Binding Proteins pathology
Female pathology
Gene Frequency genetics
Genes, Dominant genetics
Genetic Predisposition to Disease genetics
Genetic Testing genetics
Genotype genetics
Humans genetics
Lod Score genetics
Male genetics
Microsatellite Repeats genetics
Mutation genetics
Pedigree genetics
Protein-Serine-Threonine Kinases metabolism
Tumor Cells, Cultured metabolism
Tumor Suppressor Proteins metabolism
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
REGISTRYNUMBER NAMEOFSUBSTANCE
0 Cell Cycle Proteins
0 DNA-Binding Proteins
0 Tumor Suppressor Proteins
EC 2.7.11.1 ATM protein, human
EC 2.7.11.1 Ataxia Telangiectasia Mutated Proteins
EC 2.7.11.1 Protein-Serine-Threonine Kinases
OTHER ID's
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