Hereditary Cancer in Clinical Practice最新文献

{"title":"Delineating the role of osteoprotegerin as a marker of breast cancer risk among women with a BRCA1 mutation","authors":"Park, Sarah Sohyun, Uzelac, Aleksandra, Kotsopoulos, Joanne","doi":"10.1186/s13053-022-00223-3","DOIUrl":"https://doi.org/10.1186/s13053-022-00223-3","url":null,"abstract":"Women with a pathogenic germline mutation in the BRCA1 gene face a very high lifetime risk of developing breast cancer, estimated at 72% by age 80. Prophylactic bilateral mastectomy is the only effective way to lower their risk; however, most women with a mutation opt for intensive screening with annual MRI and mammography. Given that the BRCA1 gene was identified over 20 years ago, there is a need to identify a novel non-surgical approach to hereditary breast cancer prevention. Here, we provide a review of the emerging preclinical and epidemiologic evidence implicating the dysregulation of progesterone-mediated receptor activator of nuclear factor κB (RANK) signaling in the pathogenesis of BRCA1-associated breast cancer. Experimental studies have demonstrated that RANK inhibition suppresses Brca1-mammary tumorigenesis, suggesting a potential target for prevention. Data from studies conducted among women with a BRCA1 mutation further support this pathway in BRCA1-associated breast cancer development. Progesterone-containing (but not estrogen-alone) hormone replacement therapy is associated with an increased risk of breast cancer in women with a BRCA1 mutation. Furthermore, BRCA1 mutation carriers have significantly lower levels of circulating osteoprotegerin (OPG), the decoy receptor for RANK-ligand (RANKL) and thus endogenous inhibitor of RANK signaling. OPG levels may be associated with the risk of disease, suggesting a role of this protein as a potential biomarker of breast cancer risk. This may improve upon current risk prediction models, stratifying women at the highest risk of developing the disease, and further identify those who may be targets for anti-RANKL chemoprevention. Collectively, the evidence supports therapeutic inhibition of the RANK pathway for the primary prevention of BRCA1-associated breast cancer, which may generate unique prevention strategies (without prophylactic surgery) and enhance quality of life.","PeriodicalId":55058,"journal":{"name":"Hereditary Cancer in Clinical Practice","volume":"49 3","pages":""},"PeriodicalIF":1.7,"publicationDate":"2022-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138509842","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Germline BRCA1 and BRCA2 mutations and the risk of bladder or kidney cancer in Poland","authors":"Złowocka-Perłowska, Elżbieta, Tołoczko-Grabarek, Aleksandra, Narod, Steven A., Lubiński, Jan","doi":"10.1186/s13053-022-00220-6","DOIUrl":"https://doi.org/10.1186/s13053-022-00220-6","url":null,"abstract":"The role of the BRCA1 and BRCA2 genes in bladder and renal tumorigenesis is unclear. Our goal was to determine the prevalence of specific founder mutations genes BRCA1 (5328 insC, C61G and 4153 delA) and BRCA2 (C5972T) mutations in bladder and kidney cancer patients from Poland. We genotyped 1028 patients with bladder cancer and 688 cases with kidney cancer and two control groups. A BRCA1 mutation (all variants combined) was detected in peripheral blood leukocytes in 5 out of 1028 (0.5%) bladder cases and in 17 of 4000 controls (0.4%) (odds ratio [OR], (OR = 1.1; 95% CI 0.42–3.11; p = 1.0). Among 688 unselected kidney cancer cases a BRCA1 mutations was reported in three patients (0.4%) (OR = 1.0; 95% CI 0.29–3.51; p = 1.0). The mutation C5972T in BRCA2 was observed in 54 bladder cancer patients (5.2%) and in 159 of 2791 healthy controls (5.7%) (OR = 0.9; 95% CI 0.66–1.26; p = 0.6). Fifty kidney cancer cases carried a BRCA2 mutation (7.3%) (OR = 1.3; 95% CI 0.93–1.80; p = 0.1). In conclusion, we found no difference in the prevalence of BRCA1 and BRCA2 founder mutations between cases and healthy controls. The mutations BRCA1 and BRCA2 seem not to play a role in bladder and kidney cancer development in Polish patients.","PeriodicalId":55058,"journal":{"name":"Hereditary Cancer in Clinical Practice","volume":"53 4","pages":"13"},"PeriodicalIF":1.7,"publicationDate":"2022-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138509787","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Frequency of BRCA1 and BRCA2 mutations in ovarian cancer patients in South-East Poland","authors":"A. Jasiewicz, H. Rudnicka, W. Kluźniak, Wojciech Gronwald, T. Kluz, C. Cybulski, A. Jakubowska, J. Lubiński, J. Gronwald","doi":"10.1186/s13053-022-00219-z","DOIUrl":"https://doi.org/10.1186/s13053-022-00219-z","url":null,"abstract":"","PeriodicalId":55058,"journal":{"name":"Hereditary Cancer in Clinical Practice","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2022-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44866374","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic susceptibility to hereditary non-medullary thyroid cancer","authors":"Tina Kamani, Parsa Charkhchi, A. Zahedi, M. Akbari","doi":"10.1186/s13053-022-00215-3","DOIUrl":"https://doi.org/10.1186/s13053-022-00215-3","url":null,"abstract":"","PeriodicalId":55058,"journal":{"name":"Hereditary Cancer in Clinical Practice","volume":"20 1","pages":""},"PeriodicalIF":1.7,"publicationDate":"2022-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"65766707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multiple endocrine neoplasia type 1: a new germline “homozygous” variant (c.201delC) caused by detection errors","authors":"Zhang, Fan, Yu, Xiaohui, Wang, Xiaoli, Shao, Hua","doi":"10.1186/s13053-022-00216-2","DOIUrl":"https://doi.org/10.1186/s13053-022-00216-2","url":null,"abstract":"Multiple endocrine neoplasia type 1 (MEN1) is a hereditary cancer syndrome caused by germline variants in the MEN1 gene located on chromosome 11q13. We found a Chinese woman who had a pancreatic tumor, parathyroid tumor, adrenal tumor, and suspicion of gastrinoma. The proband and her immediate family members underwent genetic detection. The results showed that two of the proband’s six relatives had the same variants as the proband, and her sister also had the typical symptoms of MEN1. However, the first- and second-time genetic detection results showed that they were homozygous variants, which did not conform to Mendelian inheritance laws. Multiplex ligation-dependent probe amplification (MLPA) was used to rule out homozygous variants caused by a deletion of gene fragments in the proband and her immediate family members. The MLPA results showed that the gene deletion was absent in the MEN1. The results from the third genetic detection (redesigned the primer) showed that they had a heterozygous variant. A new MEN1 germline variant [c.201delC (p.Ala68Profs*51)], which could induce MEN1, was found in this study. This newly identified germline variant could improve the identification of clinical phenotypes and the early diagnosis of MEN1. Clinician should consider the present of situation that intron variant causing detection error. Re-designing the primers close to the variant site for gene detection could avoid this situation.","PeriodicalId":55058,"journal":{"name":"Hereditary Cancer in Clinical Practice","volume":"52 4","pages":""},"PeriodicalIF":1.7,"publicationDate":"2022-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138509799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prevalence of germline TP53 mutation among early onset middle eastern breast cancer patients.","authors":"Abdul Khalid Siraj,&nbsp;Tariq Masoodi,&nbsp;Rong Bu,&nbsp;Sandeep Kumar Parvathareddy,&nbsp;Kaleem Iqbal,&nbsp;Saud Azam,&nbsp;Maha Al-Rasheed,&nbsp;Dahish Ajarim,&nbsp;Asma Tulbah,&nbsp;Fouad Al-Dayel,&nbsp;Khawla Sami Al-Kuraya","doi":"10.1186/s13053-021-00206-w","DOIUrl":"https://doi.org/10.1186/s13053-021-00206-w","url":null,"abstract":"<p><strong>Background: </strong>The data on prevalence and clinical relevance of TP53 germline mutations in early onset Middle-Eastern breast cancer (BC) is limited.</p><p><strong>Methods: </strong>We determined TP53 germline mutations in a cohort of 464 early onset BC patients from Saudi Arabia using capture sequencing based next generation sequencing.</p><p><strong>Results: </strong>Germline TP53 pathogenic mutations were found in 1.5% (7/464) of early onset Saudi BC patients. A total of six pathogenic missense mutations, one stop gain mutation and two variants of uncertain significance (VUS) were detected in our cohort. No TP53 pathogenic mutations were detected among 463 healthy controls. TP53 mutations carriers were significantly more likely to have bilateral breast cancer (p = 0.0008). At median follow-up of 41 months, TP53 mutations were an unfavorable factor for overall survival in univariate analysis. All the patients carrying TP53 mutations were negative for BRCA1 and BRCA2 mutations. Majority of patients (85.7%; 6/7) carrying TP53 mutation had no family history suggestive of Li-Fraumeni Syndrome (LFS) or personal history of multiple LFS related tumors. Only one patient had a positive family history suggestive of LFS.</p><p><strong>Conclusions: </strong>TP53 germline mutation screening detects a clinically meaningful risk of early onset BC from this ethnicity and should be considered in all early onset BC regardless of the family history of cancer, especially in young patients that are negative for BRCA mutations.</p>","PeriodicalId":55058,"journal":{"name":"Hereditary Cancer in Clinical Practice","volume":"19 1","pages":"49"},"PeriodicalIF":1.7,"publicationDate":"2021-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8670057/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39724107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retroperitoneal leiomyosarcoma in a female patient with a germline splicing variant RAD51D c.904-2A > T: a case report.","authors":"Mashu Futagawa,&nbsp;Hideki Yamamoto,&nbsp;Mariko Kochi,&nbsp;Yusaku Urakawa,&nbsp;Reimi Sogawa,&nbsp;Fumino Kato,&nbsp;Mika Okazawa-Sakai,&nbsp;Daisuke Ennishi,&nbsp;Katsunori Shinozaki,&nbsp;Hirofumi Inoue,&nbsp;Hiroyuki Yanai,&nbsp;Akira Hirasawa","doi":"10.1186/s13053-021-00205-x","DOIUrl":"https://doi.org/10.1186/s13053-021-00205-x","url":null,"abstract":"<p><strong>Background: </strong>RAD51D (RAD51 paralog D) is an intermediate cancer susceptibility gene for primary ovarian cancer, including fallopian tube and peritoneal carcinomas and breast cancer. Although gynecological non-epithelial tumors such as uterine sarcomas are associated with genomic instability, including BRCA impairment, there is no clear evidence of the relationship between RAD51D variants and the risk of sarcoma development.</p><p><strong>Case presentation: </strong>A Japanese woman in her 50s underwent multiple surgical resections and several regimens of chemotherapy for tumors that originated in the retroperitoneum and recurred in the peritoneum over a clinical course of approximately 4 years. The peritoneal tumor was histologically diagnosed as a leiomyosarcoma and was genetically identified to show a splice variant of RAD51D c.904-2A > T [NM_002878] through tumor profiling performed as a part of cancer precision medicine. The confirmatory genetic test performed after genetic counseling revealed that the RAD51D splicing variant detected in her tumor was of germline origin. In silico analyses supported the possible pathogenicity of the detected splice variant of RAD51D with a predicted attenuation in mRNA transcription and truncated protein production due to frameshifting, which was attributed to a single-nucleotide alteration in the splicing acceptor site at the 3'-end of intron 9 of RAD51D. Considering her unfavorable clinical outcome, which showed a highly aggressive phenotype of leiomyosarcoma with altered RAD51D, this case provided novel evidence for the relationship of a RAD51D splicing variant with malignant tumor development or progression. We report the findings of this rare case with possible involvement of the germline variant of RAD51D c.904-2A > T as a potential predisposing factor for malignant tumors, including leiomyosarcoma.</p><p><strong>Conclusions: </strong>We present the findings of a case of leiomyosarcoma in the peritoneum of a female patient with a novel germline splicing variant of RAD51D as potential evidence for the pathogenicity of the variant and its involvement in the risk of sarcoma etiology and/or development. To the best of our knowledge, this is the first case report describing a leiomyosarcoma carrying a germline RAD51D splicing variant and elucidating its pathogenicity on the basis of computational prediction of the impairment of normal transcription and the presumed loss of functional protein production.</p>","PeriodicalId":55058,"journal":{"name":"Hereditary Cancer in Clinical Practice","volume":"19 1","pages":"48"},"PeriodicalIF":1.7,"publicationDate":"2021-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8627011/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39924811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: Massive parallel sequencing in individuals with multiple primary tumours reveals the benefit of re-analysis.","authors":"Karin Wallander,&nbsp;Håkan Thonberg,&nbsp;Daniel Nilsson,&nbsp;Emma Tham","doi":"10.1186/s13053-021-00204-y","DOIUrl":"https://doi.org/10.1186/s13053-021-00204-y","url":null,"abstract":"","PeriodicalId":55058,"journal":{"name":"Hereditary Cancer in Clinical Practice","volume":"19 1","pages":"47"},"PeriodicalIF":1.7,"publicationDate":"2021-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8594138/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39629421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Massive parallel sequencing in individuals with multiple primary tumours reveals the benefit of re-analysis.","authors":"Karin Wallander, Håkan Thonberg, Daniel Nilsson, Emma Tham","doi":"10.1186/s13053-021-00203-z","DOIUrl":"10.1186/s13053-021-00203-z","url":null,"abstract":"<p><p>Multiple primary cancers, defined as three or more primary tumours, are rare, and there are few genetic studies concerning them. There is a need for increased knowledge on the heritability of multiple primary cancers and genotype-phenotype correlations. We have performed whole-genome/exome sequencing (WGS/WES) in ten individuals with three or more primary tumours, with no previous findings on standard clinical genetic investigations. In one individual with a clinical diagnosis of MEN1, a likely pathogenic cryptic splice site variant was detected in the MEN1 gene. The variant (c.654C > A) is synonymous but we showed in a cDNA analysis that it affects splicing and leads to a frameshift, with the theoretical new amino acid sequence p.(Gly219Glufs*13). In one individual with metachronous colorectal cancers, ovarian cancer, endometrial cancer and chronic lymphocytic leukaemia, we found a likely pathogenic variant in the MLH1 gene (c.27G > A), and two risk factor variants in the genes CHEK2 and HOXB13. The MLH1 variant is synonymous but has previously been shown to be associated to constitutional low-grade hypermethylation of the MLH1 promoter, and segregates with disease in families with colorectal and endometrial cancer. No pathogenic single nucleotide or structural variants were detected in the remaining eight individuals in the study. The pathogenic variants found by WGS/WES were in genes already sequenced by Sanger sequencing and WES in the clinic, without any findings. We conclude that, in individuals with an unequivocal clinical diagnosis of a specific hereditary cancer syndrome, where standard clinical testing failed to detect a causative variant, re-analysis may lead to a diagnosis.</p>","PeriodicalId":55058,"journal":{"name":"Hereditary Cancer in Clinical Practice","volume":"19 1","pages":"46"},"PeriodicalIF":1.7,"publicationDate":"2021-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8555269/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39823924","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Can harmful lifestyle, obesity and weight changes increase the risk of breast cancer in BRCA 1 and BRCA 2 mutation carriers? A Mini review.","authors":"A Daniele,&nbsp;R Divella,&nbsp;B Pilato,&nbsp;S Tommasi,&nbsp;P Pasanisi,&nbsp;M Patruno,&nbsp;M Digennaro,&nbsp;C Minoia,&nbsp;M Dellino,&nbsp;S Pisconti,&nbsp;P Casamassima,&nbsp;E Savino,&nbsp;A V Paradiso","doi":"10.1186/s13053-021-00199-6","DOIUrl":"https://doi.org/10.1186/s13053-021-00199-6","url":null,"abstract":"<p><strong>Background and aim: </strong>The BRCA 1 and BRCA 2 genes are associated with an inherited susceptibility to breast cancer with a cumulative risk of 60% in BRCA 1 mutation carriers and of 30% in BRCA 2 mutation carriers. Several lifestyle factors could play a role in determining an individual's risk of breast cancer. Obesity, changes in body size or unhealthy lifestyle habits such as smoking, alcohol consumption and physical inactivity have been evaluated as possible determinants of breast cancer risk. The aim of this study was to explore the current understanding of the role of harmful lifestyle and obesity or weight change in the development of breast cancer in female carriers of BRCA 1/2 mutations.</p><p><strong>Methods: </strong>Articles were identified from MEDLINE in October 2020 utilizing related keywords; they were then read and notes, study participants, measures, data analysis and results were used to write this review.</p><p><strong>Results: </strong>Studies with very large case series have been carried out but only few of them have shown consistent results. Additional research would be beneficial to better determine the actual role and impact of such factors.</p>","PeriodicalId":55058,"journal":{"name":"Hereditary Cancer in Clinical Practice","volume":"19 1","pages":"45"},"PeriodicalIF":1.7,"publicationDate":"2021-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8554866/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39563774","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}