An international initiative to identify genetic modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers: the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA)

Queensland Institute for Medical Research, Brisbane, Australia.
Breast cancer research: BCR (Impact Factor: 5.88). 02/2007; 9(2):104. DOI: 10.1186/bcr1670
Source: PubMed

ABSTRACT BRCA1 and BRCA2 mutations exhibit variable penetrance that is likely to be accounted for, in part, by other genetic factors among carriers. However, studies aimed at identifying these factors have been limited in size and statistical power, and have yet to identify any convincingly validated modifiers of the BRCA1 and BRCA2 phenotype. To generate sufficient statistical power to identify modifier genes, the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) has been established. CIMBA contains about 30 affiliated groups who together have collected DNA and clinical data from approximately 10,000 BRCA1 and 5,000 BRCA2 mutation carriers. Initial efforts by CIMBA to identify modifiers of breast cancer risk for BRCA1 and BRCA2 mutation carriers have focused on validation of common genetic variants previously associated with risk in smaller studies of carriers or unselected breast cancers. Future studies will involve replication of findings from pathway-based and genome-wide association studies in both unselected and familial breast cancer. The identification of genetic modifiers of breast cancer risk for BRCA1 and BRCA2 mutation carriers will lead to an improved understanding of breast cancer and may prove useful for the determination of individualized risk of cancer amongst carriers.

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    ABSTRACT: The AURORA-A/BTAK/STK15 gene encodes a centrosome-associated kinase that causes centrosome amplification, failure of cytokinesis, and aneuploidy when amplified and/or overexpressed in breast tumors. A number of gene association studies using matching breast cancer cases and controls have shown that the F31I polymorphism in STK15 increases risk of breast. We hypothesized that the F31I polymorphism is associated with increased risk of breast cancer in BRCA1 and BRCA2 mutation carriers. Using over 7,000 carriers of BRCA1 and BRCA2 deleterious mutations we showed that F31I has no influence on breast cancer risk. In parallel, we completed an association study of 2400 polymorphisms in other cell division regulatory genes in 800 breast cancer cases and 800 controls collected at the Mayo Clinic. A total of 52 of these polymorphisms along with 332 other polymorphisms displaying associations with breast cancer risk were evaluated for associations with breast cancer risk in approximately 5,400 BRCA1 and BRCA2 mutation carriers. Several polymorphisms displaying significant associations (p<10-4) with risk of breast cancer in BRCA2 mutation carriers were observed.
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    ABSTRACT: Genome-wide association studies (GWAS) provide a powerful method for the identification of commonly inherited, low penetrance susceptibility loci for many diseases, including breast cancer. This approach takes advantage of the known position of millions of commonly inherited genetic variants and is independent of prior knowledge of the position of disease loci. Several GWAS of breast cancer have been completed and several others are ongoing. Taken together, these studies have identified and validated 11 susceptibility loci not previously predicted to contribute to this disease. Several of these alleles also appear to modify breast cancer risk in BRCA1 and BRCA2 mutation carriers. These findings have led to GWAS of BRCA1 and BRCA2 carriers aimed at identifying genetic modifiers of breast cancer risk in these populations. Whereas risks conferred by these loci individually are low, the combined effects may be sufficient for use in risk assessment, screening, and targeted prevention.
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    ABSTRACT: Breast cancer is the most commonly occurring cancer among women, and its incidence is increasing worldwide. Positive family history is a well established risk factor for breast cancer, and it is suggested that the proportion of breast cancer that can be attributed to genetic factors may be as high as 30%. However, all the currently known breast cancer susceptibility genes are estimated to account for 20-30% of familial breast cancer, and only 5% of the total breast cancer incidence. It is thus likely that there are still other breast cancer susceptibility genes to be found. Cellular responses to DNA damage are crucial for maintaining genomic integrity and preventing the development of cancer. The genes operating in DNA damage response signaling network are thus good candidates for breast cancer susceptibility genes. The aim of this study was to evaluate the role of three DNA damage response associated genes, ATM, RAD50, and p53, in breast cancer. ATM, a gene causative for ataxia telangiectasia (A-T), has long been a strong candidate for a breast cancer susceptibility gene because of its function as a key DNA damage signal transducer. We analyzed the prevalence of known Finnish A-T related ATM mutations in large series of familial and unselected breast cancer cases from different geographical regions in Finland. Of the seven A-T related mutations, two were observed in the studied familial breast cancer patients. Additionally, a third mutation previously associated with breast cancer susceptibility was also detected. These founder mutations may be responsible for excess familial breast cancer regionally in Northern and Central Finland, but in Southern Finland our results suggest only a minor effect, if any, of any ATM genetic variants on familial breast cancer. We also screened the entire coding region of the ATM gene in 47 familial breast cancer patients from Southern Finland, and evaluated the identified variants in additional cases and controls. All the identified variants were too rare to significantly contribute to breast cancer susceptibility. However, the role of ATM in cancer development and progression was supported by the results of the immunohistochemical studies of ATM expression, as reduced ATM expression in breast carcinomas was found to correlate with tumor differentiation and hormone receptor status. Aberrant ATM expression was also a feature shared by the BRCA1/2 and the difficult-to-treat ER/PR/ERBB2-triple-negative breast carcinomas. From the clinical point of view, identification of phenotypic and genetic similarities between the BRCA1/2 and the triple-negative breast tumors could have an implication in designing novel targeted therapies to which both of these classes of breast cancer might be exceptionally sensitive. Mutations of another plausible breast cancer susceptibility gene, RAD50, were found to be very rare, and RAD50 can only be making a minor contribution to familial breast cancer predisposition in UK and Southern Finland. The Finnish founder mutation RAD50 687delT seems to be a null allele and may carry a small increased risk of breast cancer. RAD50 is not acting as a classical tumor suppressor gene, but it is possible that RAD50 haploinsufficiency is contributing to cancer. In addition to relatively rare breast cancer susceptibility alleles, common polymorphisms may also be associated with increased breast cancer risk. Furthermore, these polymorphisms may have an impact on the progression and outcome of the disease. Our results suggest no effect of the common p53 R72P polymorphism on familial breast cancer risk or breast cancer risk in the population, but R72P seems to be associated with histopathologic features of the tumors and survival of the patients; 72P homozygous genotype was an independent prognostic factor among the unselected breast cancer patients, with a two-fold increased risk of death. These results present important novel findings also with clinical significance, as codon 72 genotype could be a useful additional prognostic marker in breast cancer, especially among the subgroup of patients with wild-type p53 in their tumors. Rintasyöpä on naisten yleisin syöpä teollistuneissa maissa: Suomessa jopa joka yhdeksäs nainen sairastuu elinaikanaan rintasyöpään. Yksi suurimpia rintasyövän riskitekijöitä on rintasyövän esiintyminen suvussa. Jopa kolmanneksen kaikista rintasyövistä uskotaan syntyvän perinnöllisen alttiuden seurauksena, mutta nykyisin tunnetut alttiusgeenit kattavat kuitenkin vain noin 5 % rintasyövistä. Koska suurin osa näistä geeneistä toimii DNA:n korjauksessa, myös uusia alttiusgeenejä on perusteltua etsiä DNA:n korjausgeenien joukosta. Näiden geenien muutoksilla voi olla vaikutusta paitsi sairastumisriskiin myös syövän etenemiseen ja potilaan ennusteeseen. Tässä työssä tutkittiin kolmen DNA:n vauriokorjaukseen liittyvän geenin, ATM:n, RAD50:n ja p53:n, osuutta rintasyövässä. ATM, jonka mutaatiot aiheuttavat harvinaisen taudin, ataxia telangiectasian (A-T), on pitkään ollut vahva ehdokas rintasyöpäalttiusgeeniksi, sillä se on DNA:n korjausmekanismien keskeinen säätelijä. Tutkimme suomalaisten A-T-mutaatioiden esiintyvyyttä suomalaisissa rintasyöpäsuvuissa ja valikoimattomilla rintasyöpäpotilailla. Lisäksi etsimme muita ATM-geenin muutoksia eteläsuomalaisilta rintasyöpäpotilailta. Sekä A-T-mutaatiot että muut ATM-geenin muutokset olivat hyvin harvinaisia (kunkin esiintyvyys alle 1 %). Kolmea A-T-mutaatiota esiintyi pohjois- ja keskisuomalaisissa rintasyöpäsuvuissa, ja nämä alueelliset mutaatiot saattavat vaikuttaa suvuittaisen rintasyövän esiintymiseen näillä alueilla, mutta Etelä-Suomessa ATM-geenin muutoksilla ei näytä olevan juurikaan vaikutusta rintasyövän esiintymiseen. Tutkimme myös ATM-geenin ilmentymistä rintasyöpäkasvaimissa, ja havaitsimme, että geenin ilmentyminen on alentunut etenkin hormonireseptorinegatiivisissa ja huonommin erilaistuneissa kasvaimissa. Lisäksi ATM:n ilmenemisen alentuminen on yleisempää BRCA1- ja BRCA2-geenien ituratamutaatioiden kantajien kasvaimissa kuin muissa rintasyövissä, samoin vaikeahoitoisissa reseptorinegatiivisissa rintasyövissä. Tällä havainnolla voi olla kliinistä merkitystä uusia rintasyövän hoitomuotoja kehitettäessä. Tutkimme myös toisen DNA:n korjausgeenin, RAD50:n, muutosten esiintymistä englantilaisissa ja suomalaisissa rintasyöpäsuvuissa. Kaikkiaan RAD50-geenin muutokset olivat hyvin harvinaisia sekä englantilaisissa että suomalaisissa suvuissa ja niiden vaikutus perinnölliseen rintasyöpäalttiuteen jää hyvin pieneksi kummassakin väestössä. p53-geenin yleisellä polymorfismilla (p53 R72P) ei tulostemme mukaan ole vaikutusta rintasyöpäriskiin, mutta eri genotyypit yhdistyivät kasvainten erilaiseen histologiaan ja erilaistumiseen. Havaitsimme myös, että genotyypiltään PP-homotsygooteilla rintasyöpäpotilailla on merkitsevästi huonompi eloonjäämisennuste verrattuna muihin genotyyppeihin. PP-genotyyppi oli monimuuttuja-analyysissa itsenäinen ennustetekijä ja riippumaton myös p53-geenin ilmentymisestä kasvaimissa: PP-genotyyppiin liittyi muihin genotyyppeihin nähden kaksinkertainen riski kuolla rintasyöpään. Jos havaintomme voidaan vahvistaa myöhemmissä tutkimuksissa, sillä voi olla myös kliinistä merkitystä potilaiden ennustetta laadittaessa ja hoitoa suunniteltaessa.

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