Early-onset Breast Cancer Cases Research Articles

Genetic evaluation based on family history and Her2 status correctly identifies TP53 mutations in very early onset breast cancer cases

Currently, hereditary breast cancer is being attributed to more than 20 genes of differing penetrance. Although BRCA1 and BRCA2 are still the genes of reference for breast cancer susceptibility, extreme breast cancer phenotypes may be the result of deleterious alleles of other genes. Here, we report three families with early-onset breast cancer that were initially referred for BRCA1/BRCA2 genetic testing. They were diagnosed with breast cancer at an extraordinarily early age. On the basis of their extensive family history, which included multiple cancer types, and their Her2 status, they were suspected for Li-Fraumeni syndrome. Indeed, all three probands were found to harbor TP53 tumor suppressor gene mutations. These included p.C275X, described here for the first time, as well as p.R213X and p.Y220C, which have been described in the past. Our conclusion is that decisions on genetic analysis for inherited early onset breast cancer should always be based on detailed pedigree information, combined with Her2 status.

A Genome-wide Association Study of Early-Onset Breast Cancer IdentifiesPFKMas a Novel Breast Cancer Gene and Supports a Common Genetic Spectrum for Breast Cancer at Any Age

Early-onset breast cancer (EOBC) causes substantial loss of life and productivity, creating a major burden among women worldwide. We analyzed 1,265,548 Hapmap3 single-nucleotide polymorphisms (SNP) among a discovery set of 3,523 EOBC incident cases and 2,702 population control women ages ≤ 51 years. The SNPs with smallest P values were examined in a replication set of 3,470 EOBC cases and 5,475 control women. We also tested EOBC association with 19,684 genes by annotating each gene with putative functional SNPs, and then combining their P values to obtain a gene-based P value. We examined the gene with smallest P value for replication in 1,145 breast cancer cases and 1,142 control women. The combined discovery and replication sets identified 72 new SNPs associated with EOBC (P < 4 × 10(-8)) located in six genomic regions previously reported to contain SNPs associated largely with later-onset breast cancer (LOBC). SNP rs2229882 and 10 other SNPs on chromosome 5q11.2 remained associated (P < 6 × 10(-4)) after adjustment for the strongest published SNPs in the region. Thirty-two of the 82 currently known LOBC SNPs were associated with EOBC (P < 0.05). Low power is likely responsible for the remaining 50 unassociated known LOBC SNPs. The gene-based analysis identified an association between breast cancer and the phosphofructokinase-muscle (PFKM) gene on chromosome 12q13.11 that met the genome-wide gene-based threshold of 2.5 × 10(-6). In conclusion, EOBC and LOBC seem to have similar genetic etiologies; the 5q11.2 region may contain multiple distinct breast cancer loci; and the PFKM gene region is worthy of further investigation. These findings should enhance our understanding of the etiology of breast cancer.

RAD51 and Breast Cancer Susceptibility: No Evidence for Rare Variant Association in the Breast Cancer Family Registry Study

BackgroundAlthough inherited breast cancer has been associated with germline mutations in genes that are functionally involved in the DNA homologous recombination repair (HRR) pathway, including BRCA1, BRCA2, TP53, ATM, BRIP1, CHEK2 and PALB2, about 70% of breast cancer heritability remains unexplained. Because of their critical functions in maintaining genome integrity and already well-established associations with breast cancer susceptibility, it is likely that additional genes involved in the HRR pathway harbor sequence variants associated with increased risk of breast cancer. RAD51 plays a central biological function in DNA repair and despite the fact that rare, likely dysfunctional variants in three of its five paralogs, RAD51C, RAD51D, and XRCC2, have been associated with breast and/or ovarian cancer risk, no population-based case-control mutation screening data are available for the RAD51 gene. We thus postulated that RAD51 could harbor rare germline mutations that confer increased risk of breast cancer.Methodology/Principal FindingsWe screened the coding exons and proximal splice junction regions of the gene for germline sequence variation in 1,330 early-onset breast cancer cases and 1,123 controls from the Breast Cancer Family Registry, using the same population-based sampling and analytical strategy that we developed for assessment of rare sequence variants in ATM and CHEK2. In total, 12 distinct very rare or private variants were characterized in RAD51, with 10 cases (0.75%) and 9 controls (0.80%) carrying such a variant. Variants were either likely neutral missense substitutions (3), silent substitutions (4) or non-coding substitutions (5) that were predicted to have little effect on efficiency of the splicing machinery.ConclusionAltogether, our data suggest that RAD51 tolerates so little dysfunctional sequence variation that rare variants in the gene contribute little, if anything, to breast cancer susceptibility.

Expanded genetic analysis of a PALB2 c.3113G&gt;A mutation carrying multiple-case breast cancer family via exome sequencing

PALB2 is a breast cancer (BC) susceptibility gene. Its product is the binding partner of BRCA1 and BRCA2 and is involved in DNA repair. Studies of multiple-case BC families have reported that truncating mono-allelic PALB2 mutations, on average, increase BC risk two to six fold. Our recent population-based study estimated that carriers of PALB2 c.3113G>A had a cumulative BC risk of carrying PALB2 c.3113G>A to be 91% (95%CI=41-100) by age 70, comparable to 65% (95%CI=44-78) and 45% (95%CI=31-56) average risk estimates for BRCA1 and BRCA2 mutation carriers respectively. One of these pedigrees used for the above estimation, extensively screened but not found to carry a BRCA1 or BRCA2 mutation, exhibited ten diagnoses of BC, including five under 50 years of age, and a pedigree structure that does not allow for all cases to be explained by a single genetic factor. In view of such a high risk estimate and the observations of BC in non-PALB2 mutation carriers in this and other pedigrees, we hypothesise that there may be other genetic risk factors segregating through this family. Several genetic modifiers of BC risk have been verified in BRCA1 and BRCA2 mutation carriers. Although these genetic modifiers are associated with small changes in risk individually, collectively they may account for considerable risk modification for some women. Other moderate to highly penetrant genetic factors could also influence risk in BRCA1 and BRCA2 mutation carriers and non-carriers in BC families harbouring such genetic variants. Similarly, the presence of other genetic factors in the subject PALB2 c.3113G>A pedigree of this study, could alter the risk for mutation carriers and/or convey BC risk to non-PALB2 mutation carriers. Such additional factors could further explain the multiple cases of early onset BC and the high estimated risk of PALB2 c.3113G>A in this family. Whole exome capture followed by massively parallel sequencing was performed on four strategically selected affected females of this family. We have shortlisted 15 variants in this family predicted to be protein damaging by SIFT in genes with plausible relevance to cancer aetiology. Eight such variants are predicted to result in protein truncation or are variants predicted to have strong effects on splicing efficiency, one of which have been observed in key DNA repair genes. Six of the genes have roles in DNA repair, three in cell cycle checkpoint regulation, one controls telomerase activity and another has been reported to be a prostate cancer predisposition gene. Further analyses of these candidate BC predisposition genes will be presented.

Frequency of the CHEK2 1100delC mutation among women with early-onset and bilateral breast cancer

We read with great interest the recent Breast Cancer Research paper by Desrichard and colleagues [1] reporting the association between CHEK2 mutations and non-BRCA hereditary breast cancer risk. This report summarized the results of different case-control studies to provide an overview of CHEK2 1100delC mutation and susceptibility to early-onset breast cancer (EOBC) and bilateral breast cancer (BBC). We believe there are significant issues to note regarding the authors' study. To investigate the role of CHEK2 1100delC mutation in BBC susceptibility, Desrichard and colleagues performed a systematic review and pooled analysis based on five studies. Notably, another study that showed contradictory results indicating that the 1100delC mutation might not be a modifier in BBC [2] was not included in these analyses. Rashid and colleagues [3] have also shared their data, which failed to identify CHEK2 1100delC mutations among cases of BBC. Interestingly, the study by de Jong and colleagues [4] categorized individuals with BBC as unselected breast cancer cases. However, the BBC cases were included in the group of 192 patients identified with early-onset/familial breast cancer from an Irish study [5]. Hence, ongoing uncertainty exists and, in our opinion, the conclusion reached by Desrichard and colleagues may not be fully supported by the available data. An additional issue is the association between CHEK2 mutations and EOBC risk. Using the same search strategy as that of Desrichard and colleagues, we located three relevant case-control studies in PubMed comprising a total of 3,742 EOBC cases and 8,405 controls [6-8], which were not included in the pooled analyses. Furthermore, we have combined all of the studies on European populations into a new pooled analysis. By using a fixed-effect model, significant associations were found to be associated with CHEK2 1100delC mutation in patients with EOBC (odds ratio 3.14, 95% confidence interval 1.86 to 5.28). In conclusion, the association between CHEK2 1100delC mutation and BBC risk may be complex, and further studies will likely be needed to clarify the correlation of BBC and familial breast cancer characteristics. Similarly, further studies on EOBC-specific populations would be helpful for the purpose of better evaluating the association between CHEK2 1100delC mutation and EOBC risk.

P2-07-01: Copy Number Variants in Early-Onset-Breast Cancer.

Abstract Background: Copy number variants (CNVs) are known to contribute to the risk for development of immune diseases, neurological disorders and to a lesser extent cancer. Many CNVs do not directly involve gene sequences. CHL1, a cell adhesion molecule with homology to L1CAM, is down-regulated in a large proportion of breast cancer. A deletion CNV immediately 5’ of the CHL1 transcriptional start site has been described. The CHL1 CNV's role in breast cancer risk has not previously been explored. Material and Methods: 50 research subjects recruited to the Washington University/Siteman Cancer Center Young Women's Breast Cancer Program (YWBCP) were selected for a CNV discovery study. These women were diagnosed breast cancer &amp;lt; age 40, tested negative for BRCA1/2 mutations and have a negative family history for breast cancer. The selection criteria enriched for de novo mutations. Comparative genomic hybridization (CGH) analyses were undertaken using the NimbleGen 2.1 million oligonucleotide array. DNA copy number was compared between proband and each of her parents to identify potential deletions or amplifications in the daughter relative to both parents (de novo changes). PCR was used to confirm a subset of the CGH-predicted differences in copy number. Chi-square test was used to determine statistical significances of CNV occurrences near the CHL1 gene between women with breast cancer and control cases. Results: aCGH data analysis has been completed for 25 YWBC trios (patients and parents). 247 differences in copy number in the breast cancer cases relative to their parents were identified (1-18 putative de novo CNVs per case). 91% of the observed changes were deletions and 9% were amplifications. One proband showed an 11,560 bp deletion 5’ of the CHL1 gene that was not seen in her parents. Conventional PCR confirmed a homozygous deletion of a ∼3 kb region in the patient, in the region of a known CNV with a reported frequency of ∼3%. Testing an additional 368 early-onset breast cancer cases for the CHL1 deletion revealed 25 additional homozygous deletions (6.8%). The deletion was present in 9 of 197 controls (4.5%). qPCR studies revealed the parents of the patient with the CHL1 deletion each carried a single copy of the CNV, making de novo copy number change in the proband very unlikely. Deletion specific assays for the CHL1 CNV are being used to test CNV genotypes in an extended case-control study. Discussion: CHL1 expression has previously been shown to be down-regulated in primary breast tumors. Our preliminary analysis of YWBC cases and controls indicates the CHL1 regulatory region CNV is unlikely to be associated with risk for early-onset breast cancer. Additional candidate de novo copy number changes seen in the genomes of patients with early-onset breast cancer are being evaluated to determine their roles as genetic risk factors. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-07-01.

5101 POSTER 86 Cases of Early-onset Breast Cancer in Hungary – Retrospective Analysis of Immunohistochemistry (IHC) and Family-history Data -Assessing the Risk of Carrying BRCA1 and BRCA2 Mutation

5101 POSTER 86 Cases of Early-onset Breast Cancer in Hungary – Retrospective Analysis of Immunohistochemistry (IHC) and Family-history Data -Assessing the Risk of Carrying BRCA1 and BRCA2 Mutation

Underutilization of BRCA1/2 testing to guide breast cancer treatment: Black and Hispanic women particularly at risk

PurposeWomen with early-onset (age ≤40 years) breast cancer are at high risk of carrying deleterious mutations in the BRCA1/2 genes; genetic assessment is thus recommended. Knowledge of BRCA1/2 mutation status is useful in guiding treatment decisions. To date, there has been no national study of BRCA1/2 testing among newly diagnosed women. MethodsWe used administrative data (2004–2007) from a national sample of 14.4 million commercially insured patients to identify newly diagnosed, early-onset breast cancer cases among women aged 20–40 years (n = 1474). Cox models assessed BRCA1/2 testing, adjusting for covariates and differential lengths of follow-up. ResultsOverall, 30% of women aged 40 years or younger received BRCA1/2 testing. In adjusted analyses, women of Jewish ethnicity were significantly more likely to be tested (hazard ratio = 2.83, 95% confidence interval: 1.52–5.28), whereas black women (hazard ratio = 0.34, 95% 0.18–0.64) and Hispanic women (hazard ratio = 0.52, 95% confidence interval: 0.33–0.81) were significantly less likely to be tested than non-Jewish white women. Those enrolled in a health maintenance organization (hazard ratio = 0.73, 95% confidence interval: 0.54–0.99) were significantly less likely to receive BRCA1/2 testing than those point of service insurance plans. Testing rates increased sharply for women diagnosed in 2007 compared with 2004. ConclusionsIn this national sample of patients with newly diagnosed breast cancer at high risk for BRCA1/2 mutations, genetic assessment was low, with marked racial differences in testing. Genet Med 2011:13(4):349–355.

Composite likelihood-based meta-analysis of breast cancer association studies

For detecting low risk disease variants in genome-wide association panels, meta-analysis is a powerful strategy to increase power. We apply a composite likelihood-based method, which models association with disease in regions defined on a linkage disequilibrium map and combines the evidence across multiple genome-wide samples. This fixed region approach has the advantage that, as only one statistical test is made per region, there is no increased multiple testing penalty in higher marker density panels. Imputation of missing genotypes is also advantageous to increase coverage. Meta-analysis of three breast cancer data sets combines evidence from samples that show heterogeneity in phenotype and, particularly, in marker coverage. The FGFR2 gene has the highest rank, consistent with previous analysis of one of these samples and supported by the small number of early-onset breast cancer cases included. The 8q24 breast cancer region also ranks highly and is supported by evidence from both early-onset and post-menopausal breast cancer samples. The PIK3AP1 gene region is highlighted in this analysis as a strong candidate for further study.

Increased cancer risks for relatives of very early-onset breast cancer cases with and without BRCA1 and BRCA2 mutations

Background:Little is known regarding cancer risks for relatives of women with very early-onset breast cancer.Methods:We studied 2208 parents and siblings of 504 unselected population-based Caucasian women with breast cancer diagnosed before age 35 years (103 from USA, 124 from Canada and 277 from Australia), 41 known to carry a mutation (24 in BRCA1, 16 in BRCA2 and one in both genes). Cancer-specific standardised incidence ratios (SIRs) were estimated by comparing the number of affected relatives (50% verified overall) with that expected based on incidences specific for country, sex, age and year of birth.Results:For relatives of carriers, the female breast cancer SIRs were 13.13 (95% CI 6.57–26.26) and 12.52 (5.21–30.07) for BRCA1 and BRCA2, respectively. The ovarian cancer SIR was 12.38 (3.1–49.51) for BRCA1 and the prostate cancer SIR was 18.55 (4.64–74.17) for BRCA2. For relatives of non-carriers, the SIRs for female breast, prostate, lung, brain and urinary cancers were 4.03 (2.91–5.93), 5.25 (2.50–11.01), 7.73 (4.74–12.62), 5.19 (2.33–11.54) and 4.35 (1.81–10.46), respectively. For non-carriers, the SIRs remained elevated and were statistically significant for breast and prostate cancer when based on verified cancers.Conclusion:First-degree relatives of women with very early-onset breast cancer are at increased risk of cancers not explained by BRCA1 and BRCA2 mutations.

Comparing the frequency of common genetic variants and haplotypes between carriers and non-carriers of BRCA1 and BRCA2deleterious mutations in Australian women diagnosed with breast cancer before 40 years of age

BackgroundBRCA1 and BRCA2 mutations are found in a proportion of families with multiple early-onset breast cancers. There are a large number of different deleterious mutations in both genes, none of which would be detectable using standard genetic association studies. Single common variants and haplotypes of common variants may capture groups of deleterious mutations since some low prevalence haplotypes of common variants occur more frequently among chromosomes that carry rare, deleterious mutations than chromosomes that do not.MethodsDNA sequence data for BRCA1 and BRCA2 was obtained from 571 participants from the Australian Breast Cancer Family Study. Genetic variants were classified as either deleterious mutations or common genetic variants. Variants tagging common polymorphisms were selected and haplotypes resolved using Haploview. Their frequency was compared to those with and without deleterious mutations using a permutation test.ResultsA common genetic variant in BRCA1 (3232A > G) was found to be over-represented in deleterious mutation carriers (p = 0.05), whereas a common genetic variant in BRCA2 (1342A > C) occurred less frequently in deleterious mutation carriers (p = 0.04). All four of the common BRCA1 variants used to form haplotypes occurred more frequently in the deleterious mutation carriers when compared to the non-carriers, but there was no evidence of a difference in the distributions between the two groups (p = 0.34). In BRCA2, all four common variants were found to occur less frequently in the deleterious mutation carriers when compared to non-carriers, but the evidence for difference in the distribution between the two groups was weak (p = 0.16). Several less common haplotypes of common BRCA1 variants were found to be over-represented among deleterious mutation carriers but there was no evidence for this at the population level. In BRCA2, only the most common haplotype was found to occur more frequently in deleterious mutation carriers, with again no evidence at the population level.ConclusionsWe observed differences in the frequency of common genetic variants of the BRCA1 and BRCA2 and their haplotypes between early-onset breast cancer cases who did and did not carry deleterious mutations in these genes. Although our data provide only weak evidence for a difference in frequencies at the population level, the number of deleterious mutation carriers was low and the results may yet be substantiated in a larger study using pooled data.

BRCA1 mutations in women with familial or early-onset breast cancer and BRCA2 mutations in familial cancer in Estonia

BackgroundThe aim of this study was to identify BRCA1 and BRCA2 mutations in the Estonian population. We analyzed genetic data and questionnaire from 64 early-onset (< 45 y) breast cancer patients, 47 familial cases (patients with breast or ovarian cancer and a case of these cancers in the family), and 33 predictive cases (patients without breast or ovarian cancer, with a family history of such diseases) from Estonia for mutations in the BRCA1 gene. A sub-set of familial cases and predictive cases were also analyzed for mutations in the BRCA2 gene.MethodsFor mutation detection, we used the Polymerase Chain Reaction-Single Stranded Conformation Polymorphism Heteroduplex Analysis (PCR-SSCP-HD), followed by direct DNA sequencing.ResultsWe identified three clinically important mutations in the BRCA1 gene, including seven occurrences of the c.5382insC mutation, three of c.4154delA, and one instance of c.3881_3882delGA. We also detected six polymorphisms: c.2430T>C, c.3232A>G, c.4158A>G, c.4427T>C, c.4956A>G, and c.5002T>C. Four sequence alterations were detected in introns: c.560+64delT, c.560+ [36-38delCTT, 52-63del12], c.666-58delT, and c.5396+60insGTATTCCACTCC. In the BRCA2 gene, two clinically important mutations were found: c.9610C>T and c.6631delTTAAATG. Additionally, two alterations (c.7049G>T and c.7069+80delTTAG) with unknown clinical significance were detected.ConclusionsIn our dataset, the overall frequency of clinically important BRCA1 mutations in early-onset patients, familial cases, and predictive testing was 7.6% (144 cases, 11 mutation carriers). Pathogenic mutations were identified in 4 of the 64 early-onset breast cancer cases (6.3%). In familial cases, clinically important mutations in the BRCA1 gene were found in 6 of the 47 individuals analyzed (12.8%). In predictive cases, 1 clinically important mutation was detected in 33 individuals studied (3%). The occurrence of clinically important mutations in BRCA2 in familial cases of breast cancer was 2 of the 16 individuals analyzed (12.5%).

PALB2 sequence variants in young South African breast cancer patients

PALB2 (partner and localizer of BRCA2) is a recently identified breast cancer susceptibility gene, in which mutations confer doubling of breast cancer risk with moderate to low penetrance. Recent studies in various populations report that deleterious mutations in this gene account for approximately 1% of familial or early-onset breast cancer cases. This study aimed to determine the involvement of PALB2 mutations in a cohort of 48 young (29-45 years) South African breast cancer patients unselected for family history of breast cancer. The complete coding region and intron-exon boundaries of PALB2 were analyzed. A novel truncating mutation, c.697delG (V233fs) was identified in one patient. A missense variant (E211G), identified in another patient, appears to be segregating with the disease, but in silico analysis using SIFT, PolyPhen and A-GVGD, indicates that this variant is nonpathogenic. In addition, four other missense, one synonymous and three intronic variants were detected, all of which appear polymorphic. This represents the second study to analyze the role of PALB2 in early-onset breast cancer patients unselected for family history. The first study, of a Chinese population, established that PALB2 was responsible for 1.3% of early-onset breast cancer cases. Our study reports that deleterious mutations in PALB2 account for approximately 2% (1/48) of South African early-onset breast cancer.

Estrogen receptor status in CHEK2‐positive breast cancers: implications for chemoprevention

To investigate the relationship between CHEK2 mutation status and estrogen receptor (ER) status in unselected cases of early-onset breast cancer from Poland, we screened 4441 women diagnosed with breast cancer younger than 51 years and 7217 controls for three inherited mutations in CHEK2 (1100delC, IVS2+1G>A, del5395). ER status was compared between CHEK2-positive and CHEK2-negative breast cancer cases. A truncating mutation in CHEK2 was seen in 140 of 4441 cases and in 70 of 7217 controls [odds ratio (OR) = 3.3; 95% CI = 2.5-4.4; p < 0.0001]. ER status was available for 92 of 140 mutation carriers and for 3001 of 4301 non-carriers with breast cancer. The OR was higher for ER-positive cancers (OR = 3.9; 95% CI = 2.7-5.4; p < 0.0001) than for ER-negative cancers (OR = 2.1; 95% CI = 1.3-3.3; p = 0.002). Sixty-six of the 92 breast cancers in carriers of CHEK2 truncating mutations were ER positive compared with 1742 of the 3001 breast cancers in non-carriers (72% vs 58%; p = 0.01). Women with a CHEK2 mutation face a fourfold increase in the risk of ER-positive breast cancer and might be candidates for tamoxifen chemoprevention.

PEL: an unbiased method for estimating age‐dependent genetic disease risk from pedigree data unselected for family history

Providing valid risk estimates of a genetic disease with variable age of onset is a major challenge for prevention strategies. When data are obtained from pedigrees ascertained through affected individuals, an adjustment for ascertainment bias is necessary. This article focuses on ascertainment through at least one affected and presents an estimation method based on maximum likelihood, called the Proband's phenotype exclusion likelihood or PEL for estimating age-dependent penetrance using disease status and genotypic information of family members in pedigrees unselected for family history. We studied the properties of the PEL and compared with another method, the prospective likelihood, in terms of bias and efficiency in risk estimate. For that purpose, family samples were simulated under various disease risk models and under various ascertainment patterns. We showed that, whatever the genetic model and the ascertainment scheme, the PEL provided unbiased estimates, whereas the prospective likelihood exhibited some bias in a number of situations. As an illustration, we estimated the disease risk for transthyretin amyloid neuropathy from a French sample and a Portuguese sample and for BRCA1/2 associated breast cancer from a sample ascertained on early-onset breast cancer cases.

Vitamin D receptor variants and breast cancer risk in the Polish population

The aim of the study was to determine whether four VDR gene single nucleotide polymorphisms (SNPs: rs1544410, rs731236, rs10735810 and rs4516035) are associated with breast cancer risk in Polish population. Two independent series of female patients were employed: 960 consecutive breast cancer cases, and 800 unselected early onset cases diagnosed under the age of 51. The control group for the consecutive breast cancer cases consisted of 960 healthy, age-matched women with a negative cancer family history. 550 healthy women, aged 51 or less, with negative cancer family history were selected as the independent controls for the early onset breast cancer cases. The frequencies of the VDR polymorphisms in the unselected cases when compared to the respective control population failed to reveal any association between the individual SNPs and disease. Examination of the group of early-onset patients, revealed an association between rs10735810 and increased breast cancer risk. Heterozygous carriers for the change had an OR = 1.73 (95% CI 1.33-2.26, P < 0.0001) and homozygous carriers OR = 2.34 (95% CI 1.71-3.21, P < 0.0001). The remaining three examined SNPs failed to show any association with disease risk. In summary, this study has identified an association between the VDR gene and early onset breast cancer risk in the Polish population.

Time to Check CHEK2 in Families With Breast Cancer?

Time to Check <i>CHEK2</i> in Families With Breast Cancer?

Cancer incidence in first-degree relatives of a population-based set of cases of early-onset breast cancer

Cancer incidence in first-degree relatives of a population-based set of cases of early-onset breast cancer

The prevalence of BRCA1 and BRCA2 germline mutations in high-risk breast cancer patients of Chinese Han nationality: two recurrent mutations were identified

To have an overview of the role of BRCA1 and BRCA2 genes among Chinese high-risk breast cancer patients, we analyzed 489 such high-risk breast cancer patients from four breast disease clinical centers in China, by using PCR-DHPLC or SSCP-DNA sequencing analysis. Allelotype analysis was done at five short tandem repeat (STR) markers in or adjacent to BRCA1 on the recurrent mutation carriers. For those analyzed both genes, 8.7% of early-onset breast cancer cases and 12.9% of familial breast cancer cases had a BRCA1 or BRCA2 mutation, as compared with the 26.1% of cases with both early-onset breast cancer and affected relatives. For those reporting malignancy family history other than breast/ovarian cancer, the prevalence of BRCA1/2 mutation is about 20.5%, and it was significantly higher than the patients only with family history of breast/ovarian cancer (P = 0.02). The family history of ovarian cancer (26.7% vs. 11.9%) and stomach cancer (23.8% vs. 11.8%) doubled the incidence of BRCA1/2, but the difference did not reach the statistical significance. Two recurrent mutations in BRCA1, 1100delAT and 5589del8, were identified. The recurrent mutations account for 34.8% BRCA1 mutations in our series. Similar allelotypes were detected in most STR status for those harboring the same mutations. The BRCA1 associated tumors were more likely to exhibit a high tumor grade, negative C-erbB-2/neu status and triple negative (ER, PgR and C-erbB-2/neu negative) status (P < 0.05). We recommended the BRCA1 and BRCA2 genetic analysis could be done for high-risk breast cancer patient in Chinese population, especially for those with both early-onset breast cancer and affected relatives. There may be some degree of shared ancestry for the two recurrent BRCA1 mutations in Chinese.

MDM2 SNP309 accelerates familial breast carcinogenesis independently of estrogen signaling

A single nucleotide polymorphism (SNP309T>G) in the intronic promoter of MDM2 was recently found to accelerate carcinogenesis in early-onset cancer cases. This cancer acceleration presumably was due to increased SP1 binding, resulting in enhanced MDM2 transcriptional activation by estrogens. We evaluated MDM2 SNP309 in 343 familial breast cancer cases with known mutation status for CHEK2 1100delC, BRCA1 and BRCA2. Cancer acceleration was indeed observed in early-onset familial breast cancer cases (diagnosed <or= 51 years), with 16% of cases carrying the MDM2 SNP309 GG genotype as compared to 4% of late-onset cases (P = 0.029). The cancer acceleration was even more pronounced in the non-mutant familial breast cancer cases, with 17% of early-onset cases carrying MDM2 SNP309 GG as compared to 2% of late-onset cases (n = 214; P = 0.015). There was no evidence for an influence of estrogen signaling in the cancer acceleration by MDM2 SNP309, as there were no differences in the prevalence of MDM2 SNP309 GG among CHEK2 1100delC and BRCA2 mutant cases (with 90% ER-positive cancers) or BRCA1 mutant cases (10% ER-positive cancers). Nor did we observe differences in MDM2 SNP309 frequencies among 75 familial breast cancer cases of our cohort with known ER status. Overall, our data suggest that MDM2 SNP309 accelerates familial breast carcinogenesis, but that this acceleration is not influenced by estrogen signaling.