This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mosquera-Miguel, A. Articles by Salas, A. Search for Related Content PubMed PubMed Citation Articles by Mosquera-Miguel, A. Articles by Salas, A.

Is Mitochondrial DNA Variation Associated with Sporadic Breast Cancer Risk?

Unidade de Xenética, Instituto de Medicina Legal, Facultade de Medicina, Galicia, Spain

Ana Vega and Ángel Carracedo

Fundación Pública Galega de Medicina Xenómica, El Centro de Investigacion Biomedica en Red de Enfermedades Raras, Hospital Clínico Universitario, Universidad de Santiago de Compostela, Galicia, Spain

Roger Milne

Centro Nacional de Genotipado, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

Antonio Cabrera de León

Universidad de La Laguna and Hospital San Juan de Dios, Tenerife, Spain

Javier Benitez

Programa de Genética del Cáncer Humano, Centro de Investigacion Biomedica en Red de Enfermedades Raras, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

Ángel Carracedo and Antonio Salas

Grupo de Medicina Xenómica, Hospital Clínico Universitario, Santiago de Compostela, Galicia, Spain

To the Editor: In the May 15, 2007 issue of Cancer Research, Bai et al. (1) claimed that individuals carrying haplogroup K mitochondrial DNA (mtDNA) lineages are at significantly increased risk of developing breast cancer, whereas those bearing haplogroup U lineages have a significantly decreased risk. However, this study has a number of drawbacks. First, haplogroup K is phylogenetically nested within haplogroup U; consequently, diagnostic mutations in haplogroup U are necessarily also diagnostic in haplogroup K (in particular, A11467G, A12308G, and G12372A). Therefore, how can there be 29 cases belonging to haplogroup K but only 12 belonging to the broader group U? This is not trivial because these were the only two haplogroups found to be associated with breast cancer risk after correction for multiple testing. Second, the study does not investigate nor even mention the potential influence of population stratification in their sample of 156 European-American breast cancer patients and 260 controls, nor are their results replicated in an independent population. The door is therefore open to false-positive findings (type I error).

We have collected breast cancer patients and ethnicity-matched controls from two different Spanish locations. One sample consisted of 464 cases and 453 controls from continental Spain (2), whereas the second, from Canary Islands, included 302 cases and 295 controls. The first sample has been tested for population stratification using a panel of neutral single nucleotide polymorphisms (SNP; ref 2). Our samples were genotyped for a set of 25 mtDNA SNPs, including all those with evidence of association based on unadjusted P values in (1) as well as the variant G10398A reported in (3, 4). We found no evidence of association for any of the variants after adjustment for multiple testing in either sample (Table 1 ). With the Spanish mainland sample alone, we had 80% power to detect odds ratios (OR) as low as 2.00 for G9055A and 1.50 for A12308G (the two variants that define haplogroups K and U, respectively). In fact, OR estimates for the variants G9055A and A12308G were in the opposite direction to those reported in (1): 0.65 [95% confidence interval (95% CI), 0.36–1.18] and 0.87 (95% CI, 0.45–1.66) in Spanish mainland and Canary Island samples, respectively, for G9055A; and 0.74 (95% CI, 0.55–0.99) and 0.77 (95% CI, 0.52–1.14), respectively, for A12308G.

Footnotes

Grant support: The Ramón y Cajal' Spanish programme from the Ministerio de Educación y Ciencia (RYC2005-3), the grants from the Xunta de Galicia (PGIDIT06PXIB208079PR) and (PGIDIT06BTF910101PR) given to A. Salas and A. Vega respectively, two different grants from the Fundación de Investigación Médica Mutua Madrileña awarded to A. Salas and A. Vega, and the Spanish grant of the Ministerio de Sanidad y Consumo (PI052275) given to A. Vega supported this project. A. Mosquera-Miguel received a FPU grant from the Ministerio de Educación y Ciencia.

References

1. Bai RK, Leal SM, Covarrubias D, Liu A, Wong LJ. Mitochondrial genetic background modifies breast cancer risk. Cancer Res 2007;67:4687–94.[Abstract/Free Full Text]
2. Milne RL, Ribas G, González-Neira A, et al. ERCC4 associated with breast cancer risk: a two-stage case-control study using high-throughput genotyping. Cancer Res 2006;66:9420–7.[Abstract/Free Full Text]
3. Canter JA, Kallianpur AR, Parl FF, Millikan RC. Mitochondrial DNA G10398A polymorphism and invasive breast cancer in African-American women. Cancer Res 2005;65:8028–33.[Abstract/Free Full Text]
4. Darvishi K, Sharma S, Bhat AK, Rai E, Bamezai RN. Mitochondrial DNA G10398A polymorphism imparts maternal Haplogroup N a risk for breast and esophageal cancer. Cancer Lett 2007;249:249–55.[CrossRef][Medline]
5. Kong Q-P, Bandelt H-J, Sun C, et al. Updating the East Asian mtDNA phylogeny: a prerequisite for the identification of pathogenic mutations. Hum Mol Genet 2006;15:2076–86.[Abstract/Free Full Text]
6. Salas A, Bandelt HJ, Macaulay V, Richards M. Phylogenetic investigations: the role of trees in forensic genetics. Forensic Sci Int 2007;168:1–13.[CrossRef][Medline]

This article has been cited by other articles:

				C. Ye, Y.-T. Gao, W. Wen, J. P. Breyer, X. O. Shu, J. R. Smith, W. Zheng, and Q. Cai Association of Mitochondrial DNA Displacement Loop (CA)n Dinucleotide Repeat Polymorphism with Breast Cancer Risk and Survival among Chinese Women Cancer Epidemiol. Biomarkers Prev., August 1, 2008; 17(8): 2117 - 2122. [Abstract] [Full Text] [PDF]

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mosquera-Miguel, A. Articles by Salas, A. Search for Related Content PubMed PubMed Citation Articles by Mosquera-Miguel, A. Articles by Salas, A.