Examples Of These Models In

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For the examples below, we have decided to use some of the models discussed on three sample pedigrees. The pedigrees are not real pedigrees but are based on real histories given by families seen in our cancer genetics clinics, and the mutation status of each family is known. They have been selected to illustrate the various strengths and weaknesses of the models. We have, in addition to the models themselves, incorporated an assessment by an "experienced clinician." This reflects the opinion of a recognized cancer geneticist with many years' experience in the clinical setting.

The family history evident from Figure 2 Pedigree 1, on assessment by an experienced clinician, would yield a high expectation that a BRCA mutation is present in the family. Because of the young ages of onset and multiple affected individuals with breast cancer in this family, this would be more likely to be BRCA1 on first inspection. Analysis of BRCA1/2 by full sequencing and multiplex ligation-dependent probe amplification (MLPA) showed a BRCA1 mutation to be present in the family, and, on predictive testing, this was shown to be present in the unaffected proband.

Figure 3 Pedigree 2 is more complicated because of the presence of cancers other than breast and ovarian in the family history. These other cancers are not considered by many of the risk assessment models, and the result is that the estimates of BRCA1/2 carrier probability are extremely variable in this family. An experienced clinician, however, would rate this family as being highly likely to carry a BRCA2 mutation and rather less likely to carry a BRCA1 mutation. Genetic analysis by the methods detailed above did show a BRCA2 mutation to be present in this family. It was found to be present in the unaffected proband on predictive testing.

Figure 4 Pedigree 3 is a low-risk family on initial assessment. It was included in order that the discriminatory strengths of the models could be demonstrated. No mutations were found in this family.

The following table summarizes the results for Pedigree 1:

Model used

BRCA1 risk

BRCA2 risk

Manchester scoring system Myriad

Breast and Ovarian Analysis of Disease

Incidence and Carrier Estimation Algorithm IBIS

BRCAPRO Experienced clinician

High risk (test first)

High risk

Even in this obviously high-risk breast/ovarian cancer family, the models produce widely differing results. There are a total of six cancers in this family in first- and second-degree relatives to the proband. The fact that the proband is unaffected by cancer herself means that her individual risk on the Myriad tables is much lower than one would expect looking at this pedigree. If the Myriad tables are consulted regarding the proband's sister, however, a risk of 39.2% of carrying a BRCA1/2 mutation is seen. Interestingly, however, not all affected relatives are involved in the calculation by the Myriad tables, and the extremely young ages of onset, which would lead the experienced clinician to their "high-risk" assessment, (when taken together with the pattern of inheritance in the family and the number of relatives affected), are not considered by the Myriad tables to be relevant. Both BOADICEA and BRCAPRO give this pedigree a much lower risk of BRCA2 than BRCA1. The extremely low risk given by BRCAPRO illustrates its tendency to overestimate BRCA1 risk and underestimate BRCA2 risk. The IBIS data here also agree that the likelihood is of a BRCA1 mutation over a BRCA2 mutation; however, lifestyle factors were not used in this analysis. The Manchester scoring system gives a high-risk score to each gene, slightly higher for BRCA1 than for BRCA2. Using data to convert the Manchester score into a percentage chance of a BRCA1 or a BRCA2 mutation being present, however, the probabilities are 21% for BRCA1 and 14% for BRCA2.

The following table summarizes the results for Pedigree 2:

Model used BRCA1 risk BRCA2 risk

Manchester

12 (score)

11 (score)

Myriad

12.2%

12.2%

Breast and Ovarian Analysis of Disease

10.6%

15%

Incidence and Carrier Estimation Algorithm

IBIS

6.5%

4.6%

BRCAPRO

14.9%

1.1%

Experienced clinician

High risk

High risk (test first)

This case highlights the shortcomings of all the models when a family history falls outside the strict remit of the model. The family history depicted in the pedigree is strongly suggestive of a mutation in BRCA2 to the experienced clinician, given the additional prostate cancer and melanoma on a background of early-onset breast cancer and ovarian cancer. Both these types of cancer have been found to be associated with BRCA2 mutations rather than BRCA1 mutations in recent studies [EMBRACE, unpublished, Thompson et al. (37)]. Out of the models above, only the Manchester scoring system and BOADICEA consider the additional cancers, and neither of them incorporates melanoma into their calculations yet. It is unexpected that the Myriad risk assessment for this family is identical to that for the family in Pedigree 1. This reflects the limitations of that model in terms of the number of relatives it assesses and the cancers it will consider. This pedigree also serves to demonstrate further the shortcomings of BRCAPRO in terms of its overestimation of BRCA1 at the expense of BRCA2. The IBIS model also performs poorly in this assessment, probably due to not incorporating the other cancers into its calculations.

The following table summarizes the results for Pedigree 3:

Model used

Manchester Myriad

Breast and Ovarian Analysis of Disease

Incidence and Carrier Estimation Algorithm IBIS

BRCAPRO

Experienced clinician

BRCA1 risk BRCA2 risk

1.5% 0.7% Moderate risk (no test) Moderate risk (no test)

The results for Pedigree 3 demonstrate that the models are all capable of discriminating between families that are clearly low risk and families that may require testing. All the models rated Pedigree 3 as low risk, and this family would not have warranted genetic testing under current UK National Institute for Clinical Excellence (NICE) guidelines (38).

Breast Ca 32y Figure 3 Pedigree 2.

Figure 4 Pedigree 3.

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