Contribution Of Known Genes To Breast Cancer Incidence

The frequency of BRCA1 and BRCA2 mutations in breast cancer cases has been estimated by a number of studies. By pooling data from a number of population-based studies, Thompson and Easton (78) estimated that the prevalences of BRCA1 and BRCA2 mutations among breast cancer patients diagnosed below their mid-30s were approximately 4.6% and 3.5%, respectively. In contrast, the Anglian Breast Cancer Study (the largest population-based study to date) found the prevalences among cases diagnosed between 45 and 54 years of age to be just 0.3% and 1.0%, respectively (79). These studies underestimate the true prevalence of mutations because studies use methods that are not fully sensitive. Indeed, the fraction of mutations that are detected by such studies is somewhat uncertain because some variants in BRCA1 and BRCA2 are of uncertain significance and may or may not be associated with risk. Nevertheless, overall fraction of breast cancer patients in outbred populations carrying BRCA1 and BRCA2 mutations is probably close to 1% to 2% for each gene. As noted above, the frequency can be significantly higher in founder populations (see Table 3).

TP53 and PTEN mutations are very rare and account for much less than 1% of breast cancer cases. Mutations in ATM, CHEK2, BRIP1, and PALB2 are also uncommon and also each account for 1% or less of cases. The CASP8 302H allele, however, is common, and the estimated attribution fraction is 8% while the attributable fractions for

The Genetic Epidemiology of Hereditary Breast Cancer Table 3 Low Risk Breast Cancer Susceptibility-Genes

Population Contribution to frequency of Relative risk Attributable familial risk of Gene mutations (%)b (Refs.) risk (%)c breast cancer (%)c

Carriers:

ATM

0.3

~2.3 (66,67)

0.8

0.7

CHEK2

0.5a

~2.2 (69,70)

1

1

BRIPI

0.1

2.1 (71)

0.1

0.1

PALB2

0.1

2.3 (72)

0,3

0.2

Hctd

Horne

CASP8 D302H

13 (0)

0.89

0.74

8.0

0.2

(74)

FGFR2 (rs2981582)

38 (30)

1.23

1.63

16.6

2.0

(75)

TNCR9/LOC643714

25 (60)

1.23

1.39

10.0

1.0

(rs3803662)

(75)

MAP3K1 (rs8893l2)

28 (54)

1.13

1.27

6.9

0.4

(75)

LSP1 (rs3817198)

30 (14)

1.06

1.17

3.9

0.16

(75)

8q (rs13281615)

40 (56)

1.06

1.18

5.4

0.22

(75)

2q (rs13387042)

50 (12)

1.11

1.44

14.2

1.3

(76)

'Frequency of the 1100delC mutations that is predominant in Western Europeans. Other mutations have been reported at significant frequency in Poland and in Ashkenazi Jews. bEstimated frequency of mutation carrier or, for common polymorphisms, of the minor allele in European populations, For common polymorphisms, frequency of the corresponding allele in East Asian populations given in brackets. c Estimates based on frequencies in European populations. d Relative risk in heterozygotes.

e Relative risk to homozygotes of the minor allele in Europeans.

'Frequency of the 1100delC mutations that is predominant in Western Europeans. Other mutations have been reported at significant frequency in Poland and in Ashkenazi Jews. bEstimated frequency of mutation carrier or, for common polymorphisms, of the minor allele in European populations, For common polymorphisms, frequency of the corresponding allele in East Asian populations given in brackets. c Estimates based on frequencies in European populations. d Relative risk in heterozygotes.

e Relative risk to homozygotes of the minor allele in Europeans.

the loci identified through the genome scans range from 3.9-16.6%. Attributable fraction is, however, not a particularly useful concept for low-penetrance alleles. These risks cannot be avoided, and as more alleles are identified, these fractions are likely to add up to much more than 100%.

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