Breast Cancer Gene Mutations Research Articles

Genetic anticipation in BRCA1/BRCA2 families after controlling for ascertainment bias and cohort effect.

Genetic anticipation, the earlier onset of disease in successive generations, has been reported in hereditary breast and ovarian cancer syndrome (HBOC), but little is known about its underlying mechanisms. Ascertainment bias has been suggested as a reason in previous studies. Likewise, cohort effect, which may be caused by environmental factors, can be misinterpreted as genetic anticipation. The authors reviewed the pedigrees of 176 kindreds, segregating those with deleterious mutations in breast cancer genes 1 and 2 (BRCA1/BRCA2) who had at least 2 consecutive generations of the same cancer (breast or ovarian). By using mutation probabilities as analytical weights in weighted random-effect models, generational differences in the age at onset of breast/ovarian cancer were calculated. The analyses were further controlled for ascertainment bias by excluding probands and adjusting for birth-cohort effect in the anticipation models. The mean age at the onset of breast cancer for the probands' generation was 41.9 years, which was 6.8 years and 9.8 years earlier than the parents' and grandparents' generations, respectively. The anticipation effect for breast cancer remained significant after excluding the probands. There was a birth-cohort effect: patients who were born in 1930s and 1940s had breast cancer 5.0 years and 7.6 years earlier than patients who were born before 1920. The difference in breast cancer age of onset across generations was no longer significant after adjusting for birth-cohort effect. The observed anticipation effect was driven mainly by a decrease in age of onset across birth cohorts, underscoring the need for risk-reducing interventions that target changing environmental/lifestyle factors in BRCA1/BRCA2 carriers. Cancer 2016;122:1913-20. © 2016 American Cancer Society.

Abstract B50: Breast cancer in the Caribbean – A six-country cohort

Abstract Introduction: In Low and Middle Income Countries (LMIC) non-communicable chronic diseases are now the leading cause of premature mortality. Breast cancer is the leading cause of cancer death in Caribbean women. A Caribbean wide study was launched to determine the demographics of breast cancer and the contribution of breast cancer gene mutations to its incidence. Methods: Breast and ovarian cancer patients were recruited from public and private clinics in the Cayman Islands, Jamaica, Barbados, Dominica, Trinidad & Tobago, Haiti and at the University of Miami/ Jackson Memorial Hospital between 2010 and January 2015. Study participants had to have at least 1 grandparent born in one of the participating countries. All women provided written consent. The study was approved by the ethics review board in all participating institutions and/or countries. A saliva sample was taken. A pedigree was drawn and demographic and clinical pathologic data was collected from 855 women and men. Summary statistics and t-tests and ANOVA were used to analyze study population characteristics. Results: Afro Caribbean women have a young age of onset of breast cancer mean age 49.1 yrs. Within the cohort, Trinidad & Tobago had significantly p<0.0001) younger participants - mean age 43 (19 - 80 yr, 95%CI 41.9-44.0); Barbados mean age 46.4 (p<0.05) compared to Cayman Islands (51.4), Dominica (52) and Haiti (51.1). The mean BMI for the cohort was 28.2: Barbados 27.5, Cayman lslands 30.3, Dominica 28.7, Haiti 25.9, Jamaica 28.2 and Trinidad & Tobago 27.4. Estrogen receptors were found in 62% (95%CI 51.6-72.6) of AC women although in Dominica and Haiti they were seldom done and all therapy was empirically guided. AC women had Her-2 overexpression in 19% (95%CI 10.7-) although it was higher in Haiti and Jamaica, 38% and 27%. Stage at presentation was skewed to stages III and IV in 5/6 countries studied (except in Cayman Islands). 30-40% of participants presented at an advance stage compared to their American counter parts where Stage III and IV account for 12%. In the cohort, women who were nulliparous had an earlier age at presentation of invasive breast cancer by 7 years (p<0.0001) compared to women with 1 or more children. Similarly 1 or more pregnancies, increased the age at invasive breast cancer diagnosis (p<0.0001). Women who underwent a TAH-BSO had a later age of onset of diagnosis by 5.1yrs (p=0.0001) Deleterious mutations in the breast cancer genes were a frequent cause of breast cancer in the Bahamas (28% of unselected patients) and Trinidad & Tobago (12% of unselected patients). 94% of breast cancers were detected by the patient. Conclusions: This population-based study provides information on the tumor stage and characteristics as well as risk factors such as genetic, weight and fertility factors that contribute to the incidence of breast cancer in AC women. AC women develop breast cancer at an earlier age than either European American (EA) or African American (AA) women (AC 49.1, AA 58, EA 62). 60% of AC women were diagnosed between the ages of 35-54 compared to 30% of AA women. Breast cancer in AC women presents at a higher stage than in AA or EA women (30-40% Stage III&IV vs 12%). Genetic factors play a large role in the etiology of breast cancer in the Bahamas and Trinidad & Tobago. Fertility factors have a direct effect on the age of onset of breast cancer. Mammography is not readily available and most cancers are detected by palpation. Financial constraints limit diagnostic capacity, treatment options and genetic testing. Breast cancer is the leading cause of cancer death in the Caribbean and as the countries in the Caribbean move rapidly from the third world into the first world, the breast cancer incidence will increase. Understanding the factors that contribute to the cause of breast cancer will enable the countries to strategy. Citation Format: Sophia HL George, Talia Donenberg, Mohammad Akbari, Cheryl Alexis, Gilian Wharfe, Hedda Dyer, Sook Yin, Theodore Turnquest, Jameel Ali, Vincent DeGennaro, Jr., Steven A. Narod, Judith Hurley. Breast cancer in the Caribbean – A six-country cohort. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr B50.

Abstract P6-06-03: Novel hereditary breast cancer gene mutations: Should there be greater concern regarding ovarian cancer risk?

Abstract INTRODUCTION: As the use of multi-gene breast cancer panel testing increases the phenotype of the included genes continues to evolve. PALB2 and NBN have a well characterized association with breast cancer and are included on many breast cancer gene panels. Germline PALB2 and NBN mutations have been identified in a small percentage of ovarian carcinoma cases with one study reporting a non-significant twofold increase in carriers of the PALB2 mutations amongst ovarian cancer patients (P= 0.4). Similar to BRCA1 and BRCA2 both genes are members of the Fanconi Anemia pathway therefore a potential increased risk for both breast and ovarian cancer could be anticipated. However at present overall the current literature on the association with ovarian cancer is sparse. Here we present the cases of three hereditary breast and ovarian cancer families found to carry pathogenic mutations within the PALB2 and NBN genes. In all three families the proband was diagnosed with ovarian or fallopian tube cancer and carries a pathogenic PALB2 or NBN mutation. Our PALB2 family carries the well-known French Canadian founder mutation, c.2323C>T, and includes the proband who was diagnosed with a stage II-C, grade 3, fallopian tube carcinoma at age 58, her heterozygote sister with ovary cancer at 68 and her mother with ovary cancer at 43 who was not able to be tested. This PALB2 proband has 5 sisters, 7 brothers and 41 nieces and nephews with only one sister diagnosed with breast cancer at 69 who also is PALB2 positive and a maternal grandmother with breast cancer at 48 who was unable to be tested. The NBN Slavic founder mutation, c.657_661del, was discovered in a 66 year old woman with stage IV, high-grade serous ovarian cancer having a mother with breast cancer at 91 and a maternal aunt with ovary cancer at 59 who have not yet been tested. Lastly, our patient from Laos with a diagnosis of a stage II-C endometrioid adenocarcinoma of the ovary diagnosed at 38 years old was found to carry the deleterious NBN mutation, c.1550dupA. She is not aware of any cancer family history and reports a large family including five brothers, four sisters and multiple aunts and uncles on both side of the family. CONCLUSION: These case studies suggest a link between PALB2 and NBN, two known breast cancer susceptibility genes, and hereditary ovarian cancer risk. These observations suggest that further data are needed to accurately evaluate ovarian cancer risk within novel hereditary breast cancer genes now commonly tested as part of multiplex panel analysis. Citation Format: Nassikas N, Wilbur JS, Laprise JK, Legare RD. Novel hereditary breast cancer gene mutations: Should there be greater concern regarding ovarian cancer risk?. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-06-03.

BRCA1, BRCA2 and PALB2 mutations and CHEK2 c.1100delC in different South African ethnic groups diagnosed with premenopausal and/or triple negative breast cancer.

BackgroundCurrent knowledge of the aetiology of hereditary breast cancer in the four main South African population groups (black, coloured, Indian and white) is limited. Risk assessments in the black, coloured and Indian population groups are challenging because of restricted information regarding the underlying genetic contributions to inherited breast cancer in these populations. We focused this study on premenopausal patients (diagnosed with breast cancer before the age of 50; n = 78) and triple negative breast cancer (TNBC) patients (n = 30) from the four South African ethnic groups. The aim of this study was to determine the frequency and spectrum of germline mutations in BRCA1, BRCA2 and PALB2 and to evaluate the presence of the CHEK2 c.1100delC allele in these patients.MethodsIn total, 108 South African breast cancer patients underwent mutation screening using a Next-Generation Sequencing (NGS) approach in combination with Multiplex Ligation-dependent Probe Amplification (MLPA) to detect large rearrangements in BRCA1 and BRCA2.ResultsIn 13 (12 %) patients a deleterious mutation in BRCA1/2 was detected, three of which were novel mutations in black patients. None of the study participants was found to have an unequivocal pathogenic mutation in PALB2. Two (white) patients tested positive for the CHEK2 c.1100delC mutation, however, one of these also carried a deleterious BRCA2 mutation. Additionally, six variants of unknown clinical significance were identified (4 in BRCA2, 2 in PALB2), all in black patients. Within the group of TNBC patients, a higher mutation frequency was obtained (23.3 %; 7/30) than in the group of patients diagnosed before the age of 50 (7.7 %; 6/78).ConclusionThis study highlights the importance of evaluating germline mutations in major breast cancer genes in all of the South African population groups. This NGS study shows that mutation analysis is warranted in South African patients with triple negative and/or in premenopausal breast cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1913-6) contains supplementary material, which is available to authorized users.

Clinical Practice Guideline for the prevention and early detection of breast and ovarian cancer in women from HBOC (hereditary breast and ovarian cancer) families.

An estimated 10% of breast cancer cases exhibit a higher familial incidence, and functional mutations in BRCA (breast cancer-gene) 1 or 2 are responsible for the development of malignant tumors in approximately half of these cases. Women with a germline mutation in either of the two genes have a lifetime risk of up to 85% to develop breast cancer, and of up to 60% risk to develop ovarian cancer. This clinical practice guideline defines the individual and familial tumor constellations that represent an indication for BRCA germline testing. It also describes the therapeutic options (early detection programme vs prophylactic surgery) that arise from the result of a BRCA mutational analysis. This guideline further includes recommendations regarding the use of multigene panels and therapeutic aspects that arise from the selective use of poly ADP ribose polymerase (PARP) inhibitors in patients with known BRCA1 or 2 mutations. It replaces the previous version of the "Clinical Practice Guideline for the Prevention and Early Detection of Breast- and Ovarian Cancer in women from HBOC (hereditary breast and ovarian cancer) families" which was published in 2012.

Molecular Technologies in Gynecologic Oncology

Molecular Technologies in Gynecologic Oncology

Label-Free and Sensitive Detection of BRCA1 and TB4 DNA Sequences with Water-Soluble Cationic Polythiophenes

A sensitive method for BRCA1 and TB4 DNA sequences detection using water-soluble cationic polythiophenes, poly(3-(1′-ethoxy-2′-N-methyl imidazole)thiophene) (PT) is presented. The fluorescence of PT could be dramatically quenched by the addition of single-stranded DNA (ssDNA; TB4 and BRCA1 sequences). The KSV (Stern–Volmer constant) for TB4 and BRCA1 DNA sequences are 1.46 × 108 and 3.28 × 108 M–1 respectively, and the limits of detection of these two sequences are 1.26 × 10–10 and 0.483 × 10–10 M respectively. The fluorescence of PT would recover to its initial intensity after the addition of complementary ssDNA, whereas sequences with one to three mismatched bases would not. The influences of buffer pH and concentration of NaCl were also investigated systemically in order to further improve the sensitivity. This assay can be completed in a short period of time without any further procedure. Hence, this sensitive, cost-effective, and rapid detection method for BRCA1 and TB4 DNA sequences may contribute to the clinical diagnosis of breast cancer gene mutations in the future.

Abstract 2948: Combination treatment of PARP inhibitor, BMN 673 and DNMT inhibitor, Azacytidine: A potential therapy for BRCA negative and positive, triple negative breast cancers

Abstract Poly-ADP-ribose polymerase inhibitors (PARPis) represent one of the most exciting recent developments in cancer therapy and have shown efficacy in a minority (5-10%) of triple negative (estrogen, progesterone and herceptin receptor negative) breast cancers (TNBCs) with inherited mutations in breast cancer genes BRCA1/2 (BRCA-ve). In PARPi clinical trials, approximately of 60% BRCA-ve patients showed responses, while a significant proportion did not. In addition, sporadic TNBCs with intact BRCA1/2 have failed PARPi therapy. This suggests the urgent need for additional novel therapies for breast cancer. Our studies are underpinned by 4 important findings: (1) the development of a new class of potent PARPis exemplified by BMN 673, (2) the mechanism of cytotoxicity of PARPis, including BMN 673, is attributed to its ability to trap PARP-DNA complexes in chromatin, (3) unpublished findings by our group that PARP interacts with epigenetic factors such as DNMT1 in a high molecular weight complex on chromatin in response to DNA damage and (4) DNMT inhibitors (DNMTis) such as FDA approved Azacytidine (AzaC) covalently trap DNMTs in DNA as their mechanism of action. Therefore, the interaction of PARP and DNMT1 suggest a therapeutic opportunity for combining PARPis and DNMTis in an effort to enhance the effects of PARPi therapy. We first set out to determine whether a combination of these two drugs would enhance trapping of PARP-DNA complexes in chromatin, leading to increased cytotoxicity of TNBC. We treated MDA-MB-231 with BMN 673 (10-100nM) or AzaC (150nM) alone, or the two drugs in combination, and measured PARP trapping in chromatin extracts following induction of DNA damage by radiation (2Gy) after 72hrs. As expected, BMN 673 treatment leads to PARP trapping as determined by western blotting of proteins from chromatin extracts. Interestingly, treatment with AzaC treatment alone also leads to the presence of PARP in chromatin. Importantly, AzaC in combination with BMN 673 treatment shows an at least a 2-fold increase in PARP trapping, compared to the individual drug treatments. To determine whether PARP trapping correlates with cytotoxicity and cell death, BRCA+ve TNBC lines MDA-MB-231 and MDA-MB-468 and BRCA-ve TNBC lines SUM149PT and HCC1937 cells were treated with the drugs alone and in combination and placed in colony forming assays. Compared with single drug treatments, the combination treatment showed a significant (p<0.05) decrease in colony formation in both BRCA positive and negative cell lines indicating BMN 673 could potentially be used in combination with AzaC to improve treatment of TNBCs. In vivo xenograft studies are underway to determine the efficacy of the drug combination compared with single treatments and vehicle controls. Citation Format: Khadiza Chowdhury, Rena G. Lapidus, Eun Yong Choi, Stephen Baylin, Feyruz V. Rassool. Combination treatment of PARP inhibitor, BMN 673 and DNMT inhibitor, Azacytidine: A potential therapy for BRCA negative and positive, triple negative breast cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2948. doi:10.1158/1538-7445.AM2015-2948

Pilot Testing of a Psycho-educational Telephone Intervention for Women Receiving Uninformative BRCA1/2 Genetic Test Results.

Evidence suggests that women who receive uninformative results for breast and ovarian cancer (BRCA1/2) gene mutations may experience as much distress as women whose results indicate the presence of a gene mutation. No intervention to reduce distress after receipt of uninformative results has yet been tested. The purpose of this study was to test the feasibility and preliminary effects of a psycho-educational telephone (PET) intervention to reduce distress in women who receive uninformative BRCA1/2 results. A single group with repeated measures was used to assess the impact of the intervention on 72 such women. After receiving the results, most of the women continued to feel uncertain about their carrier genetic status. However, their distress significantly decreased between receipt of uninformative results and 3 months post-intervention (p = 0.01). The preliminary findings suggest that a PET uncertainty intervention is clinically feasible and may reduce the distress of receiving uninformative results.

The Genetic Testing Experience of BRCA-Positive Women: Deciding Between Surveillance and Surgery.

Little is known about how the breast cancer (BRCA) gene mutation affects women's decision-making processes. I use a feminist standpoint lens to explore the process by which BRCA-positive women came to socially construct and understand their risk for developing breast and/or ovarian cancer and the treatment options they elected post-testing. This study included in-depth interviews with 64 BRCA-positive mutation women, some of whom sought surveillance and others who opted for preventive surgical intervention. The in-depth analysis and case study approach revealed a complex cancer risk assessment resulting in a "nexus of decision making" that does not mirror a statistical medical model of risk assessment. The particular configuration of women's nexus of decision making impacted their pre- and posttesting BRCA experience as empowering or disempowering, regardless of whether they elected surgery or surveillance. I discuss the implications for development of clinical strategies that will serve to enhance women's pre- and post-BRCA decision making.

Morphological and immunohistochemical study of ovarian and tubal dysplasia associated with tamoxifen.

Ovarian epithelial dysplasia was initially described in material from prophylactic oophorectomies for BReast CAncer gene (BRCA) mutation. Similar histopathological abnormalities have been revealed after ovulation stimulation. Given that tamoxifen (TAM) has a clomid-like effect and is sometimes used to induce ovulation, we studied the morphological features and immunohistochemical expression patterns of neoplasia-associated markers in adnexectomies previously exposed to TAM for breast cancer. We blindly reviewed 173 histopathological slides of adnexectomies according to three groups – oophorectomies associated with TAM exposure (n=42), oophorectomies associated with clomiphene exposure (n=15) and a spontaneously fertile non cancerous control group (n=116). Morphological features (with an ovarian and tubal dysplasia scoring system) and immunohistochemical expression patterns of Ki-67, p53 and Aldehyde dehydrogenase 1 (ALDH1 is an enzyme significantly associated with earlystage ovarian cancer) were evaluated and correlated. Mean tubal dysplasia score was significantly higher in the TAM group and clomiphen group than in controls (respectively 7.8 vs 3.5, P<0.007 and 6.8 vs 3.5, P=0.008). There is no statistical difference for the ovarian score in TAM group in comparison with the control group whereas we found a significant score for clomiphen group (6.5, P=0.009). Increased ALDH1 expression was observed in the two exposed group whereas expression patterns of Ki67 and p53 were moderate. Interestingly, ALDH1 expression was low in non-dysplastic epithelium, high in dysplasia, and constantly low in the two carcinoma.Furthemore, we confirm our previous results showing that ALDH1 may be a useful tissue biomarker in the subtle histopathological diagnosis of tubo-ovarian dysplasia.

Abstract P6-06-06: Family history and young breast cancer patients in the UK: The POSH study

Abstract Background Approximately 4% of breast cancer cases occur in women under 40 years. Young age at diagnosis is associated with inferior survival compared to older patients. It is unclear whether an increased incidence of adverse biological features fully explains this. An underlying genetic pre-disposition to breast cancer is characterised by young age of disease onset, yet even at a very young age of diagnosis most individuals do not have an identifiable mutation in a known high risk breast cancer gene. Genome wide association studies have identified low penetrance genetic variants which may account for unexplained family histories of breast cancer. The effect of a BRCA 1/2 mutation on breast cancer prognosis remains controversial with retrospective studies reporting inconsistent outcomes for mutation carriers compared to sporadic tumours. The prognostic effect of low penetrance breast cancer susceptibility genes is under investigation. POSH is a prospective observational cohort study designed to investigate prognostic factors in young breast cancer patients. Here we report pathology, treatment and outcome of these patients according to their family history of breast cancer. Methods 2956 patients aged ≤40 at breast cancer diagnosis were recruited from 126 UK hospitals between 2001 and 2007. Details of personal characteristics, tumour pathology and treatment were collected. Family history details were collected using a questionnaire completed by participants at recruitment. BRCA mutation testing is in progress. Follow-up data were collected at 6 and 12 months and then annually. Results Family history data were available for 2850 patients. 1878 (65.9%) reported no family history of breast/ ovarian malignancies and 972 (34.1%) reported breast/ ovarian cancer in one or more 1st or 2nd degree relative. Patients with a positive family history were significantly more likely to have a surveillance detected breast cancer than those without a family history (3.0% vs. 0.1% p&amp;lt;0.001) and patients with an affected 1st degree relative had a higher incidence of surveillance detected tumours than those with an affected 2nd degree relative (6.0% vs. 0.7% p&amp;lt;0.001). Patients with a positive family history were significantly more likely to have a grade 3 tumour than patients with a negative family history (63.3% vs. 58.9% p = 0.04). There were no significant differences in median tumour diameter, incidence of nodal involvement or presence of metastases between the positive and negative family history groups. The frequency of ER and PR overexpressing tumours did not vary significantly between family history groups. Patients with a negative family history were significantly more likely to have a HER2 positive tumour than those with a positive family history (28.8% vs.24.7% p = 0.031). There were no significant differences in tumour grade, size, nodal status, and ER, PR or HER2 status between patients with 1st degree or 2nd degree affected relatives. Conclusions Our data indicates that having a first or second degree relative with a breast/ ovarian cancer is associated with an increased frequency of grade 3 and HER2 negative breast tumours but not with other pathological features. Further analyses will investigate the independent effect of family history on breast cancer survival and recurrence rates. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-06-06.

Mutations in components of antiviral or microbial defense as a basis for breast cancer.

In-depth functional analyses of thousands of breast cancer gene mutations reveals vastly different sets of mutated genes in each of 21 different breast cancer genomes. Despite differences in which genes are mutated, innate immunity pathways and metabolic reactions supporting them are always damaged. These functions depend on many different genes. Mutations may be rare individually but each set of mutations affects some aspect of pathogen recognition and defense, especially those involving viruses. Some mutations cause a dysregulated immune response, which can also increase cancer risks. The frequency of an individual mutation may be less important than its effect on function. This work demonstrates that acquired immune deficiencies and immune dysregulation in cancer can occur because of mutations. Abnormal immune responses represent a hidden variable in breast cancer-viral association studies. Compensating for these abnormalities may open many new opportunities for cancer prevention and therapy.

Psychosocial approaches to participation in BRCA1/2 genetic risk assessment among African American women: a systematic review

Breast cancer is a significant health concern for African American women. Nonetheless, uptake of genetic risk assessment (including both genetic counseling and testing) for breast cancer gene mutations among these populations remains low. This paper systematically reviews cognitive (i.e., beliefs) and affective (i.e., emotions) factors influencing BRCA1/2 genetic risk assessment among African American women as well as psychosocial interventions to facilitate informed decision making in this population. A systematic search of CINAHL, PubMed, and PsycINFO was undertaken, yielding 112 published studies. Of these, 18 met the eligibility criteria. African American woman are likely to participate in genetic risk assessment if they are knowledgeable about cancer genetics, perceive a high risk of developing breast cancer, have low expectancies of stigmatization from medical professionals, view themselves as independent from family, and have fatalistic beliefs and a future temporal orientation. Anticipated negative affective responses, such as an inability to “handle” the results of testing, are barriers to uptake. Specific perceptions, beliefs, and emotional factors are associated with genetic risk assessment among African American women. Understanding these factors is key in the development of interventions to facilitate informed decision making in this population.

Inherited mutations in breast cancer genes in African American breast cancer patients revealed by targeted genomic capture and next-generation sequencing.

CRA1501 Background: African American (AA) women are disproportionately affected by early-onset and triple-negative breast cancer (TNBC). One explanation for these disparities may be a higher frequency of inherited mutations among AA women in genes in DNA repair pathways, including BRCA1 and BRCA2. Using targeted genomic capture and next generation sequencing (NGS), we screened DNA from AA women with breast cancer for mutations in all 18 known breast cancer genes. Methods: A total of 249 unrelated AA women with breast cancer were ascertained through the Cancer Risk Clinic at The University of Chicago. Genomic DNA was extracted from peripheral blood and 3 micrograms were used for targeted capture and sequencing. Average read depth across the 1.4 MB targeted region was 320-fold. Sequence reads were aligned and all classes of variants identified: point mutations, small insertions and deletions, and large genomic rearrangements. Only unambiguously damaging mutations were called: stops, complete genomic deletions, and missenses demonstrated experimentally to cause loss of protein function. Variants were validated by PCR or Taqman analysis. Results: Fifty-six of 249 subjects (22%) carried at least one loss-of-function mutation, distributed among BRCA1 (n=26), BRCA2 (n=20), CHEK2 (n=3), PALB2 (n=3), ATM (n=5), and PTEN (n=1). The majority of mutations were unique. Damaging mutations were carried by 30% of patients with TNBC, 27% of patients diagnosed at age ≤45, 49% with a second breast primary, and 30% with a family history of either breast or ovarian cancer in any close relative. Conclusions: We present the first comprehensive screen of all known breast cancer susceptibility genes among AA women using NGS. Mutation carrier frequencies are &gt;25% for major subsets of patients defined by tumor or host characteristics. These high carrier frequencies suggest the importance of screening for mutations in all breast cancer genes in all AA breast cancer patients diagnosed at a young age, with a family history, or with TNBC as a way to identify at-risk family members for life-saving interventions.

Inherited mutations in breast cancer genes in African American breast cancer patients revealed by targeted genomic capture and next generation sequencing.

CRA1501 The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Monday, June, 3, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Monday edition of ASCO Daily News.

Countercurrents: A New Kind of Breast Cancer Gene Mutation

A fascinating article, recently published in Nature and titled “Mosaic PPM1D Mutations Are Associated with Predisposition to Breast and Ovarian Cancer” by Nazneen Rahman and her colleagues, is a rare example of a discovery that causes a re-evaluation of our assumptions about cancer and cancer genes. [...]

The role of BRCA1 in homologous recombination repair in response to replication stress: significance in tumorigenesis and cancer therapy

Germ line mutations in breast cancer gene 1 (BRCA1) predispose women to breast and ovarian cancers. Although BRCA1 is involved in many important biological processes, the function of BRCA1 in homologous recombination (HR) mediated repair is considered one of the major mechanisms contributing to its tumor suppression activity, and the cause of hypersensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors when BRCA1 is defective. Mounting evidence suggests that the mechanism of repairing DNA double strand breaks (DSBs) by HR is different than the mechanism operating when DNA replication is blocked. Although BRCA1 has been recognized as a central component in HR, the precise role of BRCA1 in HR, particularly under replication stress, has remained largely unknown. Given the fact that DNA lesions caused by replication blockages are the primary substrates for HR in mitotic cells, functional analysis of BRCA1 in HR repair in the context of replication stress should benefit our understanding of the molecular mechanisms underlying tumorigenesis associated with BRCA1 deficiencies, as well as the development of therapeutic approaches for cancer patients carrying BRCA1 mutations or reduced BRCA1 expression. This review focuses on the current advances in this setting and also discusses the significance in tumorigenesis and cancer therapy.

Original Research

Women who carry a BRCA1 or BRCA2 gene mutation face a risk of developing breast or ovarian cancer at an earlier age than women without such a mutation. Relatively little is known about the psychosocial consequences-especially regarding marriage and childbearing-in young women who test positive for one of these mutations. In 2006, participants were recruited from Web sites for women with breast cancer or BRCA gene mutations. Forty-four women ages 18 to 39 from 22 states and Canada who had had genetic testing and were found to carry a BRCA mutation were interviewed by phone or e-mail. A qualitative, grounded theory analysis was performed on the data, focusing on the participants' being young and having had genetic testing for the BRCA mutation. The findings reported here focus on three characteristics of the participants-whether or not they were married, had children, or had a breast cancer diagnosis-and how those characteristics were affected by the women's knowledge of their genetic risk. Among the 13 unmarried participants, issues of when to disclose information about their genetic risk in intimate relationships were discussed. Many of the 24 participants who had children reported "staying alive" for their children as a primary goal; the childless women reported an urgency to have children. Of the 21 who had a breast cancer diagnosis, the youngest was 24 years old, and several said knowledge of their genetic risk influenced their decision to have the unaffected breast removed prophylactically. A sense of being different and not understood was expressed in these interviews. These findings suggest that nurses should be aware of psychosocial issues, especially those surrounding marriage and childbearing, in their interactions with young women who carry a BRCA1 or BRCA2 gene mutation.

A Patient With Metastatic Breast Cancer 15 Years After Bilateral Prophylactic Total Mastectomy and Oophorectomy

Introduction It is estimated that 5%–10% of breast cancer is hereditary with 60%–70% of those arising from a Breast Cancer gene mutation in clinical practice (BRCA)1 or BRCA2 mutation. Women with RCA1 or BRCA2 mutations have a 55%–85% lifetime risk of nvasive breast cancer. Among women with BRCA1, 36%–63% deelop ovarian cancer and among patients with BRCA2 10%–27% evelop ovarian cancer. BRCA1-related breast cancers tend to be of he basal subtype, with predominant lymphocytic infiltration, and re often more aggressive and associated with negative prognostic actors. They are usually Estrogen (ER)/Progesterone (PR)/ ER2neu negative. BRCA2-related breast cancers tend to be of the uminal type, and are usually ER/PR positive. The median age of reast cancer onset ranges from 40 to 50 years in BRCA1 and RCA2 carriers compared with 60–70 years in sporadic cases.