Hereditary Breast Cancer Genes Research Articles

How Far Do We Go With Genetic Evaluation? Gene, Panel, and Tumor Testing

The traditional model by which an individual was identified as harboring a hereditary susceptibility to cancer was to test for a mutation in a single gene or a finite number of genes associated with a particular syndrome (e.g., BRCA1 and BRCA2 for hereditary breast and ovarian cancer or mismatch repair genes for Lynch syndrome). The decision regarding which gene or genes to test for was based on a review of the patient’s personal medical history and their family history. With advances in next-generation DNA sequencing technology, offering simultaneous testing for multiple genes associated with a hereditary susceptibility to cancer is now possible. These panels typically include high-penetrance genes, but they also often include moderate- and low-penetrance genes. A number of the genes included in these panels have not been fully characterized either in terms of their cancer risks or their management options. Another way some patients are unexpectedly identified as carrying a germline mutation in a cancer ...

A Systematic Comparison of Traditional and Multigene Panel Testing for Hereditary Breast and Ovarian Cancer Genes in More Than 1000 Patients

Gene panels for hereditary breast and ovarian cancer risk assessment are gaining acceptance, even though the clinical utility of these panels is not yet fully defined. Technical questions remain, however, about the performance and clinical interpretation of gene panels in comparison with traditional tests. We tested 1105 individuals using a 29-gene next-generation sequencing panel and observed 100% analytical concordance with traditional and reference data on >750 comparable variants. These 750 variants included technically challenging classes of sequence and copy number variation that together represent a significant fraction (13.4%) of the pathogenic variants observed. For BRCA1 and BRCA2, we also compared variant interpretations in traditional reports to those produced using only non-proprietary resources and following criteria based on recent (2015) guidelines. We observed 99.8% net report concordance, albeit with a slightly higher variant of uncertain significance rate. In 4.5% of BRCA-negative cases, we uncovered pathogenic variants in other genes, which appear clinically relevant. Previously unseen variants requiring interpretation accumulated rapidly, even after 1000 individuals had been tested. We conclude that next-generation sequencing panel testing can provide results highly comparable to traditional testing and can uncover potentially actionable findings that may be otherwise missed. Challenges remain for the broad adoption of panel tests, some of which will be addressed by the accumulation of large public databases of annotated clinical variants.

Abstract S5-05: Defective stalled replication fork repair and predisposition to hereditary breast cancer

Abstract BRCA1 is a tumor suppressor gene, and germ line BRCA1 mutations increase the risk of breast cancer. While all cells with BRCA1 mutations exhibit a heterozygous BRCA1mut/+ genotype, cancer develops primarily in females, often at young ages and affects almost exclusively the breast and ovaries. Why BRCA1 shows such tissue specificity, and how a normal cell in a BRCA1 mutation carrier (BRCA1mut/+) gives rise to invasive tumor cells are largely unknown. To determine whether BRCA1 heterozygosity in cells confers defect in any of the multiple, known, BRCA1 functions is a potentially valuable step in achieving a better understanding of BRCA1 mutation-driven cancer predisposition. Thus, we have analyzed a collection of primary mammary BRCA1mut/+ epithelial cells and skin fibroblasts obtained from BRCA1 mutation carriers for such functions. We, and others have recently shown that BRCA1 exhibits a new DNA damage repair function – i.e. repair of stalled replication forks (SFR). Stalled forks, when not resolved, lead to mutations, or collapse into double strand breaks (DSBs). Both outcomes result in what is commonly referred to as replication stress (RS), which, when chronic, is a driving force behind cancer development. To determine if SFR is defective in normal/healthy breast cells in BRCA1 mutation carriers, and whether this haploinsufficiency results in the kind of genomic changes that lead to cancer, we have now generated 18 primary fibroblast strains from skin punch biopsies and 10 primary mammary epithelial cell (MECs) strains from prophylactic mastectomies performed on BRCA1 mutation carrying women. This collection includes N=23 different BRCA1 mutations, which, together, span almost the entire BRCA1 gene. BRCA1+/+ control MECs were derived from tissue collected during reduction mammoplasties and control fibroblasts were derived from skin punch biopsies from women with no BRCA1 mutation. Our current data shows that BRCA1mut/+ strains exhibited multiple, normal BRCA1 functions, including the support of homologous recombination- type double strand break repair (HR-DSBR), cell cycle- associated checkpoint functions, centrosome number control, spindle pole formation, Slug expression and satellite RNA suppression. By contrast, nearly all strains were defective in the repair of stalled replication forks and in the suppression of fork collapse, i.e. replication stress. These defects were rescued by reconstituting BRCA1 heterozygous cells with wild-type BRCA1 cDNA, indicating that they are a product of BRCA1 haploinsufficiency. In addition, the development of sufficient replication stalling rendered BRCA1mut/+ cells defective in an otherwise intact BRCA1 function, HR-DSBR. No such ‘conditional’ haploinsufficiency was detected in any of the other non-haploinsufficient functions, noted above. Given the importance of replication stress in cancer development and of an HR defect in breast cancer pathogenesis, these defects, when they develop serially, could contribute to the BRCA1 breast cancer development pathway. Finally, given the important role of BRCA2, another hereditary breast cancer gene, in stalled fork stability, a similar analysis for BRCA2mut/+ cells from BRCA2 mutation carriers is currently underway and will also be reported at the meeting. Citation Format: Shailja Pathania, Sangeeta Bade, Morwenna Le Guillou, Karly Burke, Ying Su, David T Ting, Kornelia Polyak, Andrea L Richardson, Jean Feunteun, Judy E Garber, David M Livingston. Defective stalled replication fork repair and predisposition to hereditary breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S5-05.

Heterozygous Mutations in DNA Repair Genes and Hereditary Breast Cancer: A Question of Power

Heterozygous Mutations in DNA Repair Genes and Hereditary Breast Cancer: A Question of Power

Genetic Testing by Cancer Site

It is estimated that 5% to 10% of pancreatic cancer is familial. Although there is evidence of a major pancreatic cancer susceptibility gene, the majority of families with multiple cases of pancreatic cancer do not have an identifiable causative gene or syndrome. However, a subset of pancreatic cancer is attributable to known inherited cancer predisposition syndromes, including several hereditary breast cancer genes (BRCA1, BRCA2, and PALB2), CDKN2A, hereditary pancreatitis, hereditary nonpolyposis colorectal cancer, and Peutz-Jeghers syndrome. In addition to explaining a proportion of familial pancreatic cancer, individuals with these conditions are at increased risk for pancreatic cancer. Relatives from familial pancreatic cancer kindreds without one of these identifiable syndromes may have as high as a 32-fold risk of pancreatic cancer, depending on the number of affected first-degree relatives. Such high-risk individuals may benefit from increased surveillance, and strategies for early detection of pancreatic cancer are under evaluation.

Abstract 2597: Identification of new genes for hereditary breast cancer

Abstract Major hereditary breast cancer (BC) genes, BRCA1 and BRCA2, contribute to no more than 20-25% of familial BC clustering; therefore the majority of BC-predisposing mutations remain to be identified. We have selected for the study 95 BC cases, which showed accumulation of clinical signs of the genetic disease (e.g., occurrence of BC among multiple relatives and/or bilaterality and/or young age at onset), but could not be explained either by BRCA1/2 sequence alterations or by Russian founder mutations in CHEK2 (c.1100delC, c.444+1G>A, del5395) or NBN (657del5) genes. The entire coding regions of DNA repair genes were examined using high resolution melting (HRM) analysis and DNA sequencing. Three of 16 genes selected for the study (CHEK2, NBN, PALB2, BRIP1, BARD1, RAD51C, BLM, FANCG, CHEK1, PARP1, PARP2, ERCC1, XPE, BRD7, RNF8, RAD51A) contained potentially deleterious mutations. Two patients carried inactivating lesion in the PALB2 gene (p.R414X and p.Q921X); both these carriers had the bilateral form of BC disease. 1 woman harbored mutation in the FANCG gene (c.520_524delTCTAinsC), which resulted in the loss of serine at position 174 and lysine to glutamine substitution at position 175. The analysis of the BLM gene revealed two heterozygous carriers of the c.1642 C>T (Q548X) allele. This mutation was subjected to the extended study, which confirmed its recurrent character and strong association with BC risk: BLM c.1642 C>T (Q548X) heterozygotes were detected in 17/1,498 (1.1%) BC patients as compared to 2/1,093 (0.2%) healthy females (p = 0.004). As expected for BC-predisposing gene, the BLM 1670 C>T allele tended to be associated with first-degree family history of BC, early onset and bilateral appearance of the disease. This is the first demonstration of the role of the BLM heterozygosity in the determination of BC risk. The impact of constitutional BLM mutations in hereditary cancer predisposition deserves to be tested in other ethnic groups as well as in other tumor types. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2597. doi:1538-7445.AM2012-2597

P2-13-10: Detection, Visualization and High Resolution Physical Mapping of Large Rearrangements by Molecular Combing in the Hereditary Breast Cancer Genes BRCA1 and BRCA2.

Abstract The BRCA1 and BRCA2 genes are involved, with high penetrance, in breast and ovarian cancer susceptibility. About 2% to 4% of breast cancer patients with a positive family history who are negative for BRCA1 and BRCA2 point mutations can be expected to carry large genomic alterations (deletion or duplication) in one of the two genes, and especially BRCA1. However, large rearrangements are missed by direct sequencing. Molecular Combing is a powerful FISH-based technique for direct visualization of single DNA molecules, allowing the entire genome to be examined at high resolution in a single analysis. We have developed a novel genetic test based on Molecular Combing. For that purpose, we designed specific BRCA1 and BRCA2 “Genomic Morse Codes” (GMC), also covering the non-coding regions and including large genomic portions flanking both genes. We developed a measurement strategy for the GMC signals, and validated our approach by blindly testing 10 breast cancer patients with a positive family history and 10 control patients. Large rearrangements, corresponding to deletions and duplications of one or several exons and with sizes ranging from 3 kb to 40 kb, were detected on both genes, including the characterization of 4 new mutations (for BRCA1: Del ex 3, Del ex 24 and Dup ex 3; for BRCA2: Dup ex 17–20). The identified mutations confirmed the results obtained with high-resolution zoom-in aCGH (11 k) in the same patients, with a resolution in the 1–2 kb range. Importantly, the developed GMC allowed to unambiguously localize several tandem repeat duplications on both genes, and to precisely map large rearrangements in the problematic Alu-rich 5'-region of BRCA1. We propose the developed Molecular Combing genetic test as a valuable tool for the screening of tandem repeat duplications, CNVs, and other complex rearrangements in BRCA1 and BRCA2, such as translocations and inversions, to be combined in clinical settings with an essay that allows the detection of point mutations. We see the main application of the developed molecular diagnostic tool as a predictive genetic test. However, we envisage to extended the application of the developed tool as a companion diagnostic test, for instance in the screening of BRCA-mutated cells in the context of the development of PARP inhibitors. Thus, the genetic test may be applied not only to clinical blood samples, but also to circulating cells and heterogeneous cell populations, such as tumor tissues. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-13-10.

Novel LOVD databases for hereditary breast cancer and colorectal cancer genes in the Chinese population

The Human Variome Project (HVP) is an international consortium of clinicians, geneticists, and researchers from over 30 countries, aiming to facilitate the establishment and maintenance of standards, systems, and infrastructure for the worldwide collection and sharing of all genetic variations effecting human disease. The HVP-China Node will build new and supplement existing databases of genetic diseases. As the first effort, we have created a novel variant database of BRCA1 and BRCA2, mismatch repair genes (MMR), and APC genes for breast cancer, Lynch syndrome, and familial adenomatous polyposis (FAP), respectively, in the Chinese population using the Leiden Open Variation Database (LOVD) format. We searched PubMed and some Chinese search engines to collect all the variants of these genes in the Chinese population that have already been detected and reported. There are some differences in the gene variants between the Chinese population and that of other ethnicities. The database is available online at http://www.genomed.org/LOVD/. Our database will appear to users who survey other LOVD databases (e.g., by Google search, or by NCBI GeneTests search). Remote submissions are accepted, and the information is updated monthly.

An amalgamated risk estimation model (REM) and assay integration into future REMs

The clinical reality of the post-genomic era is that we now face even more complex disease processes when provided with genomic information, including multifactorial genetic and genomic influences, and epigenetic and environmental factors. A useful example of the promise and perils of genomic technologies and information is breast cancer. By the mid-1990s, two genes (BRCA1 and BRCA2) had been identified, accounting for approximately 5% of affected individuals. Since then, surprisingly few genetic breast cancer risk factors have been identified to account for the remaining 95%. To efficiently and cost-effectively identify individuals at high risk, a combination of information components is required: a patient-reported personal and family medical history; clinical data (for example, a physical exam, pathology results, laboratory test results and imaging); and genetic/genomic results. Gaining comprehensive data from all of these areas provides the best risk assessment and management options for patients. Furthermore, high quality patient and clinical information is essential for the accurate and reliable interpretation of genomic results. We have clinically implemented a platform that integrates all three informational components with multiple risk estimation models (REMs) to produce an effective automated method for risk-stratifying patients. Although this platform can be and has been applied to a wide range of genetic conditions, this presentation will use breast cancer to illustrate the approach. This system consists of three primary components: a secure web-based questionnaire used by patients to enter personal and family medical history; a tablet-based system for collecting clinical and genomic information; and an analysis engine that seamlessly integrates REMs that have been developed to calculate either a woman’s risk of developing breast cancer during her lifetime (Claus, Gail II, BRCAPRO, BOADICEA and IBIS) or the probability of detecting a hereditary breast cancer gene mutation (Myriad, Penn II, BRCAPRO, BOADICEA and IBIS).This use of multiple or amalgamated REM (aREM) results offers one of the most comprehensive breast cancer risk assessments available for predicting the lifetime risk of developing breast cancer or the presence of BRCA mutations. Additional uses for aREMs include rapid analyses of existing breast cancer datasets, external validation of new REMs, and prospective outcome comparisons based on initial aREM results. Numerous biomarkers for breast cancer, in addition to BRCA1 and BRCA2 mutations, have been reported, but few molecular markers or assays have been adopted for clinical use. The addition of novel REMs that integrate a new molecular assay or classifiers can facilitate the identification of an enriched population for screening (for example, lowering the number needed to screen) or for diagnostic, prognostic or therapeutic purposes. REMs are rapidly integrating multiple genetic influences, whole genome sequencing data and epigenetic modifications, so structured comparisons of the performance of existing and emerging predictive REMs are required for safe and effective clinical application.

Direct to Confusion: Lessons Learned from Marketing BRCA Testing

Myriad Genetics holds a patent on testing for the hereditary breast and ovarian cancer genes, BRCA1 and BRCA2, and therefore has a forced monopoly on this critical genetic test. Myriad launched a Direct-to-Consumer (DTC) marketing campaign in the Northeast United States in September 2007 and plans to expand that campaign to Florida and Texas in 2008. The ethics of Myriad's patent, forced monopoly and DTC campaign will be reviewed, as well as the impact of this situation on patient access and care, physician liability, and the future of DTC campaigns for genetic testing.

PARP Inhibitor Development for Systemic Cancer Targeting

Poly(ADP-ribose) polymerase 1 (PARP-1) is a DNA-binding enzyme that is activated by DNA breaks, converting them into an intracellular signal via poly(ADP-ribosyl)ation of nuclear proteins. Negatively charged polymers of ADP-ribose (PAR) attached to PARP-1 itself and histones lead to chromatin relaxation, facilitating the access of base excision/single strand break repair proteins and activating these repair enzymes. PARP inhibitors have been developed to investigate the role of PARP-1 in cell biology and to overcome DNA repair-mediated resistance of cancer cells to cytotoxic therapy. Since the early benzamide inhibitors of the 1980s PARP inhibitors, developed through structure-activity relationships and crystal structure-based drug design, that are 1,000 x more potent have been identified. These novel PARP inhibitors have been shown to enhance the antitumour activity of temozolomide (a DNA-methylating agent), topoisomerase poisons and ionising radiation in advanced pre-clinical studies and are now under clinical evaluation. PARP inhibitors can also selectively kill cells and tumours with homozygous defects in the hereditary breast cancer genes, BRCA1 and BRCA2.

High‐resolution oligonucleotide array‐CGH applied to the detection and characterization of large rearrangements in the hereditary breast cancer gene BRCA1

We have developed a new method for detecting and characterizing large rearrangements in the BRCA1 gene based on high-resolution oligonucleotide array-CGH technology. We designed a specific CGH array for the BRCA1 gene and its flanking regions. We then used this approach to analyze nine DNA samples known to contain large deletions and large duplications. When possible, the deleted or duplicated region was sequenced to identify the break point. All the large rearrangements were detected by the new method, and their size was estimated to be within 1--2 kb. This enabled us to develop a simple polymerase chain reaction screening test for other family members. A refined choice of oligonucleotides should improve the precision of the breakpoint determination. Finally, the high resolution of oligonucleotide array-CGH should help to detect new large rearrangements missed by other current methods.

Analysis of the DNA Substrate Specificity of the Human BACH1 HelicaseAssociated with BreastCancer

We have investigated the DNA substrate specificity of BACH1 (BRCA1-associated C-terminal helicase). The importance of various DNA structural elements for efficient unwinding by purified recombinant BACH1 helicase was examined. The results indicated that BACH1 preferentially binds and unwinds a forked duplex substrate compared with a duplex flanked by only one single-stranded DNA (ssDNA) tail. In support of its DNA substrate preference, helicase sequestration studies revealed that BACH1 can be preferentially trapped by forked duplex molecules. BACH1 helicase requires a minimal 5 ' ssDNA tail of 15 nucleotides for unwinding of conventional duplex DNA substrates; however, the enzyme is able to catalytically release the third strand of the homologous recombination intermediate D-loop structure irrespective of DNA tail status. In contrast, BACH1 completely fails to unwind a synthetic Holliday junction structure. Moreover, BACH1 requires nucleic acid continuity in the 5 ' ssDNA tail of the forked duplex substrate within six nucleotides of the ssDNA-dsDNA junction to initiate efficiently DNA unwinding. These studies provide the first detailed information on the DNA substrate specificity of BACH1 helicase and provide insight to the types of DNA structures the enzyme is likely to act upon to perform its functions in DNA repair or recombination.

Breast cancer risk and the DNA double-strand break end-joining capacity of nonhomologous end-joining genes are affected by BRCA1.

A tumorigenic role of the nonhomologous end-joining (NHEJ) pathway for the repair of DNA double-strand breaks (DSBs) has been suggested by the finding of a significant association between increased breast cancer risk and a cooperative effect of single nucleotide polymorphisms (SNPs) in NHEJ genes. However, the lack of an association between hereditary breast cancer and defective NHEJ genes prevents conclusions from being drawn about a link between NHEJ and breast cancer development. Recently, BRCA1-deficient mouse embryonic fibroblasts were found to have significantly reduced NHEJ activity, suggesting an accessory role of BRCA1 in NHEJ. The present study was performed to confirm this observation in human breast cancer cell lines and to examine whether the interaction between BRCA1 and NHEJ was of tumorigenic significance. Support for this hypothesis came from the findings that (a) a case-control study (469 breast cancer patients and 740 healthy controls) showed that the breast cancer risk associated with high-risk genotypes of NHEJ genes was significantly modified by the BRCA1 genotype. A significant increase in the cancer risk associated either with harboring one additional putative high-risk NHEJ genotype or with the joint effect of having reproductive risk factors (reflected by an interval of > or =12 years between menarche and first full-term pregnancy) and a higher number of high-risk genotypes of the NHEJ genes was only seen in women with at least one variant BRCA1 allele (i.e., the Glu/Gly or Gly/Gly forms of BRCA1 Glu(1038)Gly); and (b) a phenotype-based study measuring in vitro and in vivo NHEJ capacity showed that the precise end-joining capacity was different in breast cancer cell lines with different BRCA1 statuses being higher in BRCA1-expressing MCF-7 cells than in HCC1937 cells (defective BRCA1 expression). Furthermore, this end-joining capacity was decreased in MCF-7 cells in which BRCA1 expression was blocked using small interfering RNA and increased in HCC1937 transfected with full-length BRCA1. Because BRCA1 is a well-documented breast cancer susceptibility gene, this association between NHEJ and BRCA1 not only suggests a role of BRCA1 in NHEJ but also provides essential support for the tumorigenic contribution of NHEJ in breast cancer development.

A distinct phenotype characterizes tumors from a putative genetic trait involving chondrosarcoma and breast cancer occurring in the same patient

Recently, we documented an increased risk for the occurrence of breast- and cartilaginous tumors in the same patient, statistically pointing towards a potential genetic trait. This trait is most probably not associated with mutations in the two major hereditary breast cancer genes since no cases of enchondroma or chondrosarcoma were found in Dutch BRCA1 and BRCA2 families. We were able to collect and review the tumor tissue samples from 34 patients with both breast- and cartilaginous tumors and compared histopathological and immunohistochemical features of these tumors with controls. Breast cancer controls were available from literature data generated to compare familial breast cancers with nonselected cases. Clinical markers for chondrosarcoma controls were collected from the Netherlands Committee of Bone Tumors. Immunohistochemical data on chondro-tumor controls were available from our own files. Breast tumors of patients with cartilaginous sarcomas showed a significantly higher mitotic count (P=0.001), contained less lymphocyte infiltrate (P=0.025) and less nuclear pleomorphism. Remarkably, all cartilaginous tumors are of one common histological category originating centrally (P=0.014). Estrogen receptor and p53 expression were significantly higher (P<0.001) in breast cancer associated with chondro-tumors. p21 staining was more often negative in chondro-tumors associated with breast cancer. In seven cases of breast cancer, we found a slight decrease in CHEK2 expression. However, we could not identify the CHEK2 1100delC mutation in these cases nor in cases with normal CHEK2 expression. Hierarchical cluster analysis of all parameters within chondro-tumor-associated breast cancer specimens revealed two different subgroups, the largest one associated with estrogen receptor-positive breast cancer, which may distinguish sporadic cases from those belonging to the potential genetic trait. These distinct phenotypic findings support the existence of a new hitherto unrecognized syndrome, characterized by an increased risk to develop both breast cancer and centrally originating cartilaginous tumors.

A distinct phenotype characterizes tumors from a putative genetic trait involving chondrosarcoma and breast cancer occurring in the same patient

Recently, we documented an increased risk for the occurrence of breast- and cartilaginous tumors in the same patient, statistically pointing towards a potential genetic trait. This trait is most probably not associated with mutations in the two major hereditary breast cancer genes since no cases of enchondroma or chondrosarcoma were found in Dutch BRCA1 and BRCA2 families. We were able to collect and review the tumor tissue samples from 34 patients with both breast- and cartilaginous tumors and compared histopathological and immunohistochemical features of these tumors with controls. Breast cancer controls were available from literature data generated to compare familial breast cancers with nonselected cases. Clinical markers for chondrosarcoma controls were collected from the Netherlands Committee of Bone Tumors. Immunohistochemical data on chondro-tumor controls were available from our own files. Breast tumors of patients with cartilaginous sarcomas showed a significantly higher mitotic count (P=0.001), contained less lymphocyte infiltrate (P=0.025) and less nuclear pleomorphism. Remarkably, all cartilaginous tumors are of one common histological category originating centrally (P=0.014). Estrogen receptor and p53 expression were significantly higher (P<0.001) in breast cancer associated with chondro-tumors. p21 staining was more often negative in chondro-tumors associated with breast cancer. In seven cases of breast cancer, we found a slight decrease in CHEK2 expression. However, we could not identify the CHEK2 1100delC mutation in these cases nor in cases with normal CHEK2 expression. Hierarchical cluster analysis of all parameters within chondro-tumor-associated breast cancer specimens revealed two different subgroups, the largest one associated with estrogen receptor-positive breast cancer, which may distinguish sporadic cases from those belonging to the potential genetic trait. These distinct phenotypic findings support the existence of a new hitherto unrecognized syndrome, characterized by an increased risk to develop both breast cancer and centrally originating cartilaginous tumors.

Hereditary breast and ovarian cancer genes.

Breast cancer affects one out of every 10 women in industrialized countries, and is a leading cause of cancer morbidity and mortality in women. Ovarian cancer, although less common than breast cancer, is very difficult to treat effectively, in part due to difficulty in early diagnosis of the disease. Most cases of breast or ovarian cancer appear to occur without a clear family history of the disease. These sporadic cases account for approximately 95% of all breast cancer. Possibly, low-penetrance genes contribute as risk factors to this group of cancers. However, about 5% of breast cancers occur clustered within families. Importantly, cancer in these familial syndromes characteristically manifests at a younger age than sporadic cancer. Therefore, in terms of both the number of women affected and the effect of disease on individual families, the familial breast and/or ovarian cancer syndromes have a large impact upon society. Over the past few years, the genetic basis of familial breast and ovarian cancer has become clear. It is caused by germline mutations affecting one of two autosomal tumor suppressor genes, BRCA1 and BRCA2. Surprisingly, these two genes have been found to participate in the control of homologous recombination, suggesting that they may function as tumor suppressors by regulating genome integrity maintenance functions.

Psychological issues among children of hereditary breast cancer gene (BRCA1/2) testing participants.

Children growing up in hereditary breast cancer families may experience diminished psychological well-being. In addition to coping with having a cancer-affected parent or close relatives, these children may focus on their own health risks in light of shared genetic information. While knowledge of a parent's BRCA1/2 negative status may allay a subset of children's worries and fears about cancer, others could experience distressing thought patterns over positive test results. The purpose of this preliminary study is to explore conceptions of health, cancer risk, and psychological adjustment among children in families suggestive of carrying BRCA1/2 susceptibility genes. As part of a longitudinal investigation of the outcomes of BRCA1/2 testing in adults, 20 children of a highly select group of 15 mothers (80% previously affected by breast/ovarian cancer) completed a self-report survey of their beliefs and opinions regarding cancer and genetic testing, stress and worry about cancer, and anxiety, depression, and behavior problems. All information was completed at baseline, prior to the mother's receipt of her genetic test result. The data did not suggest unusually elevated cancer worries or psychological adjustment problems in these children at this point in the parental genetic testing process. However, children with more psychological distress symptoms did experience more frequent thoughts of becoming sick and greater cancer worries. To the extent that learning about a parent's positive test result could exacerbate these tendencies, recommendations to promote child psychological and family communications research that monitor such responses are offered.

Psychological issues among children of hereditary breast cancer gene (BRCA1/2) testing participants

Psychological issues among children of hereditary breast cancer gene (BRCA1/2) testing participants

Testing adolescents for a hereditary breast cancer gene (BRCA1): respecting their autonomy is in their best interest.

The testing of individuals before the age of 18 years for hereditary late-onset diseases has been judged ethically not acceptable in guidelines and directives published by medical professional organizations. However, there are not enough best interest arguments to deny genetic testing to an adolescent at risk of carrying a BRCA1 mutation, even if the competence of adolescents for medical decisions is considered to be lower than the competence of adults. The adolescent's decision is not irrational or of very high risk. Respecting adolescents' autonomous choices concerning genetic testing has positive consequences for their self-esteem and psychological health. Geneticists and other professionals should clearly differentiate between children and adolescents in regard to BRCA1 gene testing and recommend giving decision autonomy about the test to all psychologically "normal" adolescents.