Prevalence and Penetrance of BRCA1 and BRCA2 Gene Mutations in Unselected Ashkenazi Jewish Women With Breast Cancer

Warner, Ellen; Foulkes, William D.; Goodwin, Pamela J.; Meschino, Wendy S.; Blondal, John; Paterson, Colleen; Özçelik, Hilmi; Goss, Paul E.; Allingham-Hawkins, Diane; Hamel, Nancy; Prospero, Lisa Di; Contiga, Velita; Serruya, Corinne; Klein, Meri; Moslehi, Roxana; Honeyford, Joanne; Liede, Alexander; Glendon, Gordon; Brunet, Jean‐Sébastien; Narod, Steven A.

doi:10.1093/jnci/91.14.1241

Cited by 354 publications

(208 citation statements)

References 26 publications

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“…Jewish women are at high risk from disease caused by major mutations. Although the risk to a woman from a Jewish multiplex family (Egan et al, 1996) or a Jewish family with a BRCA1/2 mutation (Fodor et al, 1998) is increased by a factor of 3 -4, and although Jewish women are also at higher risk from additional breast cancer risk factors (Swift et al, 1987), we found that a Jewish MZ co-twin's risk of becoming affected was increased only marginally more than that to Jewish women generally (Mack et al, 1985;Warner et al, 1999). Even among multiplex Jewish families with early cases, we could identify only a few with BRCA1/2 mutations.…”

Section: Discussionmentioning

confidence: 53%

Heritable breast cancer in twins

et al. 2002

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Known major mutations such as BRCA1/2 and TP53 only cause a small proportion of heritable breast cancers. Co-dominant genes of lower penetrance that regulate hormones have been thought responsible for most others. Incident breast cancer cases in the identical (monozygotic) twins of representative cases reflect the entire range of pertinent alleles, whether acting singly or in combination. Having reported the rate in twins and other relatives of cases to be high and nearly constant over age, we now examine the descriptive and histological characteristics of the concordant and discordant breast cancers occurring in 2310 affected pairs of monozygotic and fraternal (dizygotic) twins in relation to conventional expectations and hypotheses. Like other first-degree relatives, dizygotic co-twins of breast cancer cases are at higher than usual risk (standardised incidence ratio (SIR)=1.7, CI=1.1 -2.6), but the additional cases among monozygotic co-twins of cases are much more numerous, both before and after menopause (SIR=4.4, CI=3.6 -5.6), than the 100% genetic identity would predict. Monozygotic co-twin diagnoses following early proband cancers also occur more rapidly than expected (within 5 years, SIR=20.0, CI=7.5 -53.3). Cases in concordant pairs represent heritable disease and are significantly more likely to be oestrogen receptor-positive than those of comparable age from discordant pairs. The increase in risk to the monozygotic co-twins of cases cannot be attributed to the common environment, to factors that cumulate with age, or to any aggregate of single autosomal dominant mutations. The genotype more plausibly consists of multiple co-existing susceptibility alleles acting through heightened susceptibility to hormones and/or defective tumour suppression. The resultant class of disease accounts for a larger proportion of all breast cancers than previously thought, with a rather high overall penetrance. Some of the biological characteristics differ from those of breast cancer generally.

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Section: Discussionmentioning

confidence: 53%

Heritable breast cancer in twins

et al. 2002

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“…It demonstrated that BRCA2 mutation carriers have a relative risk (RR) of PRCA of 4.65 rising to 7.33 below the age of 65 years and BRCA1 mutation carriers have an RR of PRCA of 1.82 under the age of 65 years (BCLC, 1999; Thompson et al, 2002). Similar data have been recorded in the AJ population (Struewing et al, 1997;Warner et al, 1999;Giusti et al, 2003), although smaller clinical studies have generally not demonstrated an increased frequency of founder BRCA1/2 mutations among Jewish men with PRCA (Lehrer et al, 1998;Hubert et al, 1999;Nastiuk et al, 1999;Vazina et al, 2000). In the current data set, six men were identified from a previous study conducted at The Institute of Cancer Research, as described in the Materials and Methods section.…”

Section: Discussionmentioning

confidence: 54%

Prostate cancer in male BRCA1 and BRCA2 mutation carriers has a more aggressive phenotype

et al. 2008

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There is a high and rising prevalence of prostate cancer (PRCA) within the male population of the United Kingdom. Although the relative risk of PRCA is higher in male BRCA2 and BRCA1 mutation carriers, the histological characteristics of this malignancy in these groups have not been clearly defined. We present the histopathological findings in the first UK series of BRCA1 and BRCA2 mutation carriers with PRCA. The archived histopathological tissue sections of 20 BRCA1/2 mutation carriers with PRCA were collected from histopathology laboratories in England, Ireland and Scotland. The cases were matched to a control group by age, stage and serum PSA level of PRCA cases diagnosed in the general population. Following histopathological evaluation and re-grading according to current conventional criteria, Gleason scores of PRCA developed by BRCA1/2 mutation carriers were identified to be significantly higher (Gleason scores 8, 9 or 10, P ¼ 0.012) than those in the control group. Since BRCA1/2 mutation carrier status is associated with more aggressive disease, it is a prognostic factor for PRCA outcome. Targeting screening to this population may detect disease at an earlier clinical stage which may therefore be beneficial. British Journal of Cancer (2008) Prostate cancer (PRCA) is the most commonly diagnosed malignancy in men in the United Kingdom. It is thought to be composed of aggressive and indolent varieties. Indolent PRCA may exist for many years without causing symptoms or shortening life expectancy. Aggressive PRCA may cause symptoms difficult to palliate with conventional treatments and is likely to shorten life expectancy. Distinguishing which men are at risk of which types of disease could have far-reaching consequences not only in the treatment and follow-up of patients but also in the surveillance of groups at risk of aggressive PRCA.The morphology of breast cancer found in female BRCA1 and BRCA2 germline mutation carriers has been studied extensively. The histopathological features of breast tumours from patients with BRCA1 and BRCA2 mutations differ from each other and from sporadic breast cancers . BRCA1 and BRCA2 breast cancers are of higher grade (Lakhani, 2001). BRCA1-associated tumours are more likely to be oestrogen, progesterone receptor and Her2 receptor negative, express TP53 protein, and demonstrate medullary/atypical medullary morphology. Lakhani (2001) predicts that a woman diagnosed with high-grade, oestrogen receptor-negative breast cancer before the age of 30 years has a 40-45% chance of harbouring a BRCA1 mutation, compared with a 4-5% chance if these parameters are not met (Lakhani, 2001). Many of the features identified in breast cancer in women who are BRCA1 mutation carriers are associated with a poor prognosis. If similar data were available for men with PRCA who are carriers of these mutations, weighing up the options for radical treatment or active surveillance could be simplified with this added information.Despite studies on the incidence of PRCA in male BRCA1 and BRCA2 mutation...

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“…Studies of breast cancer patients have indicated that it may be difficult to define mutation screening criteria among women with minimal or no family history (Malone et al, 1998). Furthermore, the carrier risks associated with the mutations may be highly variable, and population-based risk estimates have indicated much lower cancer risks than those obtained from multiplecase families and, therefore, lower predictive value of cancer for a positive mutation test result (Struewing et al, 1997;Fodor et al, 1998;Thorlacius et al, 1998;Warner et al, 1999). Accordingly, genetic screening would be of greatest benefit in families with high cancer risk, i.e.…”

Section: Discussionmentioning

confidence: 99%

A probability model for predicting BRCA1 and BRCA2 mutations in breast and breast-ovarian cancer families

et al. 2001

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Mutations in the two breast-ovarian cancer susceptibility genes, BRCA1 and BRCA2, account for a varying fraction of breast cancer families in different populations (Szabo and King, 1997). Both BRCA1 and BRCA2 mutations are scattered throughout the large coding regions of the genes (Breast Cancer Information Core). In admixed populations, most mutations appear uniquely in single families only, making the mutation screening laborious and expensive. Furthermore, there is also evidence of other predisposing genes (Ford et al, 1998;Kainu et al, 2000). It is, therefore, important to find the clinical risk factors that could best predict the presence of BRCA1 and BRCA2 mutations, so that the screening could be directed to potential mutation carrier families. Several probability models for mutation detection have been developed. These are, however, based only on BRCA1 (Berry et al, 1997;Couch et al, 1997;Shattuck-Eidens et al, 1997), focus on specific founder mutations in the Ashkenazi population (Foulkers et al, 1999;Hodgson et al, 1999;Hopper and Jenkins, 1999), or require information such as penetrance estimations not available in all populations (Berry et al, 1997;Parmigiani et al, 1998; ChangClaude et al, 1999).Here we have developed a model for predicting the presence of a BRCA1 or BRCA2 mutation in families with 3 or more relatives affected with breast or ovarian cancer. We also compared this model with those of Shattuck-Eidens et al (1997) and Couch et al (1997) originally designed for BRCA1 only. Additionally, the frequency of BRCA1/2 mutations was studied in 295 families with two affected family members to evaluate the feasibility of genetic screening in families with moderate family history. PATIENTS AND METHODSThe cohort studied consisted of 148 families with 3 or more 1st or 2nd degree relatives affected with breast or ovarian cancer. The families were identified by patient interviews, and full pedigrees were constructed with the confirmation of all genealogy data through the Finnish population registration as well as diagnostic data through hospital records and/or Finnish Cancer Registry as previously described (Vehmanen et al, 1997a,b;Eerola et al, 2000). Additionally, 295 breast cancer cases with one 1st degree relative affected with breast or ovarian cancer and identified in the patient cohorts described in Eerola et al (2000) were also studied. In the following, these are called small families. The family history of these cases was based on information reported by the index patient. All patients participating in the study signed an informed consent before the blood sample for the genetic analysis was taken. This study has been approved by the Ethical Committees of Departments of Obstetrics and Gynaecology, and Oncology, HUCH, and appropriate permissions were obtained from the Ministry of Social Affairs and Health in Finland.The mutations identified by a complete mutation analysis of the whole coding sequences and exon/intron boundaries of the genes in 95 of these families have been previously reported...

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Prevalence and Penetrance of BRCA1 and BRCA2 Gene Mutations in Unselected Ashkenazi Jewish Women With Breast Cancer

Cited by 354 publications

References 26 publications

Heritable breast cancer in twins

Heritable breast cancer in twins

Prostate cancer in male BRCA1 and BRCA2 mutation carriers has a more aggressive phenotype

A probability model for predicting BRCA1 and BRCA2 mutations in breast and breast-ovarian cancer families

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