A gene-environment interaction between occupation and BRCA1/BRCA2 mutations in male breast cancer?

The association of male breast cancer (MBC) with a positive breast cancer (BC) family history and with BRCA1/2 germ-line mutations points to a genetic component; a relationship with occupation has also been reported. Recently, we identified pathogenetic BRCA1/2 mutations in a population-based series of Italian MBC patients: here in, we investigated interactions between a carrier status for BRCA1/2 mutations and occupation using a case-case design and estimating case-only odds ratios (CORs). Truck-driving was the most frequent occupation (3/4 BRCA-related cases and 2/19 unrelated cases). An interaction between carrier status and working as a truck-driver emerged, when we classified MBC cases as "ever/never-held" this job title (COR 25.5; 95% Confidence Limits (CL): 1.1-1,412.5) or according to truck-driving as the "longest-held" work (COR 54.0; 95% CL: 1.6-2,997.5). The possible modifying effect on MBC risk in subjects carrying BRCA1/2 germ-line mutations of an occupation characterised by exposure to chemicals such as polycyclic aromatic hydrocarbons (PAH) that are capable of inducing DNA damage, may provide clues to the role of environmental exposures in modifying BC risk in mutation carriers in both genders.     

Infertility, treatment of infertility, and the risk of breast cancer among women with BRCA1 and BRCA2 mutations: a case–control study

Background  Women with a breast cancer susceptibility gene 1 (BRCA1) or breast cancer susceptibility gene 2 (BRCA2) mutation are at increased risk for developing breast and ovarian cancer. Various reproductive and hormonal factors have been shown to modify the risk of breast cancer. These studies suggest that estrogen exposure and deprivation are important in the etiology of hereditary cancer. Many patients are interested in the possibility of an adverse effect of fertility treatment on breast cancer risk. It is important to evaluate whether or not infertility per se or exposure to fertility medications increase the risk of breast cancer in genetically predisposed women. Methods  We conducted a matched case–control study of 1,380 pairs of women with a BRCA1 or BRCA2 mutation to determine if a history of infertility, the use of fertility medications, or undergoing in vitro fertilization (IVF) were associated with and increased the risk of breast cancer. Results  Sixteen percent of the study subjects reported having experienced a fertility problem and 4% had used a fertility medication. Women who had used a fertility medication were not at significantly increased risk of breast cancer (odds ratio [OR] = 1.21; 95% confidence interval [CI] = 0.81–1.82) compared to non-users. Furthermore, there was no risk associated with a history of use of a fertility medication when the subjects were stratified by parity: (OR = 1.29; 95% CI = 0.83–2.01 for nulliparous women and OR = 0.81; 95% CI = 0.30–2.22 for parous women). Conclusions  The results of this study suggest that the use of fertility medications does not adversely affect the risk of breast cancer among BRCA mutation carriers. Given the small sizes of the exposed subgroups, these findings should be interpreted with caution and confirmatory studies are required. Other Members of the Hereditary Breast Cancer Clinical Study Group: D. Horsman, British Columbia Cancer Agency, Vancouver, BC, Canada; B. Rosen, Familial Ovarian Cancer Clinic, Princess Margaret Hospital, Toronto, ON, Canada; C. Isaacs, Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC, USA; S. Domchek, Departments of Hematology and Oncology, University of Pennsylvania, USA; R. Gershoni-Baruch, Institute of Genetics, Rambam Medical Center, Haifa, Israel; A. Eisen, Cancer Risk Assessment Clinic, Juravinksi Cancer Centre (Hamilton Regional Cancer Centre), Hamilton, ON, Canada; O. I. Olopade, Center for Clinical Cancer Genetics, University of Chicago, Chicago, IL, USA; E. Friedman, The Suzanne Levy Gertner Oncogenetics Unit, The Chaim Sheba Medical Center, Tel-Hashomer, Israel, and the Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel; H. M. Saal, Hereditary Cancer Program, Division of Human Genetics, Children’s Hospital Medical Center, Cincinnati, OH, USA; S. L. Neuhausen, Epidemiology Division, Department of Medicine, University of California, Irvine, USA; M. Daly, Division of Population Science, Fox Chase Cancer Center, Philadelphia, PA, USA; B. Karlan and R. N. Kurz, Gynecology Oncology, Cedars Sinai Medical Center, Los Angeles, CA, USA; C. Bellati, Section of Genetics, University of Turin, Turin; Italy C. Eng, Chair of Genomic Medicine Institute at the Cleveland Clinic Foundation Cleveland, Cleveland, OH, USA; K. Sweet, Clinical Cancer Genetics Program, Comprehensive Cancer Center, Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus OH, USA; T. Wagner, Department of Gynecology, Division of Senology, Medical University of Vienna and Private Trust for Breast Health, Austria; G. Rennert, National Cancer Control Center, Carmel Medical Center, Haifa, Israel; D. Provencher and C. Maugard, University of Montreal, Quebec, Canada; J. Garber, Dana Farber Cancer Center, W. McKinnon and M. Wood, University of Vermont; D. Gilchrist, University of Alberta; M. Osborne, Strang Cancer Prevention Centre, New York, NY, USA; J. McLennan, University of San Francisco, California, USA; S. Merajver, University of Michigan Comprehensive Cancer Cente;, B. Pasche and T. Fallen, Northwestern University Cancer Genetics Program, Chicago, Illinois, USA; E. Lemire, Division of Medical Genetics, Royal University Hospital and the University of Saskatchewan, Saskatoon, Canada; A. Chudley, Children’s Hospital, Winnipeg, Manitoba, Canada; J. Weitzel, Department of Cancer Genetics, City of Hope National Medical Center, Duarte, California, USA; W. S. Meschino, North York General, North York, ON, Canada; D. Rayson, Queen Elizabeth Health Sciences Centre, Halifax, Nova Scotia, Canada; G. Evans, Regional Genetics Service, St. Mary’s Hospital, Manchester, UK; D. Agnese, Division of Human Genetics, The Ohio State University; and H. Olsson, Jubileum Institute, Department of Oncology, Lund University Hospital, Lund, Sweden.     

The deletion of exons 3–5 of BRCA1 is the first founder rearrangement identified in breast and/or ovarian cancer Spanish families

We recently described a novel g.8097_22733del14637 deletion encompassing exons 3–5 in BRCA1 gene. This rearrangement was detected in 3 of 15 (20 %) breast and/or ovarian cancer families of Eastern Spain. This finding made us suspect that the newly identified deletion could be a founder mutation. To confirm this hypothesis we studied 18 subjects belonging to the three families under study, 11 deletion carriers and 7 non-carriers. We performed a haplotype analysis using two BRCA1 intragenic microsatellite markers and two markers surrounding the BRCA1 locus. The segregation analysis showed one common particular haplotype established by D17S1325, D17S1323, D17S855 and D17S1320 markers detected in the deletion carriers but absent in the non-carriers. Our study sustain that the deletion of exons 3–5 of BRCA1, g.8097_22733del14637, identified in families of southeastern of the Valencian Community is the first founder rearrangement until now reported in Spanish population, confirming the hypothesis that this mutation could have Iberian ancestry.     

Psychological and cancer-specific distress at 18 months post-testing in women with demonstrated BRCA1 mutations for hereditary breast/ovarian cancer

Aim The aim of this longitudinal study was to explore both levels of and factors predictive of psychological and cancer-specific distress in women with demonstrated BRCA1 mutations belonging to families with hereditary breast/ovarian cancer (HBOC). Methods We included 214 women from HBOC families who had BRCA1 testing, and who were examined with a mailed questionnaire at pre-test (T1), 6 weeks after getting the test result (T2) and 18 months later (T3). Self-rating instruments for psychological distress, cancer-specific distress and personality traits were used. Results Hardly any significant changes were observed concerning the levels of psychological and cancer-specific distress from T1 via T2 to T3 for the total group or those with carrier or non-carrier status, while women with cancer had a significant reduction of cancer-specific distress over time. The pre-test levels of psychological and cancer-specific distress were significant and strong predictors of these types of distress at T3. The personality trait of neuroticism made a significant contribution to both types of distress at pre-test, and a small separate contribution to distress at T3. Carrier status, history of personal cancer, pre-test levels of optimism or multidimensional health locus of control did not significantly predict distress at T3. Conclusions Genetic testing or test results were not found to induce psychological or cancer-specific psychological distress at long-term. Neuroticism had a decisive influence at both pre-test and long-term levels of distress.     

MDM2 SNP309 accelerates breast and ovarian carcinogenesis in BRCA1 and BRCA2 carriers of Jewish–Ashkenazi descent

A functional single nucleotide polymorphism in the promoter of the MDM2 gene, SNP309 (T>G), was recently found to accelerate tumorigenesis in early onset cancer cases. The SNP309 G-allele, introduces an SP1 site in the MDM2 promoter, resulting in enhanced MDM2 expression and activity. Thus, the G-allele of MDM2 SNP309 may represent a cancer predisposing allele. In this report, we assessed the role of SNP309 as a modifier of mutant BRCA1/BRCA2 alleles in inherited breast and ovarian cancer cases among Ashkenazi–Jewish (AJ) women. We genotyped several subsets of AJ women: 138 healthy women, 140 affected BRCA1/2 mutation carriers, 120 asymptomatic BRCA1/2 mutation carriers and 187 sporadic breast cancer patients. The frequency of GG genotype of SNP309 was similar among the different groups. Interestingly, we found almost three times higher frequency of the GG genotype among BRCA1/2 carriers diagnosed with breast and/or ovarian cancer at or under the age of 51 years compared with carriers diagnosed with cancer above the age of 51 years (allele frequency, P = 0.019). The GG genotype was significantly associated with breast and ovarian cancer risk among BRCA1/2 carriers diagnosed before 51 years of age (OR, 3.93; 95% CI, 1.41–10.90, P = 0.009). No significant difference in frequency of the GG genotype was observed between early and late onset non-carrier cancer patients and no association with risk, OR, 1.30; 95% CI 0.69–2.47, P = 0.419). These data suggest that MDM2 SNP309 acts as a modifier of mutant BRCA1/2 mutant alleles in AJ and may accelerate breast and ovarian carcinogenesis in genetically predisposed individuals.     

Cancer risk and genotype–phenotype correlations in PTEN hamartoma tumor syndrome

Patients with germline PTEN mutations are at high risk of developing benign and malignant tumours. We aimed to evaluate the cumulative risk of several types of cancer and of dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease, LDD). In addition, genotype–phenotype correlations in PTEN hamartoma tumour syndrome (PHTS) were assessed. Data on patients with PTEN mutations were collected from clinical genetic centres in Western Europe, Australia, and the USA. The cumulative risk of developing cancers of the breast, thyroid, endometrium, skin, kidneys, colorectum, and lungs, and also LDD was calculated by Kaplan–Meier methods. Associations between mutations and cancer were assessed by Chi square means. A total of 180 germline PTEN mutation carriers, 81 males (45 %), from nine countries were included. The cumulative risk of developing any cancer and/or LDD at age 60 was 56 % for males and 87 % for females (p = 0.001). Females had significant higher risks of developing breast cancer, thyroid cancer, and LDD than males. The only genotype–phenotype correlation identified was a lower frequency of thyroid cancer in patients with missense mutations (p = 0.014). In conclusion, PHTS patients, particularly females, have a substantial risk of developing one or more tumours from a broad tumour spectrum. Major genotype–phenotype associations could not be identified.     

Loss of heterozygosity in BRCA1 and BRCA2 markers and high‐grade malignancy in breast cancer

Loss of heterozygosity (LOH) in loci of the 17q21 and 13q1213 regions can collaborate in the inactivation of BRCA1, BRCA2, and possibly other genes implicated in the pathogenesis of breast carcinomas. We investigate allelic losses in microsatellites of the BRCA1 and BRCA2 regions, and their correlations with seven pathologic parameters in 140 breast carcinomas. Those cases showing LOH in the region of the RB gene, 13q14, were excluded from the study. The LOH analysis was performed by amplifying DNA by PCR, using four markers of the 17q21 region (D17S856, D17S855, D17S1323, and D17S1327) and four markers of the 13q1213 region (D13S290, D13S260, D13S310, and D13S267). LOH in the BRCA1 region was found in 47% of tumors, correlating significantly with estrogen receptor content (p = 0.025), progesterone receptors (p = 0.004), higher grade (p = 0.0008), peritumoral vessel invasion (p = 0.001), and lymph node metastases (p = 0.002). When we excluded the cases with LOH in the BRCA2 region and those not informative for it, the significance disappeared. In the BRCA2 region, a rate of LOH of 51% was found; it correlated significantly with estrogen receptor content (p = 0.002), progesterone receptors (p =0.03), peritumoral vessel invasion (p = 0.005), higher grade (p =0.002), and lymph node metastases (p = 0.001). When cases with BRCA1 losses and those not informative were excluded, again the significance disappeared. Concomitant losses in the BRCA1 and BRCA2 regions were found in 32% of cases, correlating significantly with lymph node metastases (p = 0.0002), estrogen receptor content (p = 0.003), progesterone receptors (p = 0.001), histologic grade (p =0.01), and peritumoral vessel invasion (p = 0.0004). These results suggest that concomitant losses in both regions could have a functional effect, influencing the presence of a poor tumor pathophenotype in breast carcinomas.     

Are the hereditary forms of BRCA1 and BRCA2 breast cancer sensitive to estrogens?

There is emerging evidence from clinical and experimental data that familial breast cancers, including BRCA1 and BRCA2 related forms, could be in fact estrogen-sensitive. Interactions between BRCA1 gene expression and estrogens have been reported. On one hand, BRCA1 expression could be induced by estradiol in experimental models. On the other hand, recent studies indicate that BRCA 1 interacts with and regulates the activity of estrogen receptor ERalpha. Endogenous or exogenous estrogens, such as oral contraceptive, may also increase the risk of breast cancer in BRCA1 mutation carriers in clinical studies. Conversely, prophylactic oophorectomy and anti-estrogens may decrease the risk of familial breast cancer. Prospective studies are thus required to estimate the potential benefits of estrogen suppression therapies for prevention or adjuvant treatment of familial breast cancer. Oral contraception and hormonal replacement therapy after menopause should be used with caution in BRCA1 or BRCA2 mutation carriers.     

Outcome and clinical–biological characteristics of patients with advanced breast cancer undergoing removal of ovarian/pelvic metastases

BackgroundPatients with metastatic breast cancer to the ovary, without tumor debulking and after systemic therapy, have a 5-year survival rate < 10%.Patients and methodsWe analyzed a series of 37 patients, operated in one institution over 10 years, for both the primary tumor (PT) and ovarian/pelvic metastases (OPM). Estrogen receptors (ER), progesterone receptors (PgR), HER-2 and Ki-67 were determined.ResultsPatients were predominantly young: 27 (73%) patients were < 50 years. Average ER/PgR expression did not change significantly between PT (mean ER = 66%, PgR = 35%) and OPM (mean ER = 67%, PgR = 28%). Median time to OPM was 42 months (range 0–176); 5-year OS after OPM was 51% (95% confidence interval 32% to 67%). When combining ER and PgR status, patients with ER > 50% on both PT and OPM and with PgR > 50% on PT and/or OPM (good prognosis, 11 patients) had a better outcome versus0 patients with ER and PgR ≤ 50% on both PT and OPM (bad prognosis, eight patients) and also versus the remaining patients (intermediate prognosis, 18 patients), P value = 0.010.ConclusionPatients with OPM from breast cancer show a favorable prognosis after tumor debulking, whether it was radical or not, especially when a high expression of ER and PgR is present in both PT and OPM.     

Time to stop ovarian cancer screening in BRCA1/2 mutation carriers?

Women at high risk of ovarian cancer due to a genetic predisposition may opt for either surveillance or prophylactic bilateral salpingo‐oophorectomy (pBSO). Main objective of our study was to determine the effectiveness of ovarian cancer screening in women with a BRCA1/2 mutation. We evaluated 241 consecutive women with a BRCA1 or BRCA2 mutation who were enrolled in the surveillance program for hereditary ovarian cancer from September 1995 until May 2006 at the University Medical Center Groningen (UMCG), The Netherlands. The ovarian cancer screening included annual pelvic examination, transvaginal ultrasound (TVU) and serum CA125 measurement. To evaluate the effectiveness of screening in diagnosing (early stage) ovarian cancer sensitivity, specificity, positive and negative predictive values (PPV and NPV) of pelvic examination, TVU and CA125 were calculated. Three ovarian cancers were detected during the surveillance period; 1 prevalent cancer, 1 interval cancer and 1 screen‐detected cancer, all in an advanced stage (FIGO stage IIIc). A PPV of 20% was achieved for pelvic examination, 33% for TVU and 6% for CA125 estimation alone. The NPV were 99.4% for pelvic examination, 99.5% for TVU and 99.4% for CA125. All detected ovarian cancers were in an advanced stage, and sensitivities and positive predictive values of the screening modalities are low. Restricting the analyses to incident contacts that contained all 3 screening modalities did not substantially change the outcomes. Annual gynecological screening of women with a BRCA1/2 mutation to prevent advanced stage ovarian cancer is not effective. © 2008 Wiley‐Liss, Inc.     

Role of single nucleotide polymorphisms and haplotypes in BRCA1 in breast cancer: Czech case–control study

We aimed at determining whether any association exists between six single nucleotide polymorphisms in breast cancer associated gene (BRCA1) and the risk of breast cancer. We constructed haplotypes and analyzed their importance as well. Clinico-pathological characteristics of breast cancer patients were included in the study to evaluate the prognostic impact of BRCA1 polymorphisms and haplotypes. Polymerase chain reaction-restriction fragment length polymorphism-based genotyping assays were used to determine the frequency of polymorphisms in codons 356, 871, 1038, 1183, 1436, and 1613 of BRCA1 in a group of 306 incident breast cancer patients and 313 unaffected controls of Czech origin. Statistical analyses revealed that the BRCA1 Arg356 allele may play a protective role in breast cancer (age-adjusted OR = 0.61, CI = 0.39–0.94, p = 0.026). We also observed a significant correlation between polymorphism Gln356Arg and stage (p = 0.026) in premenopausal cases suggesting that carriers of the wild Gln356Gln allele are at significantly higher risk of advanced disease. The most common haplotypes of BRCA1 did not play a significant role in breast cancer either as risk factors or as prognostic factors. The study on rare BRCA1 haplotypes however should be repeated using larger groups. In conclusion, the BRCA1-Gln356 allele presents risk factor in the onset and progression of breast cancer in Czech population and its use as a possible screening tool should be considered.