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

Smith, Amanda D.; Moran, Anthony; Boyd, Marie; Bulman, Michael P.; Shenton, Andrew; Smith, Letitia; Iddenden, R; Woodward, Emma R.; Lalloo, Fiona; Maher, Eamonn R.; Evans, D. Gareth

doi:10.1136/jmg.2006.043091

Cited by 99 publications

(88 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…6 Modifiers in BRCA1 and BRCA2 mutation carriers There have been several observations supporting the hypothesis that breast cancer risk in BRCA1 and BRCA2 mutation carriers is modified by genetic factors. 61 Taking into account that women tested negative for their familial BRCA1/BRCA2 mutations still face an increased breast cancer risk, 62 one can speculate that this increased risk might be due to inherited genetic variants that act as modifier genes in BRCA1/BRCA2 mutation carriers, and also as low penetrance susceptibility polymorphisms in BRCA1/BRCA2 mutation non-carriers. Currently, vast efforts are being made to identify modifier genes in BRCA1 or BRCA2 mutation carriers (see eg, the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA)).…”

Section: Common Low-penetrance Breast Cancer Susceptibility Snpsmentioning

confidence: 99%

Breast cancer susceptibility: current knowledge and implications for genetic counselling

et al. 2008

View full text Add to dashboard Cite

Breast cancer is the most common malignancy in women in the Western world. Except for the high breast cancer risk in BRCA1 and BRCA2 mutation carriers as well as the risk for breast cancer in certain rare syndromes caused by mutations in TP53, STK11, PTEN, CDH1, NF1 or NBN, familial clustering of breast cancer remains largely unexplained. Despite significant efforts, BRCA3 could not be identified, but several reports have recently been published on genes involved in DNA repair and single nucleotide polymorphisms (SNPs) associated with an increased breast cancer risk. Although candidate gene approaches demonstrated moderately increased breast cancer risks for rare mutations in genes involved in DNA repair (ATM, CHEK2, BRIP1, PALB2 and RAD50), genome-wide association studies identified several SNPs as low-penetrance breast cancer susceptibility polymorphisms within genes as well as in chromosomal loci with no known genes (FGFR2, TOX3, LSP1, MAP3K1, TGFB1, 2q35 and 8q). Some of these low-penetrance breast cancer susceptibility polymorphisms also act as modifier genes in BRCA1/BRCA2 mutation carriers. This review not only outlines the recent key developments and potential clinical benefit for preventive management and therapy but also discusses the current limitations of genetic testing of variants associated with intermediate and low breast cancer risk.

show abstract

Section: Common Low-penetrance Breast Cancer Susceptibility Snpsmentioning

confidence: 99%

Breast cancer susceptibility: current knowledge and implications for genetic counselling

et al. 2008

View full text Add to dashboard Cite

show abstract

“…As mentioned previously, it has been assumed that mutation negative-relatives of carriers of cancer susceptibility genes might show an increased risk of cancer due to the influence of modifier genes and environmental factors, which makes these families prone to develop cancer and therefore more likely to be screened for mutations involved in cancer susceptibility genes [25,29]. However, in our cohort, we could only establish a relationship between oral contraceptive use and cancer risk in mutation-negative females.…”

Section: Modifying Factors In Cancer Susceptibility Syndromesmentioning

confidence: 86%

“…A recent study on mutation-negative first degree family members of BRCA-mutation carriers, showed them to be at an elevated risk for breast cancer when compared to the general population, suggesting an important influence of environmental and/or genetic modifying factors in mutation carriers and non carriers [29]. In order to test whether the previously listed environmental factors were of particular importance in mutation-negative females, we assessed their influence on cancer risk in mutation-negative female relatives of the hMLH1 c.C1528T mutation carriers.…”

Section: Introductionmentioning

confidence: 99%

Lynch syndrome: the influence of environmental factors on extracolonic cancer risk in hMLH1 c.C1528T mutation carriers and their mutation-negative sisters

et al. 2010

View full text Add to dashboard Cite

Lynch Syndrome (LS) is a cancer susceptibility syndrome caused mostly by mutations in the mismatch repair genes, hMLH1, hMSH2 and hMSH6. Mutation carriers are at risk of colorectal and endometrial cancer and, less frequently, cancer of the ovaries, stomach, small bowel, hepatobiliary tract, ureter, renal pelvis and brain. The influence of environmental factors on extracolonic cancer risk in LS patients has not been investigated thus far. The aim of this study was to investigate some of these factors in South African females carrying the hMLH1 c.C1528T mutation and their mutation-negative relatives. Data were collected from 87 mutation-positive females and 121 mutation-negative female relatives regarding age, cancer history, hormonal contraceptive use, parity, duration of breast feeding, height, weight and age at first birth, last birth, menarche and menopause. Influence of these factors on cancer risk was analysed by mixed-effects generalised linear models. Extracolonic cancer occurred in 14% (12/ 87) of mutation-positive females versus 7% (8/121) of mutation-negative females, (P = 0.0279, adjusted for age and relatedness between women). Breast cancer was the most common extracolonic cancer. An association was found for oral contraceptive use and extracolonic cancer risk in mutation-negative females only. No association was found for any of the other risk factors investigated, when adjusted for age. This might be due to the scarcity of extracolonic cancers in our data. Future knowledge on the influence of additional environmental factors on cancer risk in LS females can lead to evidence-based lifestyle advice for mutation carriers, thereby complementing the prevention strategies available today. In addition, it can contribute to an integrated model of cancer aetiology. Therefore, this study should be taken as a thrust for further research.

show abstract

“…Although testing negative for a family-specific mutation, it appears that some women may still be at increased risk of breast cancer if there are multiple members of the family with mutation-related breast cancer, particularly if they were detected at young ages (4,5). It is likely that these families are enriched for genetic modifiers that may increase the penetrance in both BRCA1 and BRCA2 mutations carriers and noncarriers (6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

“…However, a proportion of women in families with an identified mutation will develop breast cancer despite testing negative for the familial mutation (4). These women are considered to be phenocopies and raise difficult counseling issues in terms of determining the personal risks of breast and ovarian cancer and how to explain the issues.…”

Section: Introductionmentioning

confidence: 99%

Increased Rate of Phenocopies in All Age Groups in BRCA1/BRCA2 Mutation Kindred, but Increased Prospective Breast Cancer Risk Is Confined to BRCA2 Mutation Carriers

Evans

Ingham

Buchan

et al. 2013

Cancer Epidemiology, Biomarkers &Amp; Prevention

View full text Add to dashboard Cite

Background: To establish, if among unaffected noncarrier relatives in a family with an established BRCA1/2 mutation, there is an increased risk of breast cancer.Methods: We identified 49 women with breast cancer who were first-degree relatives of a pathogenic mutation carrier among 807 BRCA1/2 families but who tested negative for the specific mutation. A prospective analysis of breast cancer from date of family ascertainment was performed for first-degree relatives of proven BRCA1/2 mutation carriers and compared with population-expected incidence rates.Results: Women who prospectively test negative for BRCA1/2 mutations showed excess risk of breast cancer to be confined to BRCA2 noncarriers with an observed:expected (O/E) ratio of 4.57 [95% confidence interval (CI) 2.50-7.67; P < 0.0001; O/E in BRCA1 noncarriers, 1.77]; this dropped to 2.01 for BRCA2 [relative risk (RR), 1.99; 95% CI, 0.54-5.10] from date of predictive test. Genotyping of 18 breast cancer susceptibility singlenucleotide polymorphisms (SNP) defined an RR of 1.31 for BRCA2 breast cancer phenocopies with a breast cancer diagnosis at age less than 60 years.Conclusion: Noncarriers remain at risk in the prospective follow-up of women who tested negative for BRCA1/2. Women testing negative in BRCA2 families may have increased risk of breast cancer compared with population levels, particularly with strong breast cancer history in close relatives. Any increased risk in BRCA1 families is likely to be insufficient to recommend additional interventions.Impact: Our work can help with counseling women from BRCA1/2 families who have tested negative, and could impact on how individual breast cancer risk is related back to these women. Cancer Epidemiol Biomarkers Prev; 22(12); 2269-76. Ó2013 AACR.

show abstract

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

Cited by 99 publications

References 38 publications

Breast cancer susceptibility: current knowledge and implications for genetic counselling

Breast cancer susceptibility: current knowledge and implications for genetic counselling

Lynch syndrome: the influence of environmental factors on extracolonic cancer risk in hMLH1 c.C1528T mutation carriers and their mutation-negative sisters

Increased Rate of Phenocopies in All Age Groups in BRCA1/BRCA2 Mutation Kindred, but Increased Prospective Breast Cancer Risk Is Confined to BRCA2 Mutation Carriers

Contact Info

Product

Resources

About