Phenocopies in BRCA1 and BRCA2 families: evidence for modifier genes and implications for screening

A Smith; A Moran; M C Boyd; M Bulman; A Shenton; L Smith; R Iddenden; E R Woodward; F Lalloo; E R Maher; D G R Evans

doi:10.1136/jmg.2006.043091

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Phenocopies in BRCA1 and BRCA2 families: evidence for modifier genes and implications for screening

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Phenocopies in BRCA1 and BRCA2 families: evidence for modifier genes and implications for screening
D Gareth Evans
Published on: 27 April 2016
Phenocopies: actual risk or self-fulfilling prophecy?
Francois Eisinger
Published on: 27 April 2016
BRCA Phenocopies or Ascertainment Bias?
David E Goldgar
Published on: 27 April 2016
No screening yet after a negative test for the family mutation
Madeleine M Tilanus-Linthorst
Published on: 27 April 2016

Published on: 27 April 2016
Phenocopies in BRCA1 and BRCA2 families: evidence for modifier genes and implications for screening
- D Gareth Evans, Geneticist
- Other Contributors:
  Anthony Howell, and Eamon R. Maher
Dear Editor
We wish to reply to the interesting comments concerning our paper on phenocopies in families positive for mutations in BRCA1/2 genes since its e publication in October 2006 [1]. We understand the reservations about changing practice in reassuring individuals who test negative for a family mutation based on one largely retrospective analysis of families and clearly there is a need to confirm our results in other l...
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Dear Editor
We wish to reply to the interesting comments concerning our paper on phenocopies in families positive for mutations in BRCA1/2 genes since its e publication in October 2006 [1]. We understand the reservations about changing practice in reassuring individuals who test negative for a family mutation based on one largely retrospective analysis of families and clearly there is a need to confirm our results in other large series. We were particularly careful to obviate potential biases in our analyses. We would prefer that the interpretation of our article is based on the final detailed analysis of type A1 phenocopies which yielded a relative risk of three fold, equivalent to a doubling of lifetime risk. We would not suggest screening before 35 years for individuals in this category and certainly not as early as suggested in one response [2]. We agree that ultimately our study needs to be confirmed in prospective analysis, before widespread change in practice. However, we are convinced that two potential biases do not contribute substantially to our original figures [2-4]. We were also concerned that identification of families for mutation testing could be because of high-risk selection finds more families with chance breast cancers [2,3]. If this were the case the ratio of first- degree relatives (FDR) with breast cancer testing negative for the family mutation before family ascertainment should be higher than afterwards. We have carried out an analysis of our enhanced dataset now containing 52 breast cancer phenocopies. The ratio of phenocopies amongst FDR remains constant at 17% both before family ascertainment, after family ascertainment and after a mutation has been identified in the family. We also do not believe that extra mammography has made a substantial contribution [4]. The majority of phenocopy cancers were not detected by screening mammography and in particular after genetic testing women were discharged from extra mammographic surveillance which may have had the opposite effect by removing the lead time to diagnosis (if involved in screening there would be a delay to diagnosis if screening is stopped). More detailed analysis is under way in order to help determine which family structures are likely to contain phenocopies and where the extra risk pertains [3].
References
1. Smith A, Moran A, Boyd MC, Bulman M, Shenton A, Smith L, Iddenden I, Woodward E, Lalloo F, Rahman N, Maher ER, Evans DGR. The trouble with phenocopies: are those testing negative for a family BRCA1/2 mutation really at population risk? J Med Genet 2007; 44: 10-15
2. Tilanus-Linthorst M. No screening yet after a negative test for the family mutation. J Med Genet 2006 e
3. Goldgar D, Venne V, Conner T, Buys S BRCA Phenocopies or Ascertainment Bias? J Med Genet 2007e
4. Eisinger F. Phenocopies: actual risk or self-fulfilling prophecy? J Med Genet 2007e
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Conflict of Interest:
None declared.
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Published on: 27 April 2016
Phenocopies: actual risk or self-fulfilling prophecy?
- Francois Eisinger, Head Prevention and Screening Programs
Dear Editor
The contribution of Smith et al ¹ regarding the risk cancer in women who test negative for a known familial BRCA mutation is extremely valuable for both clinicians and researchers, and deserves critical attention. Indeed, not only the current NICE guidelines but most other statements on inherited risk for breast and ovarian cancer suggest reassurance for relatives found to be free of a familia...
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Dear Editor
The contribution of Smith et al ¹ regarding the risk cancer in women who test negative for a known familial BRCA mutation is extremely valuable for both clinicians and researchers, and deserves critical attention. Indeed, not only the current NICE guidelines but most other statements on inherited risk for breast and ovarian cancer suggest reassurance for relatives found to be free of a familial BRCA mutation. As Smith and colleagues point out, this reassurance might be false or misleading. However, the authors have neglected to consider one explanation for their findings.
Relatives of women with breast cancer undergone mammography screening more often and at an earlier age than women without such family history ^2-4. Currently there is substantial concern and controversy about over-diagnosis of breast cancer resulting from screening ^5-7. Moreover, this effect could be greater for women known to be from high-risk families, if their mammography studies are subjected to more cautious interpretation resulting in a higher rate of biopsy. Knowledge of risk could in this way create a self-fulfilling prophecy ⁸.
Could at least a part of the higher relative risk for breast cancer computed in the study of Smith et al ¹ be attributable to this phenomenon? Information about how cancer in the phenocopies was discovered (whether by screening or other means) and the size the tumors at diagnosis would help to evaluate this hypothesis
References:
1. Smith A, Moran A, Boyd MC, et al. Phenocopies in BRCA1 and BRCA2 families: evidence for modifier genes and implications for screening. J Med Genet 2007;44(1):10-15.
2.McCaul KD, Branstetter AD, Schroeder DM, et al. What is the relationship between breast cancer risk and mammography screening? A meta-analytic review. Health Psychol 1996;15(6):423-9.
3. Katapodi MC, Lee KA, Facione NC, et al. Predictors of perceived breast cancer risk and the relation between perceived risk and breast cancer screening: a meta-analytic review. Prev Med 2004;38(4):388-402.
4. Eisinger F, Tarpin C, Huiart L, et al. Behavioral and Economic Impact of a Familial History of Cancers. Fam Cancer 2005;4(4):307-311.
5. Zahl PH, Andersen JM, Maehlen J. Spontaneous regression of cancerous tumors detected by mammography screening. Jama 2004;292(21):2579-80; author reply 2580.
6. Moller H, Davies E. Over-diagnosis in breast cancer screening. Bmj 2006;332(7543):691-2.
7. Zackrisson S, Andersson I, Janzon L, et al. Rate of over-diagnosis of breast cancer 15 years after end of Malmo mammographic screening trial: follow-up study. Bmj 2006;332(7543):689-92.
8. Merton RK. The self fulfilling prophecy. Antioch review 1948;8(Summer):193-210.
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Conflict of Interest:
None declared.
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Published on: 27 April 2016
BRCA Phenocopies or Ascertainment Bias?
- David E Goldgar, Professor
- Other Contributors:
  Saundra Buys, Vickie Venne, Tom Conner
Dear Editor:
In a recent issue of the Journal of Medical Genetics, Smith et al ⁽¹⁾ report a significantly elevated risk of breast cancer among non-carriers in breast cancer families in which a BRCA1 or BRCA2 mutation had been identified through clinical testing. The authors found an elevated risk of approximately 5-fold, which, if true, has considerable impact on the counseling and clinical management of wom...
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Dear Editor:
In a recent issue of the Journal of Medical Genetics, Smith et al ⁽¹⁾ report a significantly elevated risk of breast cancer among non-carriers in breast cancer families in which a BRCA1 or BRCA2 mutation had been identified through clinical testing. The authors found an elevated risk of approximately 5-fold, which, if true, has considerable impact on the counseling and clinical management of women testing negative for the mutations found in their family.
Until the study of Smith et al ⁽¹⁾, the excess of cases observed among such non-carriers had been noted only anecdotally by many in both the clinical and research settings. In this respect, the systematic study of Smith et al ⁽¹⁾ was a welcome confirmation of these anecdotal observations. However, there are a number of methodological flaws in the analysis of Smith et al⁽¹⁾ that render their results difficult to interpret. This stems from the fact that the families used in the analysis are not randomly sampled from the population of all potential families with a mutation, but rather must meet certain eligibility criteria for genetic testing. Further, the decision to attend a specialty oncogenetics clinic very likely depends on the family history of the individual deciding to undergo testing; the more relatives affected with breast cancer (especially diagnosed at an early age), the more likely one is to seek genetic counseling/testing. This selection of families, whether through self-selection on family history for attending such clinics and/or through eligibility criteria for genetic testing after evaluation of family history, will result in a bias due to under-representation of families with many unaffected individuals. This bias applies to both mutation carriers and non-carriers, resulting in overestimation of both the penetrance and the phenocopy rate. Although one can correct for this ascertainment bias in estimating the penetrance in carriers through conditioning on the phenotypes in the pedigree and proband genotype ^{2, 3} it is not as clear how the ascertainment issue can be properly accounted for in estimating the relative risk of disease in non-carriers.
To examine the potential magnitude of this bias, we performed the following simulation experiment. Nuclear families consisting of two parents and six offspring were simulated under a variety of phenocopy rates and penetrance values for a rare autosomal dominant disease. Each family was simulated conditional on a single affected individual who was a (heterozygous) carrier of the disease allele. This reflects the typical situation in which an affected individual is tested and found to carry the mutation and then other family members are tested for the specific mutation identified in the index case. The phenotypes (affected/healthy) and carrier status (+/-) of the other individuals in the family were simulated using the SLINK program(4). For each set of phenocopy and penetrance values, 5000 such families were simulated in this fashion. Families were then selected for analysis according to the following ascertainment schemes:
1) No selection - all 5000 families included in analysis;
2) The probability of a family being selected in the analysis sample is linearly related to the total (including the proband) number of affected with the probabilities for 1,2,3,4,and 5+ affected given by 0.0, 0.1, 0.2, 0.3, and 0.4, respectively;
3) The probability of selection in the analysis sample is more strongly related to the number of affected, with probabilities of 0.0, 0.1, 0.3, 0.6, 1.0;
4) Only families with at least two total affected (i.e., the proband and at least one other) are included;
5) Only families with at least three total affected are included.
The results of these simulations are presented in table 1 below.
From the table it is evident that the bias in the estimate of the rate of disease in non-carriers is strongly related to the disease risk in carriers than either the phenocopy rate or the penetrance in carriers. Though this may seem counterintuitive, the lower overall rate of disease in the families increases the effect of the ascertainment/selection. For example, in the case portrayed in line 2 above, if we select only families with at least 3 total affected individuals, this eliminates all but 263 families from consideration; of these 263 families, 49 (19%) contain at least one 'phenocopy'. In contrast, if we increase the penetrance to 0.5 and leave the phenocopy rate the same, 2900 families are included after selection on 3 affecteds, of which 157 (6%) have at least one phenocopy.
To better examine the specific BRCA testing situation as analyzed by Smith et al., we performed additional simulations using an assumed penetrance model derived from the combined analysis of 22 studies of families of probands unselected for family history of Antoniou et al.⁵ Risks were averaged over estimates for BRCA1 and BRCA2, yielding cumulative risks of breast cancer in BRCA mutation carriers of 0.10 before age 40, 0.30 before age 50, 0.44 before age 60, 0.56 before age 70 and 0.65 until age 80. Corresponding rates in non-carriers were 0.0002, 0.002, 0.02, 0.04, and 0.06. In this case the phenotypes of the father and two male offspring were fixed as unaffected, the mother was assumed to be age 65 with four daughters ages 35 (proband),35,45, and 45. A total of 10,000 such families were simulated under this model and pedigree structure.
When all 10,000 simulated families were included in the dataset the calculated rate of disease in non-carriers was 0.0106, very close to the predicted value of 0.01105 based on the age distribution of the women in the pedigree and the risks specified above. For the linear, non-linear, 2+ and 3+ ascertainment schemes the estimated relative risks compared to no selection were 2.76, 3.14, 2.29, and 4.74 respectively. Although we cannot know precisely which of the ascertainment models employed best fits the clinical situation used to produce the data and corresponding estimate in Smith et al ⁽¹⁾, it seems certain that their estimate is on the order of two- to three-fold too high as a result of ascertainment bias. It is noteworthy that the limited prospective data presented by Smith et al⁽¹⁾ found an SIR of 2.1 (though confidence intervals were wide) which would correspond well with our estimates of the magnitude of ascertainment bias. We note that in all of the pedigrees simulated as described in the preceding paragraphs, all the phenocopies observed would correspond to type A1 phenocopies as defined by Smith et al ⁽¹⁾ in their supplementary information.
Our analyses taken together with the results of Smith et al ⁽¹⁾ still imply that women found to be non-carriers in BRCA positive families are at perhaps twice the population risk of breast cancer, presumably due to the effects of modifier genes or correlated environmental factors. If the latter, these factors such as parity, oral contraceptive use, menopausal status etc. can be adjusted for to produce individualized risk for such women. If, on the other hand, the aggregation is the result of unknown modifier loci, this cannot be done. As such loci are identified, both carrier and non-carrier women can be given better estimates of their risk.
In practical terms, there is a major difference between a two-fold and a five-fold increase in breast cancer risk. Doubling the risk is the approximately the numerical equivalent of having a first-degree relative with post-menopausal breast cancer, which leads neither to altered screening recommendations nor generally to a recommendation for chemoprevention. A five-fold risk, on the other hand, would lead to consideration of chemoprevention in virtually all female mutation-negative first degree relatives of mutation carriers. For example the 5-year risk for breast cancer of a 35 year old with menarche at 11 and first live birth at 28, without prior biopsy and without a family history, is 0.4% when calculated by the Gail ⁶ model. A 5-fold increase in risk would make this otherwise low-risk woman a clear candidate for chemoprevention with its associated potential toxicities. Mammographic screening and possibly even MRI would also be considered in a woman with a risk of this magnitude, with the attendant expense and high risk of false positive screens.
As Smith et al ⁽¹⁾ point out, the question of whether non-carriers in families with at least one individual testing positive for a BRCA1 or BRCA2 mutation are at elevated risk, and if so, the magnitude of this risk, can only be answered conclusively through prospective follow-up of women unaffected at the time of genetic testing. We agree with this and note that several large prospective studies of BRCA1/2 families are currently ongoing. Until the results of these studies are known, we believe that it would be premature to recommend additional screening or chemoprevention for unaffected women who test negative for the BRCA mutation segregating in their family, other than that recommended for women in their age group in the general population.
David Goldgar+, PhD Vickie Venne, MS, GC Tom Conner, BS, RN Saundra Buys, MD
High-Risk Breast Cancer Clinic Huntsman Cancer Institute (VV,TC,SB) and Department of Dermatology (DG) University of Utah
Correspondence to: David E. Goldgar
e-mail:david.goldgar@hsc.utah.edu
References:
1. Smith A, Moran A, Boyd MC, Bulman M, Shenton A, Smith L, Iddenden R, Woodward ER, Lalloo F, Maher ER, Evans DGR: Phenocopies in BRCA1 and BRCA2 families: evidence for modifier genes and implications for screening. J Med Genet 2006.
2. Easton DF, Bishop DT, Ford D, Crockford GP. Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. The Breast Cancer Linkage Consortium. Am J Hum Genet. 1993 Apr;52(4):678- 701. [PubMed]
3. Ford D, Easton DF, Stratton M, Narod S, Goldgar D, Devilee P, Bishop DT, Weber B, Lenoir G, Chang-Claude J, Sobol H, Teare MD, Struewing J, Arason A, Scherneck S, Peto J, Rebbeck TR, Tonin P, Neuhausen S, Barkardottir R, Eyfjor J, Lynch H, Ponder BA, Gayther SA, Zelada-Hedman M, et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium.Am J Hum Genet. 1998 Mar;62(3):676-89.
4. Weeks DE, Ott J, Lathrop GM. SLINK: a general simulation program for linkage analysis. Am J Hum Genet 47: 1990.
5. Antoniou, A., P. D. Pharoah, et al. (2003). Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 72(5): 1117-30.
6. Gail MH, Brinton LA, Byar DP, Corle DK, Green SB, Schairer C, et al. Projecting individual probabilities of developing breast cancer for white females who are being evaluated annually. J Natl Cancer Inst 1989;81:1879-86.
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Conflict of Interest:
None declared.
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Published on: 27 April 2016
No screening yet after a negative test for the family mutation
- Madeleine M Tilanus-Linthorst, physician
Dear Editor
In their interesting paper (1) A. Smith and colleagues postulate, that after a negative test for BRCA1 and BRCA2 women are still at increased risk. They therefore recommend to continue screening. There are several reasons why surveillance recommendations, after a negative test for the family mutation, are premature I think.
1. It should be clear how high the rest risk is: This is not really cl...
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Dear Editor
In their interesting paper (1) A. Smith and colleagues postulate, that after a negative test for BRCA1 and BRCA2 women are still at increased risk. They therefore recommend to continue screening. There are several reasons why surveillance recommendations, after a negative test for the family mutation, are premature I think.
1. It should be clear how high the rest risk is: This is not really clear from this paper as DNA-testing bias of breast cancer cases has played a part. When testing first degree relatives of a BRCA1/2 mutation carrier one would expect about 50% to test positive. However table 1 shows that 67% (376/ 560) tested positive. This strongly suggests preferential testing of breast cancer cases which will certainly also increase the percentage breast cancers in the negative tested group, without any modifying genetic factor. We have previously shown that such a DNA testing bias can wrongfully suggest increased risks in non-BRCA1/2 patients (2,3). To exclude this bias one should only take the cancer incidence after the DNA test into account.
2. In order to recommend screening one should know at which age the possible rest risk may be expected. Certainly one shouldn’t continue screening from age 25-30 onwards like in carriers if the increased risk possibly occurs mainly above age 50. Screening with mammography at age 25- 40 yrs. has too low a sensitivity, may cause too many false-positive results and possibly induce breast cancer, so is not justified for only slightly increased risk (4).
3. As the results came from families with a high caseload, one does not know whether such modifying genes will be present in BRCA1/ BRCA2 families with fewer cancers.
When many breast and ovarian cases test negative for the family mutation, a second gene mutation or risk from the untested side of the family may need to be investigated.
References: 1. Phenocopies in BRCA1 and BRCA2 families: evidence for modifier genes and implications for screening. A Smith, A Moran, MC Boyd, Bulman M, Shenton A, Smith L et al. JMed Genet 2006:doi:10.1136/jmg.2006.043091
2. Selection bias influences reported contralateral breast cancer incidence and survival in high risk non-BRCA1/BRCA2 patients. Tilanus-Linthorst MMA, Bartels K, Alves C, Bakri B, Crepin E, van den Ouweland A et al. Breast Ca Res Treat 2006;95(2):117-23.
3. Contralateral recurrence and prognostic factors in familial non-BRCA1/2 associated breast cancer. Tilanus-Linthorst MMA, Alves C, Seynaeve C, Menke-Pluymers MBE, Eggermont AMM and Brekelmans CTM. Br J Surg 2006; 93 (8):961-968.
4. Griebsch I, Brown J, Dixon A, Dixon M, Easton D, Eeles R et al. Cost-effectiveness of screening with contrast enhanced magnetic resonance imaging vs. X-ray mammography of women at a high familial risk of breast cancer. Br J Cancer. 2006 Oct 9;95(7):801-10.
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Conflict of Interest:
None declared.
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