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Articles by H Nevanlinna
Total Records ( 3 ) for H Nevanlinna
  H Jiang , H. C Reinhardt , J Bartkova , J Tommiska , C Blomqvist , H Nevanlinna , J Bartek , M. B Yaffe and M. T. Hemann
 

While the contribution of specific tumor suppressor networks to cancer development has been the subject of considerable recent study, it remains unclear how alterations in these networks are integrated to influence the response of tumors to anti-cancer treatments. Here, we show that mechanisms commonly used by tumors to bypass early neoplastic checkpoints ultimately determine chemotherapeutic response and generate tumor-specific vulnerabilities that can be exploited with targeted therapies. Specifically, evaluation of the combined status of ATM and p53, two commonly mutated tumor suppressor genes, can help to predict the clinical response to genotoxic chemotherapies. We show that in p53-deficient settings, suppression of ATM dramatically sensitizes tumors to DNA-damaging chemotherapy, whereas, conversely, in the presence of functional p53, suppression of ATM or its downstream target Chk2 actually protects tumors from being killed by genotoxic agents. Furthermore, ATM-deficient cancer cells display strong nononcogene addiction to DNA-PKcs for survival after DNA damage, such that suppression of DNA-PKcs in vivo resensitizes inherently chemoresistant ATM-deficient tumors to genotoxic chemotherapy. Thus, the specific set of alterations induced during tumor development plays a dominant role in determining both the tumor response to conventional chemotherapy and specific susceptibilities to targeted therapies in a given malignancy.

  R. L Milne , J Benitez , H Nevanlinna , T Heikkinen , K Aittomaki , C Blomqvist , J. I Arias , M. P Zamora , B Burwinkel , C. R Bartram , A Meindl , R. K Schmutzler , A Cox , I Brock , G Elliott , M. W. R Reed , M. C Southey , L Smith , A. B Spurdle , J. L Hopper , F. J Couch , J. E Olson , X Wang , Z Fredericksen , P Schurmann , M Bremer , P Hillemanns , T Dork , P Devilee , C. J van Asperen , R. A. E. M Tollenaar , C Seynaeve , P Hall , K Czene , J Liu , Y Li , S Ahmed , A. M Dunning , M Maranian , P. D. P Pharoah , G Chenevix Trench , J Beesley , kConFab Investigators , N. N Antonenkova , I. V Zalutsky , H Anton Culver , A Ziogas , H Brauch , C Justenhoven , Y. D Ko , S Haas , P. A Fasching , R Strick , A. B Ekici , M. W Beckmann , G. G Giles , G Severi , L Baglietto , D. R English , O Fletcher , N Johnson , I dos Santos Silva , J Peto , C Turnbull , S Hines , A Renwick , N Rahman , B. G Nordestgaard , S. E Bojesen , H Flyger , D Kang , K. Y Yoo , D. Y Noh , A Mannermaa , V Kataja , V. M Kosma , M Garcia Closas , S Chanock , J Lissowska , L. A Brinton , J Chang Claude , S Wang Gohrke , C. Y Shen , H. C Wang , J. C Yu , S. T Chen , M Bermisheva , T Nikolaeva , E Khusnutdinova , M. K Humphreys , J Morrison , R Platte , D. F Easton and on behalf of the Breast Cancer Association Consortium
  Background

A recent genome-wide association study identified single-nucleotide polymorphism (SNP) 2q35-rs13387042 as a marker of susceptibility to estrogen receptor (ER)–positive breast cancer. We attempted to confirm this association using the Breast Cancer Association Consortium.

Methods

2q35-rs13387042 SNP was genotyped for 31 510 women with invasive breast cancer, 1101 women with ductal carcinoma in situ, and 35 969 female control subjects from 25 studies. Odds ratios (ORs) were estimated by logistic regression, adjusted for study. Heterogeneity in odds ratios by each of age, ethnicity, and study was assessed by fitting interaction terms. Heterogeneity by each of invasiveness, family history, bilaterality, and hormone receptor status was assessed by subclassifying case patients and applying polytomous logistic regression. All statistical tests were two-sided.

Results

We found strong evidence of association between rs13387042 and breast cancer in white women of European origin (per-allele OR = 1.12, 95% confidence interval [CI] = 1.09 to 1.15; Ptrend = 1.0 x 10–19). The odds ratio was lower than that previously reported (P = .02) and did not vary by age or ethnicity (all P ≥ .2). However, it was higher when the analysis was restricted to case patients who were selected for a strong family history (P = .02). An association was observed for both ER-positive (OR = 1.14, 95% CI = 1.10 to 1.17; P = 10–15) and ER-negative disease (OR = 1.10, 95% CI = 1.04 to 1.15; P = .0003) and both progesterone receptor (PR)–positive (OR = 1.15, 95% CI = 1.11 to 1.19; P = 5 x 10–14) and PR-negative disease (OR = 1.10, 95% CI = 1.06 to 1.15; P = .00002).

Conclusion

The rs13387042 is associated with both ER-positive and ER-negative breast cancer in European women.

 
 
 
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