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1.
T. Biron-Shental L. Drucker M. Altaras J. Bernheim A. Fishman 《European journal of surgical oncology》2006,32(10):1097-1100
OBJECTIVE: To test the carrier status of the three germline founder mutations in Jewish patients with uterine serous papillary carcinoma (USPC) and to evaluate its association to their personal and familial cancer records. METHODS: Retrospective analysis of histologically confirmed USPC Jewish patients diagnosed between April 1, 1997 and December 31, 2003. All cases were genetically tested for the three BRCA1-2 founder germline mutations (185delAG and 5382insC in BRCA1 and 6174delT in BRCA2). The analysis was performed on genomic DNA extracted from whole blood or paraffin embedded normal tissue of these patients, employing PCR amplification of target sequences and differential digestion with restriction enzymes. The carrier frequency was compared to the known population frequency of these mutations. RESULTS: The study group comprised 22 Jewish patients with USPC diagnosed within this timeframe. The mean age was 71.8 years (range 56-79). FIGO surgical stage distribution revealed 59% at stages III-IV. Seven USPC patients (32%) with a previous diagnosis of breast cancer were identified. Familial cancer history was recorded in 23% of the patients (four with breast cancer and one with ovarian cancer). DNA analysis revealed six BRCA1-2 germline mutation carriers (27%) as follows: three with BRCA2-6174delT, two with BRCA1-185delAG, and one with BRCA1-5382insC mutation. Three of the carriers had a previous diagnosis of breast cancer. Four carriers had familial cancer history in first-degree relative (three with breast cancer and one with ovarian cancer). CONCLUSIONS: The high rate of BRCA germline mutations in USPC patients observed in the present study, coupled with the strong personal and familial cancer history as well as the histological and clinical resemblance to the ovarian cancer, may indicate that USPC is a part or an expression of the hereditary breast-ovarian cancer syndrome. This option may have implications in our clinical recommendations for non-affected BRCA1-2 carriers. 相似文献
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Abnormalities in several genes are known to confer susceptibility to breast cancer. In the present study, we investigated the incidence of allelic imbalance at the BRCA1, BRCA2 and TP53 loci, in 82 sporadic breast carcinomas using a bank of highly polymorphic microsatellite markers located at the BRCA1, BRCA2 and TP53 regions. Genetic alterations were observed in 58/82 (71%) cases in at least one microsatellite marker, at one of the three regions. Twenty-seven out of 82 (33%) cases exhibited loss of heterozygosity (LOH) at BRCA1 locus while in 20/82 (34%) cases LOH was observed for the BRCA2 region. Allelic deletions were detected in 28/82 (34%) cases for the TP53 locus. Our results suggest that allelic deletion at the above genetic loci play an important role to the development of sporadic breast tumours. 相似文献
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Monnerat C Chompret A Kannengiesser C Avril MF Janin N Spatz A Guinebretière JM Marian C Barrois M Boitier F Lenoir GM Bressac-de Paillerets B 《Familial cancer》2007,6(4):453-461
PURPOSE: From epidemiological studies it appears that breast cancer (BC) and cutaneous melanoma (CMM) in the same individual occur at a higher frequency than expected by chance. Genetic factors common to both cancers can be suspected. Our goal was to estimate the involvement of "high risk" genes in patients presenting these two neoplasia, selected irrespectively from family history and age at diagnosis. EXPERIMENTAL DESIGN: Eighty two patients with BC and CMM were screened for BRCA1, BRCA2, TP53, CDKN2A and CDK4 (exon 2) germline mutations. RESULTS: Deleterious mutations were identified in 6 patients: two carriers of a BRCA1 germline mutation, two carriers of TP53 germline mutations (one of which also harbored a BRCA2 deleterious mutation, the other one a BRCA2 unclassified variant), and two carriers of a CDKN2A germline mutation. In addition, 6 variants of unknown signification were identified in BRCA1 or BRCA2 genes. Regarding family history, 3/13 (23%) patients with a positive family history of BC or CMM were carriers of a germline mutation, whereas only 3/69 (4%) patients without family history were carriers of a germline mutation. CONCLUSION: Our findings show that few patients with BC and CMM who lacked family histories of these cancers are carriers of deleterious germline mutations in four of the five genes we examined. We describe for the first time, two simultaneous BRCA2 and TP53 mutations, suggesting that analysis in more than one gene could be performed if a patient's personal or familial history does not match a single syndrome. 相似文献
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Arcand SL Maugard CM Ghadirian P Robidoux A Perret C Zhang P Fafard E Mes-Masson AM Foulkes WD Provencher D Narod SA Tonin PN 《Breast cancer research and treatment》2008,108(3):399-408
About 40% of French Canadian breast and/or ovarian cancer families harbor germline BRCA1 or BRCA1 mutations where common mutations
account for about 84% of all mutations identified in cancer families. Within a series of BRCA1 and BRCA2 mutation-negative
families, a germline TP53 13398 G>A (Arg213Gln) mutation was identified, which was selected for mutation analysis in this
gene because of a family history consistent with Li–Fraumeni syndrome (LFS). Given the founder effects in this population,
the 13398 G>A mutation was screened in series of 52 BRCA1 and BRCA2 mutation-negative cancer families, and a mutation-positive
family was identified. However, pedigree inspection and expansion of mutation-positive families with the same mutation revealed
that they were closely related to each other. To further characterize the contribution of TP53 in cancer families, mutation
analysis was performed in the remaining BRCA1 and BRCA2 mutation-negative cancer families. Thirty sequence variants were identified,
the majority of which occur in intronic sequences and are not predicted to affect the functionality of TP53. However, the
14538 G>A (Arg290His) mutation was identified in a family which did not exhibit features consistent with LFS or Li–Fraumeni-like
(LFL) syndrome. Neither of the TP53 mutations was detected in 381 French Canadian women with breast cancer diagnosed before
50 years of age not selected for family history of cancer. In all, germline TP53 mutations were identified in two of 52 (3.8%)
cancer families, suggesting that TP53 is not a major contributor to BRCA1 and BRCA2 mutation-negative breast and/or ovarian
cancer families of French Canadian descent. 相似文献
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Ahn SH Son BH Yoon KS Noh DY Han W Kim SW Lee ES Park HL Hong YJ Choi JJ Moon SY Kim MJ Kim KH Kwak BS Cho DY 《Cancer letters》2007,245(1-2):90-95
We analyzed the mutation spectrum of BRCA1 and BRCA2 genes in 354 Korean breast cancer patients. Overall, 40 patients carried 25 distinct BRCA1/2 mutations including 12 novel mutations. Seven district mutations were found in multiple unrelated patients, with the BRCA2 c.7480C>T mutation detected in eight unrelated patients, accounting for 50% of the mutations detected in BRCA2. The large number (25/40, 62.5%) of recurrent mutations suggests the possibility of developing a simple screening test for these mutations. The frequency of mutations was related to the number and kinds of risk factors, varying from 10.4 to 25% in the five major risk factor groups. The frequency of BRCA mutations in patients with two or more risk factors was markedly higher than that in patients with one risk factor. 相似文献
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目的研究PTEN和p53在子宫内膜浆液性癌和宫内膜癌中的表达及临床病理意义。方法应用免疫组化方法检测26例宫内膜浆液性癌、42例宫内膜样癌和25例正常增生期宫内膜组织中PTEN、p53蛋白的表达。结果PTEN和p53蛋白在子宫浆液性癌、宫内膜样癌、正常增生期内膜中的阳性表达率分别为86.4%、28.6%、100%和76.9%、27.3%、0%。PTEN在子宫内膜样癌中阳性表达率明显低于浆液性癌(P<0.001)。p53蛋白表达与子宫内膜癌组织学类型、临床分期、病理分级、肌层浸润等因素有关(P<0.05)。结论PTEN突变和表达缺失与宫内膜样癌的发生、发展有关。p53基因突变和过表达与宫内膜浆液性癌发生发展关系密切。PTEN及p53蛋白检测对鉴别子宫浆液性癌与宫内膜样癌有重要价值。 相似文献
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目的 乳腺癌易感基因1(breast cancer susceptibility gene 1,BRCA1)和BRCA2基因已经证实与家族性乳腺癌密切相关.本研究旨在分析中国汉族家族性乳腺癌患者及家系成员BRCA1和BRCA2突变特征及携带情况.方法 收集2013 12-02-2015-06-08军事医学科学院附属医院确诊的中国汉族家族性乳腺癌患者55例及家系成员48名,共计103例样本.柚取外周静脉血提取DNA,应用聚合酶链反应(polymerase chain reaction,PCR) DNA直接测序方法检测BRCA1和BRCA2基因全编码外显子序列.结果 55例家族性乳腺癌患者中发现5个BRCA基因致病性突变位点,1个突变位点乳腺癌信息库中见报道(BRCA1:4730insG),4个为新发现突变位点(BRCA1:1937insC,4538insAG;BRCA2:1382delA,2820delA).家族性乳腺癌患者BRCA1/2突变率为9.09%(BRCA1,5.45%;BRCA2,3.64%),其中三阴性乳腺癌患者突变率为22.22%(x2 =1.99,P=0.20),早发性乳腺癌患者(≤35岁)突变率为20.00%,x2=0.79,P=0.39.48例家系成员检测到3个新发现突变位点(BRCA1:1370insA,3459insA;BRCA2:6502insT),总突变率为6.25%.结论 中国汉族家族性乳腺癌患者BRCA基因突变率显著低于国外,应重点关注有家族史的三阴性乳腺癌患者和早发性乳腺癌患者;家系成员中发现BRCA基因致病性突变,家系成员突变率和发病风险有待进一步研究,应引起重视. 相似文献
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Musolino A Naldi N Michiara M Bella MA Zanelli P Bortesi B Capelletti M Savi M Neri TM Ardizzoni A 《Breast cancer research and treatment》2005,91(2):203-205
We report the first case in Italy of a non-Ashkenazi double heterozygote for BRCA1 and BRCA2 genes. This finding is predictably rare, with a maximum frequency of 1/250,000. The proband and her mother were diagnosed with early-onset breast cancer. No other relatives with breast and/or ovarian cancer were observed. The implications of this case in regard to genetic testing and counseling are substantial. 相似文献
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Fukutomi T Ushijima T Inoue R Akashi-Tanaka S Nanasawa T Tsuda H 《Breast cancer (Tokyo, Japan)》1997,4(4):256-258
We examined germline mutations inBRCA1 andBRCA2 in 23 Japanese breast cancer families, using PCR-SSCP analysis. The same nonsense mutation (exon 5, Leu63ter) ofBRCA1 was detected in two different families. Three different mutations resulting in a truncatedBRCA2 protein (exon 9, 20, 24) were detected in three different families, including one male case of breast cancer. One base substitution
mutation inBRCA2, A10462G, was detected in the other two families. Although the mean age of onset for breast cancer in families with theBRCA1- mutation was 50 years, the age of onset in families with theBRCA2-mutation was from 28 to 43 years. Among the 23 families examined, two families had members with ovarian cancers, three had
members with prostate cancers, and one had a pancreatic cancer. However, none of these families was positive for theBRCA1 orBRCA2 mutation. Histopathologically, we observed a prevalence of histological grade 3 inBRCA2-associated familial breast cancers, because of nuclear atypia, structural atypia and mitotic activity. It is suggested thatBRCA2 may play a more important role thanBRCA1 in Japanese familial breast cancers, and these mutations are related to the aggressive nature and highly proliferative activity
of the tumors. 相似文献
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Melhem-Bertrandt A Bojadzieva J Ready KJ Obeid E Liu DD Gutierrez-Barrera AM Litton JK Olopade OI Hortobagyi GN Strong LC Arun BK 《Cancer》2012,118(4):908-913
BACKGROUND:
Germline TP53 mutations predispose to early onset breast cancer in women and are associated with Li‐Fraumeni syndrome. Published data on the pathological characteristics of breast cancer among women with TP53 mutations is limited.METHODS:
We retrospectively reviewed the clinical records of women who underwent genetic testing for suspected germline TP53 mutations and who were diagnosed with breast cancer between 2000 and 2011. The pathological characteristics of the breast tumors from patients testing positive for a mutation (cases) were compared with those testing negative (controls).RESULTS:
Patients who tested positive for germlineTP53 mutations (n = 30) were compared with controls (n = 79). Human epidermal growth factor receptor 2 (HER2) amplification and/or overexpression was found in 67% of the tumors from the cases, compared with 25% for the controls (P = .0001). Among patients with a mutation, 70% had estrogen receptor‐ and/or progesterone receptor‐positive tumors, compared with 68% in the control group (P = .87). After adjusting for age at breast cancer diagnosis, having a HER2‐positive tumor increased the odds of testing positive for a germline TP53 mutation (odds ratio, 6.9; 95% confidence interval, 2.6‐18.2). For each yearly increment in age at breast cancer diagnosis, there was decreased likelihood of having a TP53 mutation of 5% (odds ratio, 0.95; 95% confidence interval0.91‐0.99).CONCLUSIONS:
This study suggests an association between germline TP53 mutations and early onset HER2‐positive breast cancer. If confirmed in a larger cohort, these results could guide genetic testing strategies, lead to chemoprevention trials incorporating HER2‐targeted therapies, and elucidate some of the molecular pathways involved in breast cancer. Cancer 2012;. © 2011 American Cancer Society. 相似文献13.
BRCA1 and BRCA2 mutations in ovarian cancer patients from China: ethnic‐related mutations in BRCA1 associated with an increased risk of ovarian cancer
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Tingyan Shi Pan Wang Caixia Xie Sheng Yin Di Shi Congchong Wei Wenbin Tang Rong Jiang Xi Cheng Qingyi Wei Qing Wang Rongyu Zang 《International journal of cancer. Journal international du cancer》2017,140(9):2051-2059
BRCA1/2 are cancer predisposition genes involved in hereditary breast and ovarian cancer (HBOC). Mutation carriers display an increased sensitivity to inhibitors of poly(ADP‐ribose) polymerase (PARP). Despite a number of small‐size hospital‐based studies being previously reported, there is not yet, to our knowledge, precise data of BRCA1/2 mutations among Chinese ovarian cancer patients. We performed a multicenter cohort study including 916 unselected consecutive epithelial ovarian cancer (EOC) patients from eastern China to screen for BRCA1/2 mutations using the next‐generation sequencing approach. A total of 153 EOC patients were found to carry pathogenic germline mutations in BRCA1/2, accounting for an overall mutation incidence of 16.7% with the predominance in BRCA1 (13.1%) compared with BRCA2 (3.9%). We identified 53 novel pathogenic mutations, among which the c.283_286delCTTG and the c.4573C > T of BRCA1 were both found in two unrelated patients. More importantly, the most common mutation found in this study, c.5470_5477del8 was most likely to be Chinese population‐related without an apparent founder origin. This hot‐spot mutation was presumably associated with an increased risk of ovarian cancer. Taken together, germline BRCA1/2 mutations were common in Chinese EOC patients with distinct mutational spectrum compared to Western populations. Our study contributes to the current understanding of BRCA1/2 mutation prevalence worldwide. We recommend BRCA1/2 genetic testing to all Chinese women diagnosed with EOC to identify HBOC families, to provide genetic counseling and clinical management for at‐risk relatives. Mutation carriers may also benefit from PARP‐targeted therapies. 相似文献
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Xiang Zeng Tsukasa Baba Junzo Hamanishi Noriomi Matsumura Budiman Kharma Yuka Mise Kaoru Abiko Ken Yamaguchi Naoki Horikawa David G. Hunstman Kumuluzi Mulati Sachiko Kitamura Mana Taki Ryusuke Murakami Yuko Hosoe Masaki Mandai 《International journal of cancer. Journal international du cancer》2019,145(6):1635-1647
Uterine serous carcinoma (USC) is a highly aggressive histological subtype of endometrial cancers harboring highly metastatic and chemoresistant features. Our previous study showed that STAT1 is highly expressed in USC and acts as a key molecule that is positively correlated with tumor progression, but it remains unclear whether STAT1 is relevant to the malicious chemorefractory nature of USC. In the present study, we investigated the regulatory role of STAT1 toward platinum-cytotoxicity in USC. STAT1 suppression sensitized USC cells to increase cisplatin-mediated apoptosis (p < 0.001). Furthermore, phosphorylation of STAT1 was prominently observed on serine-727 (pSTAT1-Ser727), but not on tyrosine-701, in the nucleus of USC cells treated with cisplatin. Mechanistically, the inhibition of pSTAT1-Ser727 by dominant-negative plasmid elevated cisplatin-mediated apoptosis by increasing intracellular accumulation of cisplatin through upregulation of CTR1 expression. TBB has an inhibitory effect on casein kinase 2 (CK2), which phosphorylate STAT1 at serine residues. Sequential treatment with TBB and cisplatin on USC cells greatly reduced nuclear pSTAT1-Ser727, enhanced intracellular accumulation of cisplatin, and subsequently increased apoptosis. Tumor load was significantly reduced by combination therapy of TBB and cisplatin in in vivo xenograft models (p < 0.001). Our results collectively suggest that pSTAT1-Ser727 may play a key role in platinum resistance as well as tumor progression in USC. Thus, targeting the STAT1 pathway via CK2 inhibitor can be a novel method for attenuating the chemorefractory nature of USC. 相似文献
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Recently unbiased sequencing efforts identified PPP2R1A mutations in clear cell ovarian cancers (OCC). Similar mutations were also noted with high frequency in uterine serous carcinoma. Because the endometrium develops from the same developmental precursors we further examined the hypothesis that PPP2R1A mutations might also occur in diverse histologic subtypes of uterine cancer. We sequenced the PPP2R1A in 22 cell line models of uterine cancer and 10 primary cancers. We found no mutations in the cell lines originally derived from endometrioid (n = 13), undifferentiated (n = 3), clear cell (n = 1), and carcinosarcoma (n = 3) cancers. However, we found a CCC (Pro) to CGC (Arg) codon 179 mutation in the ACI‐158 serous carcinoma cell line, a CCC (Pro) to CTC (Leu) in a primary serous carcinoma as well as a CGC (Arg) to CAC (His) codon 258 mutation in a poorly differentiated endometrioid cancer. We sequenced a large panel of endometrial malignancies (n = 181) and found 12 mutants. Importantly, we confirmed a high frequency of mutation in 8 of 25 (32%) serous carcinomas a subtype with well‐recognized poor prognosis. Mutations were infrequent in endometrioid cancer and absent in clear cell and carcinosarcoma subtypes. The PPP2R1A mutation regions are conserved among species and known to interact with the regulatory subunits of the PP2A enzyme. PPP2R1A mutant endometrial cancers may represent good candidates for personalized drug therapies particularly for women with the lethal serous histologic variant of uterine cancer. © 2011 Wiley Periodicals, Inc. 相似文献
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背景与目的:BRCA1/2、ATM基因的致病性胚系突变与前列腺癌的发病风险和疾病进展密切相关,同时可对转移性去势抵抗性前列腺癌(metastatic castration-resistant prostate cancer,mCRPC)患者的PARP抑制剂治疗、铂类化疗进行指导,然而,基于中国人群的研究鲜有报道。本研究旨在揭示中国人群前列腺癌患者BRCA1/2、ATM基因的胚系突变率,从而指导基因检测和临床治疗。方法:前瞻性分析53例遗传咨询门诊确诊为前列腺癌患者的临床资料,并对这些患者的胚系DNA进行测序,将目标基因BRCA1/2、ATM的突变依据美国医学遗传学与基因组学学会(American College of Medical Genetics and Genomics,ACMG)遗传突变分类标准与指南评估致病性。同时对致病性突变与前列腺癌患者发病年龄、家族史、Gleason评分、前列腺特异抗原(prostate-specific antigen,PSA)值、肿瘤转移之间的关系进行统计学分析。结果:中国人群前列腺癌患者BRCA1/2、ATM基因的致病性胚系突变率为7.55%,转移性前列腺癌患者的突变率为9.68%。在中国人群中,BRCA1/2、ATM基因的致病性突变与前列腺癌的早期发生有关(P=0.011);但在家族史、Gleason评分、PSA水平及肿瘤转移上差异无统计学意义(P>0.05)。结论:本研究初步建立了中国人群基因检测推荐标准,对包括转移性前列腺癌患者和早发前列腺癌患者在内的高危胚系突变者推荐进行基因筛查,以更好地进行临床诊疗及遗传咨询。 相似文献
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BRCA1 and BRCA2 germline mutations are frequently demonstrated in both high‐risk pancreatic cancer screening and pancreatic cancer cohorts
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Aimee L. Lucas MD MS Laura E. Frado MD Caroline Hwang MD Sheila Kumar MD Lauren G. Khanna MD Elana J. Levinson MS MPH John A. Chabot MD Wendy K. Chung MD PhD Harold Frucht MD 《Cancer》2014,120(13):1960-1967
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E Cocco Z Hu C E Richter S Bellone F Casagrande M Bellone P Todeschini G Krikun D-A Silasi M Azodi P E Schwartz T J Rutherford N Buza S Pecorelli C J Lockwood A D Santin 《British journal of cancer》2010,103(6):812-819
Background:
Uterine serous papillary adenocarcinoma (USPC) is a highly aggressive variant of endometrial cancer. Human immuno-conjugate molecule (hI-con1) is an antibody-like molecule targeted against tissue factor (TF), composed of two human Factor VII (fVII) as the targeting domain, fused to human immunoglobulin (Ig) G1 Fc as an effector domain. We evaluated hI-con1 potential activity against primary chemotherapy-resistant USPC cell lines expressing different levels of TF.Methods:
A total of 16 formalin-fixed, paraffin-embedded USPC samples were evaluated by immunohistochemistry (IHC) for TF expression. Six primary USPC cell lines, half of which overexpress the epidermal growth factor type II (HER2/neu) receptor at 3+ levels, were assessed by flow cytometry and real-time PCR for TF expression. Sensitivity to hI-con1-dependent cell-mediated cytotoxicity (IDCC) was evaluated in 5-hour-chromium release assays. Finally, to investigate the effect of interleukin-2 (IL-2) on IDCC, 5-h 51Cr assays were also conducted in the presence of low doses of IL-2 (i.e., 50–100 IU ml−1).Results:
Cytoplasmic and/or membrane TF expression was observed in all 16 (100%) USPC samples tested by IHC, but not in normal endometrium. High expression of TF was found in 50% (three out of six) of the USPC cell lines tested by real-time PCR and flow cytometry when compared with normal endometrial cells (NECs; P<0.001). Uterine serous papillary adenocarcinoma cell lines overexpressing TF, regardless of their high or low HER2/neu expression, were highly sensitive to IDCC (mean killing±s.d., 65.6±3.7%, range 57.5–77.0%, P<0.001), although negligible cytotoxicity against USPC was seen in the absence of hI-con1 or in the presence of Rituximab control antibody. The addition of low doses of IL-2 further increased the cytotoxic effect induced by hI-con1 against chemotherapy-resistant USPC.Conclusion:
hI-con1 induces strong cytotoxicity against primary chemotherapy-resistant USPC cell lines overexpressing TF. The hI-con1 may represent a novel therapeutic agent for the treatment of patients harbouring advanced, recurrent and/or metastatic USPC refractory to standard treatment modalities. 相似文献20.
P A Daly C Nolan A Green W Ormiston N Cody T McDevitt B O'hIci D Byrne E McDermott D N Carney N O'Higgins D E Barton 《Annals of oncology》2003,14(4):549-553
BACKGROUND: Management strategies for women carrying BRCA1 and 2 mutations are becoming clearer and predictive testing for a known family mutation is commonly undertaken. Implications for men are not as clear and they participate less frequently. PATIENTS AND METHODS: Twenty-six men from 10 extended families underwent predictive testing. Their motivation, reaction and outcome were studied. Subjects had appropriate pre- and post-test counselling. Informed consent was obtained before predictive testing for known deleterious mutations. DNA analysis followed standard procedures. RESULTS: Eighteen tested positive and eight negative. Four had adverse psychological reactions and three reneged on their commitments to impart results. The spouse of another man had an adverse psychological reaction to the disclosure of his positive result. Two, already suffering from prostate cancer, were phenocopies and paternal lineage transmission was unexpectedly determined in another. Risk was removed from 33 offspring and confirmed for 56. CONCLUSIONS: Complex themes associated with genetic testing are confirmed and the spectrum extended. Men appear to understand the importance of participating in this process. Methods of avoiding adverse reactions merit further study along with other aspects of the process. 相似文献