has been suggested to be a candidate tumour suppressor gene on the basis of the findings that normal function of CHEK2 is involved in DNA-damage respond and some of the mutations identified in Li–Fraumeni families were expected to result in a truncated protein (Bell et al, 1999
). Subsequently, these findings were supported by the reports concerning identical and additional mutations in patients with Li–Fraumeni syndrome (Lee et al, 2001
) and breast cancer (Meijers-Heijboer et al, 2002
; Vahteristo et al, 2002
). While this manuscript was in preparation, another study was published showing that mutations in CHEK2
were associated also with prostate cancer risk (Dong et al, 2003
Our results suggest that CHEK2
1100delC mutation is associated with positive family history of prostate cancer. The mutation segregated almost completely in all mutation-positive families (). In family 351, there were three unaffected men, who carried the variant. Two of them were rather young, about 50 years old (III-2 and III-3), and the third unaffected carrier was 71 years old (II-5). The total PSA values of the unaffected mutation carriers of this family were measured in July 2000. The values were <0.5, 2.2, and 2.4μ
for III-2, III-3 and II-5, respectively. The mean age at diagnosis of prostate cancer in Finland was 71.1 years in 1999 (Finnish Cancer Registry; cancer statistics at
) and all three affecteds of the family 351 were over 66 years old when diagnosed for prostate cancer, thus the future diagnosis of prostate cancer cannot be ruled out for the healthy carriers of this family. On the other hand, in the four 1100delC-positive families, there were no mutation-negative prostate cancer patients. The association of 1100delC mutation with families that include small number of affected relatives, the most common types of prostate cancer families, implies that the mutation is likely to have a significant contribution to familial prostate cancer at the population level. In addition, I157T seems to be a disease-associated polymorphism at least in the Finnish population. It has a slightly higher frequency among patients with unselected prostate cancer than among control individuals and it is strongly associated with family history of the disease. However, according to the previous reports, the I157T allele does not make a significant contribution to breast cancer susceptibility (Allinen et al, 2001
; Schutte et al, 2003
). Therefore, the association with this allele is less conclusive.
Previously, Vahteristo et al (2002)
reported the strong association of the CHEK2
1100delC with breast cancer families that included only two affected patients, suggesting that 1100delC is a low-penetrance genetic alteration. In contrast to our results, Dong et al (2003)
reported the association of the CHEK2
mutations (all mutations pooled together) only with sporadic prostate cancer. In addition, they did not observe any association between prostate cancer and I157T variant. The reason why Dong et al (2003)
did not detect any association with HPC could be due to different sample settings: the families from the USA represent more extreme HPC families than the Finnish families in the present study. In their study two affected members from 149 HPC families with at minimum of three affected men over at least two generations were used. In our recent genome-wide linkage analysis, no positive signals were seen on chromosome 22 (Schleutker et al, in press
). This is probably due to the selected study material, as only the most extreme families were genotyped, possibly reflecting the same phenomenon as seen in the study of Dong et al (2003)
. Also, the low allele frequencies of CHEK2
variants (<10%) make this kind of an association almost impossible to detect by linkage analysis.
Dong et al (2003)
reported a total of 13 different CHEK2
germline mutations among 400 sporadic prostate cancer patients and 298 individuals with familial prostate cancer. Most of these mutations occurred only once in their study population. The reason why fewer variants were found in our study can possibly be due to the limited sensitivity of the SSCP analysis and the number of screened patients. Most likely, however, the reason is the study population itself. The Finnish population is genetically much more homogeneous than the US population, and therefore it is not surprising that fewer variants were detected.
Taken together, finding of the 1100delC and I157T variants in families with small numbers of affected relatives support the idea that CHEK2 variants are low-penetrance prostate cancer predisposition alleles that contribute significantly to familial clustering of prostate cancer at the population level, especially in families with small number of affected relatives. However, variants in CHEK2 gene alone do not explain the familial clustering of prostate cancer in Finland as the majority of families did not have any CHEK2 alterations. The present results warrant further studies of the role of CHEK2 variants as a risk factor for prostate cancer in other populations.