Penetrance estimates for BRCA1 and BRCA2based on genetic testing in a Clinical Cancer Genetics service setting: Risks of breast/ovarian cancer quoted should reflect the cancer burden in the family
© Evans et al; licensee BioMed Central Ltd. 2008
Received: 19 November 2007
Accepted: 30 May 2008
Published: 30 May 2008
The identification of a BRCA1 or BRCA2 mutation in familial breast cancer kindreds allows genetic testing of at risk relatives. However, considerable controversy exists regarding the cancer risks in women who test positive for the family mutation.
We reviewed 385 unrelated families (223 with BRCA1 and 162 with BRCA2 mutations) ascertained through two regional cancer genetics services. We estimated the penetrance for both breast and ovarian cancer in female mutation carriers (904 proven mutation carriers – 1442 females in total assumed to carry the mutation) and also assessed the effect on penetrance of mutation position and birth cohort.
Breast cancer penetrance to 70 and to 80 years was 68% (95%CI 64.7–71.3%) and 79.5% (95%CI 75.5–83.5%) respectively for BRCA1 and 75% (95%CI 71.7–78.3%) and 88% (95%CI 85.3–91.7%) for BRCA2. Ovarian cancer risk to 70 and to 80 years was 60% (95%CI 65–71%) and 65% (95%CI 75–84%) for BRCA1 and 30% (95%CI 25.5–34.5%) and 37% (95%CI 31.5–42.5%) for BRCA2. These risks were borne out by a prospective study of cancer in the families and genetic testing of unaffected relatives. We also found evidence of a strong cohort effect with women born after 1940 having a cumulative risk of 22% for breast cancer by 40 years of age compared to 8% in women born before 1930 (p = 0.0005).
In high-risk families, selected in a genetics service setting, women who test positive for the familial BRCA1/BRCA2 mutation are likely to have cumulative breast cancer risks in keeping with the estimates obtained originally from large families. This is particularly true for women born after 1940.
Since the identification of the BRCA1  and BRCA2  genes a great deal of debate has focussed on the issue of breast and ovarian cancer risk associated with mutations in these genes. It is clear that calculated cancer risks are dependent on the method of ascertainment of the families studied. Thus, breast cancer risks in large familial breast cancer kindreds with BRCA1/BRCA2 mutations are substantially higher than risks derived from population based studies [3, 7, 8]. In the high-risk families that recruited to the Breast Cancer Linkage Consortium (BCLC) cohort, BRCA1 and BRCA2 mutations were estimated to cause a cumulative lifetime risk of breast cancer at age 70 years of 85–87% and 77–84% respectively [3, 7, 8]. However, estimates of breast cancer risks to age 70 years of age derived from previous population based studies to date are much lower at 28–60% [4–6] for BRCA1, and lower still for BRCA2. It has been suggested that even these studies may overestimate the effect of the BRCA1/2 mutation alone . Whilst there is some evidence of variation of cancer risk by position of mutation within each gene [10–12], more variation occurs between families with the same mutation. Therefore it is likely that a substantial proportion of the breast cancer risk in strong familial clusters with a BRCA1/2 mutation (the group of families that are usually seen by a Cancer Genetics Service), might be contributed to by modifier genes . Optimum clinical practice requires, that the cancer risks provided to families undergoing genetic testing are appropriate to the setting in which the mutation was detected. To determine the most appropriate risks for women attending clinical cancer genetics services we determined the cumulative risks of breast and ovarian cancer for 385 families with pathogenic BRCA1/2 mutations identified in North West and Central England covering a population of 10 million.
Index cases and relatives
Breast and ovarian cancer families have been tested for BRCA1/2 mutations (using a whole gene analysis including a test for large deletions) since 1996 in the overlapping regions of Manchester and Birmingham in mid-north England. All genetic testing is undertaken with informed consent and consent is also taken to confirm cancer diagnosis. The study was carried out with Local Ethical committee approval. Women who attend the specialist genetic clinics in these regions with a family history of breast/ovarian cancer have a detailed family tree elicited with all first, second and if possible third degree relatives recorded. If a BRCA1/2 mutation is identified, further extensive attempts are made to ensure that all individuals at risk of inheriting the family mutation are represented on the pedigree. All cases of breast or abdominal cancers are confirmed by means of hospital/pathology records, from the Regional Cancer Registries (data available from 1960) or from death certification. Once a family specific pathogenic BRCA1/2 mutation is identified predictive testing is offered to all blood relatives. Where possible all affected women with breast/ovarian cancer are tested to establish the true extent of BRCA1/2 involvement in the family. In many large families it is possible to establish "obligate" gene carriers by testing for the same mutation in different branches of the family, thereby establishing that intervening relatives carry the same mutation.
All female BRCA1/2 mutation carriers identified were included in this study, and their details, those of all tested relatives and first-degree untested female relatives were entered onto a Filemaker Pro 5 database. The initial individual in which a mutation was identified was designated the "index" case, with all other individuals being classified as to their position in the pedigree compared to a proven mutation carrier. All women reaching 20 years were entered if untested for a mutation. The exception was mothers of a mutation carrier when it was clear that the mutation was paternally inherited. 385 index cases were studied and from these extended pedigrees information on a total of 2466 females was collected. Information was entered on date of birth, date of last follow up, breast cancer status, ovarian cancer status, dates of diagnoses and date of death (if applicable), gene mutation carried in the family, their relationship to a known mutation carrier and their mutation status and date at which testing took place.
The proportions of unaffected first-degree relatives (FDRs) testing positive or negative was derived for each age cohort. Figures from this were used to estimate the proportion of untested relatives that were likely to test positive in each age group. The proportion of untested FDRs with breast or ovarian cancer that were likely to test positive was similarly estimated from testing that had taken place in each family. Penetrance analysis was performed by including all mutation positive individuals and appropriate numbers of untested FDRs on a proportional basis. Kaplan Meier curves were derived for breast and ovarian cancer incidence for each gene and by dividing each gene into the previously identified ovarian cancer cluster region (OCCR): exon 11 (nucleotides 2401–4190) for BRCA1 and exon 11 (nucleotides 3035–6629) for BRCA2. For BRCA1 we used the nucleotide range identified by the BCLC , although this is not traditionally called an OCCR it is the region published as having the greatest proportional risk of ovarian cancer. Individuals were censored at age of death, age of last follow up, age at appropriate cancer or age at appropriate risk reducing surgery (oophorectomy for ovarian cancer, mastectomy and oophorectomy for breast cancer). The Manchester scoring system was used to assess the strength of the breast/ovarian cancer history . This system was devised to assess the likelihood of a BRCA1/2 mutation and scores breast and ovarian cancers individually in the family, giving a higher score the younger the age at diagnosis . A combined score of 20 reflects a 20% likelihood of identifying a BRCA1/2 mutation.
Proportion of living unaffected FDR females undertaking presymptomatic predictive genetic testing by gene and age cohort.
Predictive test result By age
Number positive BRCA1
Number positive BRCA2
Proportion positive BRCA1 assumed
Proportion positive BRCA2 assumed
Proportion of predictive tests positive in unaffected FDR women >50 years of age by family Manchester score for each gene
Manch score predictives
Above or =
BRCA2 >50 (23)
BRCA2 >50 (20)
BRCA1 >50 (23)
BRCA1 >50 (20)
Penetrance for breast and ovarian cancer by age for BRCA1 and BRCA2.
Cancer risk to age
BRCA1 Breast (se)
BRCA2 Breast (se)
BRCA1 Ovary (se)
BRCA2 Ovary (se)
Survival analysis from birth, BRCA1 and BRCA2 combined for each birth cohort, index case excluded
% died from birth to age
<1900 (n = 45)
1900–1919 (n = 154)
1920–1929 (n = 154)
1930–1939 (n = 124)
1940–1949 (n = 158)
1950–1959 (n = 162)
1960+ (n = 276)
Breast and ovarian cancers occurring after the family was referred to the genetics centre.
Number of women
Years f/u (Breast ca)
Number of women
Years f/u (ovarian ca)
BRCA1 FDR unknown
BRCA1 Carriers less index
BRCA2 FDR unknown
BRCA2 Carriers less index
We present data on a large cohort of women identified as carriers or presumed carriers of BRCA1 and BRCA2 mutations in a large proportion of the UK population. The penetrance estimates derived from these women are very similar to those derived from the BCLC cohort of high-risk families with lifetime risks of breast cancer of close to 85% for both genes [3, 7, 8]. The estimate of ovarian cancer was also very similar with risks to 70 years of 60% for BRCA1 carriers and 33% as opposed to 27%  for BRCA2 carriers. It is possible that the higher overall breast cancer estimates for BRCA2 were related to competing mortality from ovarian cancer. Many risk factors for breast and ovarian cancer are similar (early menarche, late menopause, nulliparity) and women with these may have died from ovarian cancer before they developed breast cancer. This effect would be more prominent for BRCA1 and would potentially explain the higher breast cancer penetrance for BRCA2. The ratio of those testing positive:negative for the BRCA mutation whilst still unaffected also gives support to high penetrance. Of those women without an affected daughter, <10% of those aged over 60 years, tested positive for BRCA1 and <20% for BRCA2. The figures over 60 years are, nonetheless based on small numbers. The earlier drop in positive:negative ratio for BRCA1 almost certainly represents a higher combined risk of both breast and ovarian cancer to 50 and 60 years. Another supportive feature is shown in Table 2. The typical families tested in our centre have a Manchester score of 20+ reflecting multiple early onset breast and/or ovarian cancer in the family. The less "high" risk clusters as evidenced by lower Manchester scores had a higher proportion testing positive >50 years. This suggests that Manchester score could be used as a bench-mark to predict penetrance particularly in BRCA2 families. Whilst all attempts to assess penetrance have their inherent biases and assumptions this cannot be said of the results of presymptomatic testing. The only potential bias would be if women had an inkling that they would test positive or negative prior to coming forward. This is not borne out by our results particularly accounting for Manchester score.
The previously reported positional effect of mutations for both BRCA1 and BRCA2 is not borne out by our analysis. No substantial effect of increased risk of ovarian cancer was seen in the respective ovarian cluster regions of each gene and only a borderline significant reduction of breast cancer risk was seen for BRCA2. Much of the OCCR association has been based on ratios of breast to ovarian cancer  or on the presence or not of ovarian cancer in the family . Even this reliance on the presence of ovarian cancer for BRCA2 has been questioned by the report of 58% of BRCA2 related ovarian cancer families having mutations outside the OCCR . Although the BCLC study on BRCA1 positional effect  included 356 families compared to our 223 families no absolute estimate of penetrance was made. Whilst the breast cancer incidence was lower in the central portion of the gene (nucleotides 2401–4190) (RR 0.71) in their analysis it was not possible to derive absolute risk figures for each portion of the gene. Additionally it is likely that our more extensive testing of unaffected relatives may provide a more accurate overall picture as reported here. Accurate estimates of cancer risk are essential for families and individuals undertaking genetic testing. Based on our analysis, it is questionable whether any account should be taken of the OCCR in each gene or indeed any substantial positional effect in genetic counselling.
It is also clear that for individuals undertaking predictive genetic testing in the context of families ascertained from cancer genetic clinics as opposed to population testing that risk figures similar to those derived in our study or the BCLC is quoted in our own clinics and we recommend that penetrance estimates are derived for the population being counselled. Our data are nonetheless at variance to a similar analysis carried out in North America . A series of 1948 families were tested for mutations in BRCA1/2 in eight centres. 283 families with BRCA1 mutations were identified and 143 in BRCA2. The authors used statistical modelling to arrive at penetrance figures by 70 years of 46% (95%CI 39–54%) for BRCA1 and 43% (95%CI 36–51%) for BRCA2. The authors did not appear to take advantage of any further testing of relatives in the family. Whilst they corrected for potential ascertainment bias, they did not allow for the effects of modifier genes in these families and purely looked at attributable risk from BRCA1 and BRCA2 mutations alone. This was based on the apparent lack of heterogeneity in another study of Jewish families from North America . What is particularly concerning is the risk attributed to "non mutation carriers" to 70 years. A figure of 5% as a general population risk for breast cancer may have been correct 20–30 years ago, but is certainly not the risk faced by women in the US or the UK today. Breast cancer risk to age 70 is 7.6% in the UK  and nearer 8% in the US. A correction for this difference might give penetrance figures of nearer 74% for BRCA1 and 69% for BRCA2. The decision not to include any adjustment in these families for the effects of modifier genes is questionable. The difference in penetrance obtained from the BCLC and from population studies strongly suggests the presence of additional genetic factors in high-risk families. We have recently reported that those testing negative for a family BRCA mutation are still at 3-fold relative risk of breast cancer . This phenocopy effect was also seen in the Iceland data for their founder BRCA2 mutation, although to a lesser extent given the strong population based element of their analysis . However, it is possible that modifier genes are more prevalent in some populations and that penetrance in North America is less affected by modifier genes than in the UK. The presence of these modifier alleles is now indisputable from recent genome wide association studies [19–21].
A potential criticism of our study is that we have not taken enough account of ascertainment bias and that additional adjustment maybe necessary beyond excluding the index case. An analysis using these adjustments was carried out in the North American study  and recent reports from the Cambridge group . These studies did not take into account the widespread testing of relatives and as explained above the American study deliberately excluded any effect other than of the BRCA1/2 mutation. Whilst it is clearly interesting to know the effect of BRCA1/2 alone, women undergoing testing will want to know what their own specific risk of breast and ovarian cancer are, including that contributed by other potential "modifier" genes in their family. We must also acknowledge that confidence intervals in table 3 should also be wider due to forcing the data on unknown FDRs into a known category.
The high-risk women testing positive is also supported by the prospective part of our study. The 2–2.7% annual risk demonstrated is equivalent to the highest risk in a 10-year period (23% BRCA1; 30% BRCA2-Table 3). Although most of the breast cancers were detected by screening, only one was detected at a prevalence mammogram. These follow up risks are also supported by a similar follow up study in the Netherlands where 8 breast cancers occurred in 63 mutation carriers with a calculated annual risk of 2.5% .
Our own study and recent analyses from North America and Iceland demonstrate that women in the most recent birth cohort have a substantially higher risk of developing breast cancer than past cohorts [16, 18]. The incidence of breast cancer in BRCA2 carriers has risen 4 fold in 80 years in Iceland (as has breast cancer in the general population) and we have observed a similar increase from <10% risk by 40 years in those born before 1930 to a 40% risk on those born after 1960, although this was less significant after allowing for ascertainment bias. It is, therefore, inappropriate to quote risks as low as 43–46% (based on population studies) for lifetime breast cancer risk to women in their twenties or early thirties if they test positive for a mutation in a high-risk family. Another potential effect of earlier breast cancer might be a reduction in life expectancy. With increasing survival from birth in the general population and improved survival from diagnosis of breast cancer we might have expected to see improved life expectancy. However, it would appear that these elements almost completely cancel each other out and there is no evidence for improved survival from birth in modern BRCA birth cohorts.
When discussing the higher risks of breast cancer in recent generations, it is nonetheless important to couch any discussion on risk in terms of future prospects for risk reduction by preventive measures. Increasing numbers of women are opting for risk reducing surgery particularly early RRO, which will substantially reduce the risk of both breast and ovarian cancer . It is also likely that new treatments or substantial changes from the Western lifestyle may have a sufficient effect to help in risk management in the future.
We believe our results show that when counselling women on their risks of breast and ovarian cancer if they carry a family BRCA1/2 mutation the risks should reflect the context of cancer in their family and not just an average risk from possibly over-corrected penetrance estimates from population studies. Indeed a recent review in a prestige journal quoted "headline" risks for BRCA2 of only 40% and 8% for breast and ovarian cancer to 80 years . Understandably many clinicians and counsellors may quote these risks. The use of family cancer burden in adjusting risks to carriers is already used in the BOADICEA programme  and the Manchester score could also be used as a bench mark of where in the range of 40–90% breast cancer risk a women should be steered, especially for BRCA2.
We would like to thank The Genesis Appeal and The Breast Cancer Research Trust (BCRT) for their financial support for this work. We also dedicate this paper to Andrew Shenton who died tragically young on February 19th 2008.
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