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Are the so-called low penetrance breast cancer genes, ATM, BRIP1, PALB2 and CHEK2, high risk for women with strong family histories?

Byrnes GB, Southey MC, Hopper JL - Breast Cancer Res. (2008)

Bottom Line: Several studies found that the frequencies of mutations in ATM, BRIP1, PALB2 and CHEK2 were many times greater for cases with a strong family history than for controls.The authors concluded that the variants are "low penetrance".They failed to note that their model fits predicted that, for some women, absolute risk may be as high as for BRCA2 mutation carriers.

View Article: PubMed Central - HTML - PubMed

Affiliation: Epidemiology Methods and Support Group, International Agency for Research on Cancer, 150 cours Albert Thomas, Lyon, France.

ABSTRACT
A woman typically presents for genetic counselling because she has a strong family history and is interested in knowing the probability she will develop disease in the future; that is, her absolute risk. Relative risk for a given factor refers to risk compared with either population average risk (sense a), or risk when not having the factor, with all other factors held constant (sense b). Not understanding that these are three distinct concepts can result in failure to correctly appreciate the consequences of studies on clinical genetic testing. Several studies found that the frequencies of mutations in ATM, BRIP1, PALB2 and CHEK2 were many times greater for cases with a strong family history than for controls. To account for the selected case sampling (ascertainment), a statistical model that assumes that the effect of any measured variant multiplies the effect of unmeasured variants was applied. This multiplicative polygenic model in effect estimated the relative risk in the sense b, not sense a, and found it was in the range of 1.7 to 2.4. The authors concluded that the variants are "low penetrance". They failed to note that their model fits predicted that, for some women, absolute risk may be as high as for BRCA2 mutation carriers. This is because the relative risk multiplies polygenic risk, and the latter is predicted by family history. Therefore, mutation testing of these genes for women with a strong family history, especially if it is of early onset, may be as clinically relevant as it is for BRCA1 and BRCA2.

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Under the multiplicative polygenic model and the logistic model for lifetime risk of breast cancer (Figure 2), for women in the general population the relative frequency as a function of lifetime risk is indicated by the solid blue line. For women with a strong family history, their relative frequency as a function of lifetime risk is indicated by the dashed red line.
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Figure 3: Under the multiplicative polygenic model and the logistic model for lifetime risk of breast cancer (Figure 2), for women in the general population the relative frequency as a function of lifetime risk is indicated by the solid blue line. For women with a strong family history, their relative frequency as a function of lifetime risk is indicated by the dashed red line.

Mentions: The reason for carriers with a strong family history being at high absolute risk is that a woman's family history provides an estimate of her polygenic risk. As a group, women with a strong family history will be distributed towards the upper end of the polygenic risk scale (Figures 2 and 3). Multiplying their polygenic risk, which is two if not more times population risk, by the factor RR will leave this group of women at considerable absolute risk. This may even be as high as for women with a BRCA2 mutation (Figure 4, and see below).


Are the so-called low penetrance breast cancer genes, ATM, BRIP1, PALB2 and CHEK2, high risk for women with strong family histories?

Byrnes GB, Southey MC, Hopper JL - Breast Cancer Res. (2008)

Under the multiplicative polygenic model and the logistic model for lifetime risk of breast cancer (Figure 2), for women in the general population the relative frequency as a function of lifetime risk is indicated by the solid blue line. For women with a strong family history, their relative frequency as a function of lifetime risk is indicated by the dashed red line.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2481495&req=5

Figure 3: Under the multiplicative polygenic model and the logistic model for lifetime risk of breast cancer (Figure 2), for women in the general population the relative frequency as a function of lifetime risk is indicated by the solid blue line. For women with a strong family history, their relative frequency as a function of lifetime risk is indicated by the dashed red line.
Mentions: The reason for carriers with a strong family history being at high absolute risk is that a woman's family history provides an estimate of her polygenic risk. As a group, women with a strong family history will be distributed towards the upper end of the polygenic risk scale (Figures 2 and 3). Multiplying their polygenic risk, which is two if not more times population risk, by the factor RR will leave this group of women at considerable absolute risk. This may even be as high as for women with a BRCA2 mutation (Figure 4, and see below).

Bottom Line: Several studies found that the frequencies of mutations in ATM, BRIP1, PALB2 and CHEK2 were many times greater for cases with a strong family history than for controls.The authors concluded that the variants are "low penetrance".They failed to note that their model fits predicted that, for some women, absolute risk may be as high as for BRCA2 mutation carriers.

View Article: PubMed Central - HTML - PubMed

Affiliation: Epidemiology Methods and Support Group, International Agency for Research on Cancer, 150 cours Albert Thomas, Lyon, France.

ABSTRACT
A woman typically presents for genetic counselling because she has a strong family history and is interested in knowing the probability she will develop disease in the future; that is, her absolute risk. Relative risk for a given factor refers to risk compared with either population average risk (sense a), or risk when not having the factor, with all other factors held constant (sense b). Not understanding that these are three distinct concepts can result in failure to correctly appreciate the consequences of studies on clinical genetic testing. Several studies found that the frequencies of mutations in ATM, BRIP1, PALB2 and CHEK2 were many times greater for cases with a strong family history than for controls. To account for the selected case sampling (ascertainment), a statistical model that assumes that the effect of any measured variant multiplies the effect of unmeasured variants was applied. This multiplicative polygenic model in effect estimated the relative risk in the sense b, not sense a, and found it was in the range of 1.7 to 2.4. The authors concluded that the variants are "low penetrance". They failed to note that their model fits predicted that, for some women, absolute risk may be as high as for BRCA2 mutation carriers. This is because the relative risk multiplies polygenic risk, and the latter is predicted by family history. Therefore, mutation testing of these genes for women with a strong family history, especially if it is of early onset, may be as clinically relevant as it is for BRCA1 and BRCA2.

Show MeSH
Related in: MedlinePlus