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: 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: 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: 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.
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: 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: 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: 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.
Authors: Roger A Greenberg; Bijan Sobhian; Shailja Pathania; Sharon B Cantor; Yoshihiro Nakatani; David M Livingston Journal: Genes Dev Date: 2006-01-01 Impact factor: 11.361
Authors: Joaquin Mateo; Suzanne Carreira; Shahneen Sandhu; Susana Miranda; Helen Mossop; Raquel Perez-Lopez; Daniel Nava Rodrigues; Dan Robinson; Aurelius Omlin; Nina Tunariu; Gunther Boysen; Nuria Porta; Penny Flohr; Alexa Gillman; Ines Figueiredo; Claire Paulding; George Seed; Suneil Jain; Christy Ralph; Andrew Protheroe; Syed Hussain; Robert Jones; Tony Elliott; Ursula McGovern; Diletta Bianchini; Jane Goodall; Zafeiris Zafeiriou; Chris T Williamson; Roberta Ferraldeschi; Ruth Riisnaes; Bernardette Ebbs; Gemma Fowler; Desamparados Roda; Wei Yuan; Yi-Mi Wu; Xuhong Cao; Rachel Brough; Helen Pemberton; Roger A'Hern; Amanda Swain; Lakshmi P Kunju; Rosalind Eeles; Gerhardt Attard; Christopher J Lord; Alan Ashworth; Mark A Rubin; Karen E Knudsen; Felix Y Feng; Arul M Chinnaiyan; Emma Hall; Johann S de Bono Journal: N Engl J Med Date: 2015-10-29 Impact factor: 91.245
Authors: Denise L Stredrick; Montserrat Garcia-Closas; Marbin A Pineda; Parveen Bhatti; Bruce H Alexander; Michele M Doody; Jolanta Lissowska; Beata Peplonska; Louise A Brinton; Stephen J Chanock; Jeffery P Struewing; Alice J Sigurdson Journal: Hum Mutat Date: 2006-06 Impact factor: 4.878