Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2006

Open Access 01-12-2006 | Research article

ATM variants and cancer risk in breast cancer patients from Southern Finland

Authors: Johanna Tommiska, Laila Jansen, Outi Kilpivaara, Hege Edvardsen, Vessela Kristensen, Anitta Tamminen, Kristiina Aittomäki, Carl Blomqvist, Anne-Lise Børresen-Dale, Heli Nevanlinna

Published in: BMC Cancer | Issue 1/2006

Login to get access

Abstract

Background

Individuals heterozygous for germline ATM mutations have been reported to have an increased risk for breast cancer but the role for ATM genetic variants for breast cancer risk has remained unclear. Recently, a common ATM variant, ATMivs38 -8T>C in cis with the ATMex39 5557G>A (D1853N) variant, was suggested to associate with bilateral breast cancer among familial breast cancer patients from Northern Finland. We have here evaluated the 5557G>A and ivs38-8T>C variants in an extensive case-control association analysis. We also aimed to investigate whether there are other ATM mutations or variants contributing to breast cancer risk in our population.

Methods

Two common ATM variants, 5557G>A and ivs38-8T>C, previously suggested to associate with bilateral breast cancer, were genotyped in an extensive set of 786 familial and 884 unselected breast cancer cases as well as 708 healthy controls. We also screened the entire coding region and exon-intron boundaries of the ATM gene in 47 familial breast cancer patients and constructed haplotypes of the patients. The identified variants were also evaluated for increased breast cancer risk among additional breast cancer cases and controls.

Results

Neither of the two common variants, 5557G>A and ivs38-8T>C, nor any haplotype containing them, was significantly associated with breast cancer risk, bilateral breast cancer or multiple primary cancers in any of the patient groups or subgoups. Three rare missense alterations and one intronic change were each found in only one patient of over 250 familial patients studied and not among controls. The fourth missense alteration studied further was found with closely similar frequencies in over 600 familial cases and controls.

Conclusion

Altogether, our results suggest very minor effect, if any, of ATM genetic variants on familial breast cancer in Southern Finland. Our results do not support association of the 5557G>A or ivs38-8T>C variant with increased breast cancer risk or with bilateral breast cancer.
Literature
1.
Shiloh Y: ATM and related protein kinases: safeguarding genome integrity. Nat Rev Cancer. 2003, 3: 155-168. 10.1038/nrc1011.CrossRefPubMed
2.
Savitsky K, Bar-Shira A, Gilad S, Rotman G, Ziv Y, Vanagaite L, Tagle DA, Smith S, Uziel T, Sfez S: A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science. 1995, 268: 1749-1753.CrossRefPubMed
3.
Lavin MF, Shiloh Y: The genetic defect in ataxia-telangiectasia. Annu Rev Immunol. 1997, 15: 177-202. 10.1146/annurev.immunol.15.1.177.CrossRefPubMed
4.
Khanna KK, Chenevix-Trench G: ATM and genome maintenance: defining its role in breast cancer susceptibility. J Mammary Gland Biol Neoplasia. 2004, 9: 247-262. 10.1023/B:JOMG.0000048772.92326.a1.CrossRefPubMed
5.
Swift M, Reitnauer PJ, Morrell D, Chase CL: Breast and other cancers in families with ataxia-telangiectasia. N Engl J Med. 1987, 316: 1289-1294.CrossRefPubMed
6.
Swift M, Morrell D, Massey RB, Chase CL: Incidence of cancer in 161 families affected by ataxia-telangiectasia. N Engl J Med. 1991, 325: 1831-1836.CrossRefPubMed
7.
Olsen JH, Hahnemann JM, Børresen-Dale AL, Brøndum-Nielsen K, Hammarström L, Kleinerman R, Kääriäinen H, Lönnqvist T, Sankila R, Seersholm N, Tretli S, Yuen J, Boice JD, Tucker M: Cancer in patients with ataxia-telangiectasia and in their relatives in the nordic countries. J Natl Cancer Inst. 2001, 93: 121-127. 10.1093/jnci/93.2.121.CrossRefPubMed
8.
Thompson D, Duedal S, Kirner J, McGuffog L, Last J, Reiman A, Byrd P, Taylor M, Easton DF: Cancer risks and mortality in heterozygous ATM mutation carriers. J Natl Cancer Inst. 2005, 97: 813-822.CrossRefPubMed
9.
Olsen JH, Hahnemann JM, Borresen-Dale AL, Tretli S, Kleinerman R, Sankila R, Hammarstrom L, Robsahm TE, Kaariainen H, Bregard A, Brondum-Nielsen K, Yuen J, Tucker M: Breast and other cancers in 1445 blood relatives of 75 Nordic patients with ataxia telangiectasia. Br J Cancer. 2005, 93: 260-265. 10.1038/sj.bjc.6602658.CrossRefPubMedPubMedCentral
10.
Cavaciuti E, Lauge A, Janin N, Ossian K, Hall J, Stoppa-Lyonnet D, Andrieu N: Cancer risk according to type and location of ATM mutation in ataxia-telangiectasia families. Genes Chromosomes Cancer. 2005, 42: 1-9. 10.1002/gcc.20101.CrossRefPubMed
11.
Thorstenson YR, Roxas A, Kroiss R, Jenkins MA, Yu KM, Bachrich T, Muhr D, Wayne TL, Chu G, Davis RW, Wagner TM, Oefner PJ: Contributions of ATM mutations to familial breast and ovarian cancer. Cancer Res. 2003, 63: 3325-3333.PubMed
12.
Heikkinen K, Rapakko K, Karppinen SM, Erkko H, Nieminen P, Winqvist R: Association of common ATM polymorphism with bilateral breast cancer. Int J Cancer. 2005, 116: 69-72. 10.1002/ijc.20996.CrossRefPubMed
13.
Angele S, Romestaing P, Moullan N, Vuillaume M, Chapot B, Friesen M, Jongmans W, Cox DG, Pisani P, Gerard JP, Hall J: ATM haplotypes and cellular response to DNA damage: association with breast cancer risk and clinical radiosensitivity. Cancer Res. 2003, 63: 8717-8725.PubMed
14.
Eerola H, Blomqvist C, Pukkala E, Pyrhonen S, Nevanlinna H, Familial breast cancer in Southern Finland: How prevalent are breast cancer families and can we trust the family history reported by the patients?. Eur J Cancer. 2000, 36: 1143-1148. 10.1016/S0959-8049(00)00093-9.CrossRefPubMed
15.
Vehmanen P, Friedman L, Eerola H, McClure M, Ward B, Sarantaus L, Kainu T, Syrjäkoski K, Pyrhönen S, Kallioniemi O, Muhonen T, Luce M, Frank T, Nevanlinna H: Low proportion of BRCA1 and BRCA2 mutations in Finnish breast cancer families: strong evidence for additional susceptibility genes. Hum Mol Genet. 1997, 6: 2309-2315. 10.1093/hmg/6.13.2309.CrossRefPubMed
16.
Vahteristo P, Eerola H, Tamminen A, Blomqvist C, Nevanlinna H: A probability model for predicting BRCA1 and BRCA2 mutations in breast and breast-ovarian cancer families. Br J Cancer. 2001, 84: 704-708. 10.1054/bjoc.2000.1626.CrossRefPubMedPubMedCentral
17.
Vahteristo P, Bartkova J, Eerola H, Syrjakoski K, Ojala S, Kilpivaara O, Tamminen A, Kononen J, Aittomaki K, Heikkila P, Holli K, Blomqvist C, Bartek J, Kallioniemi OP, Nevanlinna H: A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer. Am J Hum Genet. 2002, 71: 432-438. 10.1086/341943.CrossRefPubMedPubMedCentral
18.
Syrjäkoski K, Vahteristo P, Eerola H, Tamminen A, Kivinummi K, Sarantaus L, Holli K, Blomqvist C, Kallioniemi OP, Kainu T, Nevanlinna H: Population-based study of BRCA1 and BRCA2 mutations in 1035 unselected Finnish breast cancer patients. J Natl Cancer Inst. 2000, 92: 1529-1531. 10.1093/jnci/92.18.1529.CrossRefPubMed
19.
Kilpivaara O, Bartkova J, Eerola H, Syrjakoski K, Vahteristo P, Lukas J, Blomqvist C, Holli K, Heikkila P, Sauter G, Kallioniemi OP, Bartek J, Nevanlinna H: Correlation of CHEK2 protein expression and c.1100delC mutation status with tumor characteristics among unselected breast cancer patients. Int J Cancer. 2005, 113: 575-580. 10.1002/ijc.20638.CrossRefPubMed
20.
Dork T, Bendix R, Bremer M, Rades D, Klopper K, Nicke M, Skawran B, Hector A, Yamini P, Steinmann D, Weise S, Stuhrmann M, Karstens JH: Spectrum of ATM gene mutations in a hospital-based series of unselected breast cancer patients. Cancer Res. 2001, 61: 7608-7615.PubMed
21.
Syvänen AC, Sajantila A, Lukka M: Identification of individuals by analysis of biallelic DNA markers, using PCR and solid-phase minisequencing. Am J Hum Genet. 1993, 52: 46-59.PubMedPubMedCentral
22.
23.
Bernstein JL, Teraoka S, Haile RW, Børresen-Dale A-L, Rosenstein B, Gatti RA, Diep AT, Jansen L, Atencio D, Olsen JH, Bernstein L, Teiteilbaum SL, Thompson WD, Concannon P: Designing and implementing quality control for multi-center screening of mutations in the ATM gene among women with breast cancer. Hum Mutat. 2003, 21: 542-550. 10.1002/humu.10206.CrossRefPubMed
24.
25.
Stephens M, Smith N, Donnelly P: A new statistical method for haplotype reconstruction from population data. Am J Hum Genet. 2001, 68: 978-989. 10.1086/319501.CrossRefPubMedPubMedCentral
26.
Stephens M, Donnelly P: A comparison of bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet. 2003, 73: 1162-1169. 10.1086/379378.CrossRefPubMedPubMedCentral
27.
28.
29.
30.
31.
Schlesselman JJ: Sample Size Requirements in Cohort and Case-Control Studies of Disease. Am J Epidemiol. 1974, 99: 381-384.PubMed
32.
33.
34.
35.
Spurdle AB, Hopper JL, Chen X, McCredie MR, Giles GG, Newman B, Chenevix-Trench G, Khanna K: No evidence for association of ataxia-telangiectasia mutated gene T2119C and C3161G amino acid substitution variants with risk of breast cancer. Breast Cancer Res. 2002, 4: R15-10.1186/bcr534.CrossRefPubMedPubMedCentral
36.
Sommer SS, Jiang Z, Feng J, Buzin CH, Zheng J, Longmate J, Jung M, Moulds J, Dritschilo A: ATM missense mutations are frequent in patients with breast cancer. Cancer Genet Cytogenet. 2003, 145: 115-120. 10.1016/S0165-4608(03)00119-5.CrossRefPubMed
37.
Bretsky P, Haiman CA, Gilad S, Yahalom J, Grossman A, Paglin S, Van Den Berg D, Kolonel LN, Skaliter R, Henderson BE: The relationship between twenty missense ATM variants and breast cancer risk: the Multiethnic Cohort. Cancer Epidemiol Biomarkers Prev. 2003, 12: 733-738.PubMed
38.
Langholz B, Bernstein JL, Bernstein L, Olsen JH, Borresen-Dale AL, Rosenstein BS, Gatti RA, Concannon P: On the proposed association of the ATM variants 5557G>A and IVS38-8T>C and bilateral breast cancer. Int J Cancer. 2006, Feb 22,
39.
40.
Thorstenson YR, Shen P, Tusher VG, Wayne TL, Davis RW, Chu G, Oefner PJ: Global analysis of ATM polymorphism reveals significant functional constraint. Am J Hum Genet. 2001, 69: 396-412. 10.1086/321296.CrossRefPubMedPubMedCentral
41.
Tamimi RM, Hankinson SE, Spiegelman D, Kraft P, Colditz GA, Hunter DJ: Common ataxia telangiectasia mutated haplotypes and risk of breast cancer: a nested case-control study. Breast Cancer Res. 2004, 6: R416-422. 10.1186/bcr809.CrossRefPubMedPubMedCentral
42.
Lee KM, Choi JY, Park SK, Chung HW, Ahn B, Yoo KY, Han W, Noh DY, Ahn SH, Kim H, Wei Q, Kang D: Genetic polymorphisms of ataxia telangiectasia mutated and breast cancer risk. Cancer Epidemiol Biomarkers Prev. 2005, 14: 821-825. 10.1158/1055-9965.EPI-04-0330.CrossRefPubMed
43.
44.
Laake K, Jansen L, Hahnemann JM, Brøndum-Nielsen K, Lönnqvist T, Kääriäinen H, Sankila R, Lähdesmäki A, Hammarström L, Yuen J, Tretli S, Heiberg A, Olsen JH, Tucker M, Kleinerman R, Børresen-Dale AL: Characterization of ATM mutations in 41 Nordic families with ataxia telangiectasia. Hum Mutat. 2000, 16: 232-246. 10.1002/1098-1004(200009)16:3<232::AID-HUMU6>3.0.CO;2-L.CrossRefPubMed
45.
Broeks A, Urbanus JH, Floore AN, Dahler EC, Klijn JG, Rutgers EJ, Devilee P, Russell NS, van Leeuwen FE, van't Veer LJ: ATM-heterozygous germline mutations contribute to breast cancer-susceptibility. Am J Hum Genet. 2000, 66: 494-500. 10.1086/302746.CrossRefPubMedPubMedCentral
46.
Chenevix-Trench G, Spurdle AB, Gatei M, Kelly H, Marsh A, Chen X, Donn K, Cummings M, Nyholt D, Jenkins MA, Scott C, Pupo GM, Dork T, Bendix R, Kirk J, Tucker K, McCredie MR, Hopper JL, Sambrook J, Mann GJ, Khanna KK: Dominant negative ATM mutations in breast cancer families. J Natl Cancer Inst. 2002, 94: 205-215.CrossRefPubMed
47.
Szabo CI, Schutte M, Broeks A, Houwing-Duistermaat JJ, Thorstenson YR, Durocher F, Oldenburg RA, Wasielewski M, Odefrey F, Thompson D, Floore AN, Kraan J, Klijn JG, van den Ouweland AM, Wagner TM, Devilee P, Simard J, van't Veer LJ, Goldgar DE, Meijers-Heijboer H: Are ATM mutations 7271T-->G and IVS10-6T-->G really high-risk breast cancer-susceptibility alleles?. Cancer Res. 2004, 64: 840-843. 10.1158/0008-5472.CAN-03-2678.CrossRefPubMed
48.
Lindeman GJ, Hiew M, Visvader JE, Leary J, Field M, Gaff CL, Gardner RJ, Trainor K, Cheetham G, Suthers G, Kirk J: Frequency of the ATM IVS10-6T-->G variant in Australian multiple-case breast cancer families. Breast Cancer Res. 2004, 6: R401-407. 10.1186/bcr806.CrossRefPubMedPubMedCentral
49.
Thompson D, Antoniou AC, Jenkins M, Marsh A, Chen X, Wayne T, Tesoriero A, Milne R, Spurdle A, Thorstenson Y, Southey M, Giles GG, Khanna KK, Sambrook J, Oefner P, Goldgar D, Hopper JL, Easton D, Chenevix-Trench G, KConFab Investigators: Two ATM variants and breast cancer risk. Hum Mutat. 2005, 25: 594-595. 10.1002/humu.9344.CrossRefPubMed
50.
Allinen M, Launonen V, Laake K, Jansen L, Huusko P, Kaariainen H, Borresen-Dale AL, Winqvist R: ATM mutations in Finnish breast cancer patients. J Med Genet. 2002, 39: 192-196. 10.1136/jmg.39.3.192.CrossRefPubMedPubMedCentral
51.
FitzGerald MG, Bean JM, Hegde SR, Unsal H, MacDonald DJ, Harkin DP, Finkelstein DM, Isselbacher KJ, Haber DA: Heterozygous ATM mutations do not contribute to early onset of breast cancer. Nat Genet. 1997, 15: 307-310. 10.1038/ng0397-307.CrossRefPubMed
52.
53.
Heikkinen K, Tommiska J, Syrjakoski K, Kere J, Allinen M, Karppinen S-M, Rapakko K, Holli K, Kallioniemi H, Nevanlinna DT, Winqvist R: Involvement of three Finnish ATM founder mutations in breast cancer susceptibility. The American Society of Human Genetics, 54th Annual Meeting, Toronto, Canada. Abstract 405. 2004
Metadata
Title
ATM variants and cancer risk in breast cancer patients from Southern Finland
Authors
Johanna Tommiska
Laila Jansen
Outi Kilpivaara
Hege Edvardsen
Vessela Kristensen
Anitta Tamminen
Kristiina Aittomäki
Carl Blomqvist
Anne-Lise Børresen-Dale
Heli Nevanlinna
Publication date
01-12-2006
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2006
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-6-209

Other articles of this Issue 1/2006

BMC Cancer 1/2006 Go to the issue

Research article

Barriers in phase I cancer clinical trials referrals and enrollment: five-year experience at the Princess Margaret Hospital

Research article

Comparative effects of RRR-alpha- and RRR-gamma-tocopherol on proliferation and apoptosis in human colon cancer cell lines

Research article

SnoN expression is differently regulated in microsatellite unstable compared with microsatellite stable colorectal cancers

Research article

Endothelial progenitor cells display clonal restriction in multiple myeloma

Research article

Fusion of the BCL9 HD2 domain to E1A increases the cytopathic effect of an oncolytic adenovirus that targets colon cancer cells

Research article

A transcriptome anatomy of human colorectal cancers
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits