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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), the distribution of lifetime risk is shown as a function of the cumulative proportion of the population. For the great majority of women in the population (indicated by the solid blue line), their lifetime risk is low (for example, 70% have a lifetime risk below the population average of 11%) and less than 10% have a lifetime risk in excess of 40%. For randomly selected women with a genetic variant associated with, on average, a 2-fold increased risk (indicated by the dashed blue line), the median lifetime risk is about the average population risk and about one-quarter have a lifetime risk in excess of 40%. For women with a strong family history equivalent to a 3-fold increased risk (indicated by the solid red line), nearly 80% are above average population risk and nearly half have a lifetime risk in excess of 40%. For those with a strong family history who also have a genetic variant associated with, on average, a 2-fold increased risk (indicated by the dashed red line), 90% are above population average risk and over 70% have a lifetime risk in excess of 40%.
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Figure 4: Under the multiplicative polygenic model and the logistic model for lifetime risk of breast cancer (Figure 2), the distribution of lifetime risk is shown as a function of the cumulative proportion of the population. For the great majority of women in the population (indicated by the solid blue line), their lifetime risk is low (for example, 70% have a lifetime risk below the population average of 11%) and less than 10% have a lifetime risk in excess of 40%. For randomly selected women with a genetic variant associated with, on average, a 2-fold increased risk (indicated by the dashed blue line), the median lifetime risk is about the average population risk and about one-quarter have a lifetime risk in excess of 40%. For women with a strong family history equivalent to a 3-fold increased risk (indicated by the solid red line), nearly 80% are above average population risk and nearly half have a lifetime risk in excess of 40%. For those with a strong family history who also have a genetic variant associated with, on average, a 2-fold increased risk (indicated by the dashed red line), 90% are above population average risk and over 70% have a lifetime risk in excess of 40%.

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), the distribution of lifetime risk is shown as a function of the cumulative proportion of the population. For the great majority of women in the population (indicated by the solid blue line), their lifetime risk is low (for example, 70% have a lifetime risk below the population average of 11%) and less than 10% have a lifetime risk in excess of 40%. For randomly selected women with a genetic variant associated with, on average, a 2-fold increased risk (indicated by the dashed blue line), the median lifetime risk is about the average population risk and about one-quarter have a lifetime risk in excess of 40%. For women with a strong family history equivalent to a 3-fold increased risk (indicated by the solid red line), nearly 80% are above average population risk and nearly half have a lifetime risk in excess of 40%. For those with a strong family history who also have a genetic variant associated with, on average, a 2-fold increased risk (indicated by the dashed red line), 90% are above population average risk and over 70% have a lifetime risk in excess of 40%.
© Copyright Policy
Related In: Results  -  Collection

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Figure 4: Under the multiplicative polygenic model and the logistic model for lifetime risk of breast cancer (Figure 2), the distribution of lifetime risk is shown as a function of the cumulative proportion of the population. For the great majority of women in the population (indicated by the solid blue line), their lifetime risk is low (for example, 70% have a lifetime risk below the population average of 11%) and less than 10% have a lifetime risk in excess of 40%. For randomly selected women with a genetic variant associated with, on average, a 2-fold increased risk (indicated by the dashed blue line), the median lifetime risk is about the average population risk and about one-quarter have a lifetime risk in excess of 40%. For women with a strong family history equivalent to a 3-fold increased risk (indicated by the solid red line), nearly 80% are above average population risk and nearly half have a lifetime risk in excess of 40%. For those with a strong family history who also have a genetic variant associated with, on average, a 2-fold increased risk (indicated by the dashed red line), 90% are above population average risk and over 70% have a lifetime risk in excess of 40%.
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