Genome-wide association study of susceptibility loci for breast cancer in Sardinian population

Grazia Palomba, Angela Loi, Eleonora Porcu, Antonio Cossu, Ilenia Zara, Mario Budroni, Mariano Dei, Sandra Lai, Antonella Mulas, Nina Olmeo, Maria Teresa Ionta, Francesco Atzori, Gianmauro Cuccuru, Maristella Pitzalis, Magdalena Zoledziewska, Nazario Olla, Mario Lovicu, Marina Pisano, Gonçalo R. Abecasis, Manuela UdaFrancesco Tanda, Kyriaki Michailidou, Douglas F. Easton, Stephen J. Chanock, Robert N. Hoover, David J. Hunter, David Schlessinger, Serena Sanna, Laura Crisponi, Giuseppe Palmieri

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


Background: Despite progress in identifying genes associated with breast cancer, many more risk loci exist. Genome-wide association analyses in genetically-homogeneous populations, such as that of Sardinia (Italy), could represent an additional approach to detect low penetrance alleles. Methods: We performed a genome-wide association study comparing 1431 Sardinian patients with non-familial, BRCA1/2-mutation-negative breast cancer to 2171 healthy Sardinian blood donors. DNA was genotyped using GeneChip Human Mapping 500 K Arrays or Genome-Wide Human SNP Arrays 6.0. To increase genomic coverage, genotypes of additional SNPs were imputed using data from HapMap Phase II. After quality control filtering of genotype data, 1367 cases (9 men) and 1658 controls (1156 men) were analyzed on a total of 2,067,645 SNPs. Results: Overall, 33 genomic regions (67 candidate SNPs) were associated with breast cancer risk at the p <10-6 level. Twenty of these regions contained defined genes, including one already associated with breast cancer risk: TOX3. With a lower threshold for preliminary significance to p <10-5, we identified 11 additional SNPs in FGFR2, a well-established breast cancer-associated gene. Ten candidate SNPs were selected, excluding those already associated with breast cancer, for technical validation as well as replication in 1668 samples from the same population. Only SNP rs345299, located in intron 1 of VAV3, remained suggestively associated (p-value, 1.16x10-5), but it did not associate with breast cancer risk in pooled data from two large, mixed-population cohorts. Conclusions: This study indicated the role of TOX3 and FGFR2 as breast cancer susceptibility genes in BRCA1/2-wild-type breast cancer patients from Sardinian population.

Original languageEnglish (US)
Article number383
JournalBMC Cancer
Issue number1
StatePublished - May 10 2015
Externally publishedYes


  • BRCA1/2 mutation analysis
  • Breast cancer risk
  • Genome-wide association study
  • Sardinian population

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Genetics


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