In Response: We recently reported that European-American females with haplogroup K mitochondrial DNA (mtDNA) variants have a significant increase in the risk of developing breast cancer, whereas women bearing haplogroup U have a decreased breast cancer risk (1). Mosquera-Miguel et al. studied sporadic breast cancer patients from continental Spain and the Canary Islands and found no evidence of an association for any mtDNA variants with breast cancer (CAN-07-5706). First, all cases in our study (1) have a family history of breast cancer; therefore, the study populations are not equivalent. Our own unpublished data also suggests that mtDNA variants associated with familial breast cancer risk may not be related to sporadic breast cancer.

The mtDNA haplogroup classification used in our study is based on previously published articles (refs. 2–5; Table 1). Haplogroup U is distinguished from haplogroup K by 9055G>A; both haplogroups U and K contain 12308G. To date, there is no widely accepted standard for the classification of haplogroups U and K. Although haplogroup K is a subclade of haplogroup U in Europeans, most, if not all, published articles on haplogroups and disease association do not include haplogroup K within haplogroup U.

Table 1.

Classification of haplogroups U and K in the published references

Torroni et al. (4)
Macaulay et al. (3)
Herrnstadt et al. (2)
Ver der Walt et al. (5)
Bai et al. (1)
npUKUKUKUKUK
9055 G A G A G A G A G A 
10398 A G A A or G A G A G A A or G 
12308 G G G G G G G G G G 
Torroni et al. (4)
Macaulay et al. (3)
Herrnstadt et al. (2)
Ver der Walt et al. (5)
Bai et al. (1)
npUKUKUKUKUK
9055 G A G A G A G A G A 
10398 A G A A or G A G A G A A or G 
12308 G G G G G G G G G G 

Abreviation: np, nucleotide position.

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Our study has yet to be replicated in an independent population and therefore some of the results could be false positives (type I error). Additionally, spurious findings could have been obtained because population admixture was not controlled for beyond limiting our case and control population to non-Jewish and non-Hispanic European-American women. Although some of the results published are novel, we replicated the finding that 10398A/G plays a role in breast cancer risk. Additional studies will be necessary to establish the role that mtDNA variants and haplogroups play in the etiology of breast cancer.

1
Bai RK, Leal SM, Covarrubias D, Liu A, Wong LJ. Mitochondrial genetic background modifies breast cancer risk.
Cancer Res
 
2007
;
67
:
4687
–94.
2
Herrnstadt C, Elson JL, Fahy E, et al. Reduced-median-network analysis of complete mitochondrial DNA coding-region sequences for the major African, Asian, and European haplogroups.
Am J Hum Genet
 
2002
;
70
:
1152
–71.
3
Macaulay V, Richards M, Hickey E, et al. The emerging tree of West Eurasian mtDNAs: a synthesis of control-region sequences and RFLPs.
Am J Hum Genet
 
1999
;
64
:
232
–49.
4
Torroni A, Huoponen K, Francalacci P, et al. Classification of European mtDNAs from an analysis of three European populations.
Genetics
 
1996
;
144
:
1835
–50.
5
van der Walt JM, Nicodemus KK, Martin ER, et al. Mitochondrial polymorphisms significantly reduce the risk of Parkinson disease.
Am J Hum Genet
 
2003
;
72
:
804
–11.
©2008 American Association for Cancer Research.
2008