Background
Previous studies have reported additional cancers associated with BRCA mutations; however, type, magnitude of risk, and gender differences remain to be clarified. The purpose of this study was to evaluate the incidence of cancers other than breast and ovarian cancer in known mutation carriers.

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Cancers Associated with BRCA1 and BRCA2 Mutations other than Breast and Ovarian

The tumour suppressor breast cancer type 1 susceptibility protein (BRCA1) promotes DNA double-strand break (DSB) repair by homologous recombination and protects DNA replication forks from attrition. BRCA1 partners with BRCA1-associated RING domain protein 1 (BARD1) and other tumour suppressor proteins to mediate the initial nucleolytic resection of DNA lesions and the recruitment and regulation of the recombinase RAD51. The discovery of the opposing functions of BRCA1 and the p53-binding protein 1 (53BP1)-associated complex in DNA resection sheds light on how BRCA1 influences the choice of homologous recombination over non-homologous end joining and potentially other mutagenic pathways of DSB repair. Understanding the functional crosstalk between BRCA1-BARD1 and its cofactors and antagonists will illuminate the molecular basis of cancers that arise from a deficiency or misregulation of chromosome damage repair and replication fork maintenance. Such knowledge will also be valuable for understanding acquired tumour resistance to poly(ADP-ribose) polymerase (PARP) inhibitors and other therapeutics and for the development of new treatments. In this Review, we discuss recent advances in elucidating the mechanisms by which BRCA1-BARD1 functions in DNA repair, replication fork maintenance and tumour suppression, and its therapeutic relevance.

The antitumorigenic roles of BRCA1–BARD1 in DNA repair and replication

Carcinogenesis is a multistep process, and tumors frequently harbor multiple mutations regulating genome integrity, cell division and death. The integrity of cellular genome is closely controlled by the mechanisms of DNA damage signaling and DNA repair. The association of breast cancer susceptibility genes BRCA1 and BRCA2 with breast and ovarian cancer development was first demonstrated over 20 years ago. Since then the germline mutations within these genes were linked to genomic instability and increased risk of many other cancer types. Genomic instability is an engine of the oncogenic transformation of non-tumorigenic cells into tumor-initiating cells and further tumor evolution. In this review we discuss the biological functions of BRCA1 and BRCA2 genes and the role of BRCA mutations in tumor initiation, regulation of cancer stemness, therapy resistance and tumor progression.

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BRCA Genes: The Role in Genome Stability, Cancer Stemness and Therapy Resistance.

DNA is the source of genetic information, and preserving its integrity is essential in order to sustain life. The genome is continuously threatened by different types of DNA lesions, such as abasic sites, mismatches, interstrand crosslinks, or single-stranded and double-stranded breaks. As a consequence, cells have evolved specialized DNA damage response (DDR) mechanisms to sustain genome integrity. By orchestrating multilayer signaling cascades specific for the type of lesion that occurred, the DDR ensures that genetic information is preserved overtime. In the last decades, DNA repair mechanisms have been thoroughly investigated to untangle these complex networks of pathways and processes. As a result, key factors have been identified that control and coordinate DDR circuits in time and space. In the first part of this review, we describe the critical processes encompassing DNA damage sensing and resolution. In the second part, we illustrate the consequences of partial or complete failure of the DNA repair machinery. Lastly, we will report examples in which this knowledge has been instrumental to develop novel therapies based on genome editing technologies, such as CRISPR-Cas.

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DNA Damage: From Threat to Treatment.

We report the neuropathological findings in a patient with Parkinson's disease (PD) associated with Bas- que R1441G-LRRK2/dardarin mutation. The patient was a man with disease onset at 68 years of age, with unilat- eral rest tremor; the Parkinsonism was well controlled with medication for 15 years. He died at the age of 86, after 18 years of evolution. The neuropathological exami- nation disclosed mild neuronal loss in the substantia nigra pars compacta without a-synuclein, tau, LRRK2, or ubiq- uitin cytoplasmic inclusions. Lewy bodies and Lewy neu- rites were absent. This is the first neuropathological study of PD associated with brain with the R1441G mutation in LRRK2. � 2009 Movement Disorder Society Pathogenic mutations in the leucine-rich repeated kinase 2 (LRRK2-PARK 8) gene have been identified as the most common currently known cause of familial autosomal dominant Parkinson's disease (PD). 1,2 Patients with PD associated with the LRRK2 mutations have a clinical phenotype similar to other patients with PD without detected mutations. The R1441G-LRRK2/ dardarin mutation is frequent in the Basque country, representing 16% of the familial and 4% of apparently sporadic PD cases. 3 Patients with this mutation belong- ing to the same family have rather homogenous symp- toms and clinical course, but differences are seen between patients with this mutation in different families. The neuropathological changes in patients with PD associated with LRRK2 mutations seem to be heteroge- neous. 1 In some cases, the presence of neuronal loss in the substantia nigra (SN) and a-synuclein-positive Lewy bodies (LBs) is consistent with classic PD. In other cases, the neuropathological study shows the presence of nonspecific neuronal loss with ubiquitin- reactive cytoplasmic and nuclear inclusions, tau pathol- ogy reminiscent of progressive supranuclear palsy, or pure nigral degeneration without specific a-synuclein, tau, or ubiquitin inclusions. 1 We report here a patient with the R1441G-LRRK2/ dardarin mutation with neurological symptoms consist- ent with classic PD. The neuropathological examina- tion disclosed nonspecific nigral degeneration in the SN without a-synuclein, tau, LRRK2, or ubiquitin inclusions.

Neuropathology of Parkinson's disease with the R1441G mutation in LRRK2.

Purpose: We investigated the relationship between BRCA mutations and the distribution of familial cancers other than breast or ovary in high-risk breast cancer patients. Methods: Patients with breast cancer who had at least one of the following risk factors were enrolled: reported family history of breast or ovarian cancer; 40 years of age or younger age at diagnosis; bilateral breast cancer; or male gender. Genetic testing for BRCA mutation and questionnaires about personal and family histories of malignancies were performed. Results: Among the 238 eligible patients, 49 (20.6%) patients had BRCA1/2 mutations, which were more frequent in patients with multiple risk factors (p< 0.0001). There were 271 members of 156 (65.5%) families who had histories of other primary cancer. The distribution of the families was 119 (63.0%) and 37 (75.5%) in the BRCA-negative and positive group, respectively (p= 0.0996). Multiple familial cancers occurred in 70 families, which were significantly more frequent in BRCApositive families (p= 0.0034). By ordinal logistic regression, the occurrence of multiple familial cancers was associated with BRCA mutations (p= 0.0045), not with other risk factors. The most common site of disease was the stomach, which is the most common in nationwide. And the proportional incidence of pancreatic cancer (6.8%) was significantly higher than that of nationwide cancer statistics (2.4%, p= 0.0137). Conclusion: BRCA mutations in high-risk breast cancer patients were associated with multiple risk factors and multiple family members with other primary cancers. Genetic counseling based on accurate information should be provided to families with BRCA mutation carriers.

Associations between BRCA Mutations in High-Risk Breast Cancer Patients and Familial Cancers Other than Breast or Ovary

Purpose: The purpose of this study was to identify level of recognition of the importance, satisfaction and cont ribution of APNs' role by physicians, nurses, and advanced practice nurses. Method: Perceived importance and satisfaction were measured with a 23-item questio nnaire on APN role with 5 subcategories. APNs' contribution was investigated using a 13-item outcome questionnaire developed by the researchers. Between August 15 and October 31, 2009, the researchers collected data from 68 physicians, 265 nurses, and 23 APNs all working in a single tertiary hospital. Data were analyzed using descriptive statistics, Kruskal-Wallis Test with Bonferroni's Correction and scatter plot. Result: The importance (3.24~3.39, 4 point scale), satisfaction (3.02~3.13, 4 point scale), and contribution of APNs' role (3.39~4.12, 5 point scale) were well recognized by the health care professionals. All the three health care professional groups rated APNs' contribution high in medical service management, continuity of care, patient accessibility, improvement in patie nt satisfaction, and patient and family education. 'Importance-Satisfaction Analysis' showed that patient data management by APNs needed greater effort. Conclusions: The findings show that the importance, satisfaction, contribution of APNs' role are recognized, and indicate a need for further development of APNs' role through efforts to overco me the gaps identified through this research.

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Importance, Satisfaction and Contribution of Advanced Practice Nurses' Role Recognized by Health Care Professionals

Genetic anticipation of familial breast cancer with or without BRCA mutation in the Korean population.

https://www.koreascience.kr:443/article/JAKO201210236203242.pdf

Development and Evaluation of a Navigation Program for Newly Diagnosed Cancer Patients

Pelizaeus-Merzbacher disease (PMD) is a rare X-linked recessive disorder with a prototype of a dysmyelinating leukodystrophy that is caused by a mutation in the proteolipid protein 1 (PLP1) gene on the long arm of the X chromosome in band Xq22. This mutation results in abnormal expression or production of PLP. We here present a Korean boy with spastic quadriplegia, horizontal nystagmus, saccadic gaze, intentional tremor, head titubation, ataxia, and developmental delay. The brain magnetic resonance imaging (MRI) showed abnormally high signal intensities in the white matter tract, including a subcortical U fiber on the T2-weighted and fluid attenuated inversion recovery (FLAIR) image. The chromosomal analysis was normal; however, duplication of the PLP1 gene in chromosome Xq22 was detected when the multiplex ligation-dependent probe amplification (MLPA) method was used. We also investigated the pedigree for a genetic study related to PMD. This case suggests that the duplication mutation of the PLP1 gene in patients with PMD results in a mild clinical form of the disorder that mimics the spastic quadriplegia of cerebral palsy.

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Identification of Proteolipid Protein 1 Gene Duplication by Multiplex Ligation-Dependent Probe Amplification: First Report of Genetically Confirmed Family of Pelizaeus-Merzbacher Disease in Korea

Hye Jin Baek

Papers

Associations between BRCA Mutations in High-Risk Breast Cancer Patients and Familial Cancers Other than Breast or Ovary

Importance, Satisfaction and Contribution of Advanced Practice Nurses' Role Recognized by Health Care Professionals

Genetic anticipation of familial breast cancer with or without BRCA mutation in the Korean population.

Development and Evaluation of a Navigation Program for Newly Diagnosed Cancer Patients

Identification of Proteolipid Protein 1 Gene Duplication by Multiplex Ligation-Dependent Probe Amplification: First Report of Genetically Confirmed Family of Pelizaeus-Merzbacher Disease in Korea