Mismatch repair gene germline mutations in patients with prostate cancer / 浙江大学学报·医学版

OBJECTIVES@#To investigate the prevalence of pathogenic germline mutations of mismatch repair (MMR) genes in prostate cancer patients and its relationship with clinicopathological characteristics.@*METHODS@#Germline sequencing data of 855 prostate cancer patients admitted in Fudan University Shanghai Cancer Center from 2018 to 2022 were retrospectively analyzed. The pathogenicity of mutations was assessed according to the American College of Medical Genetics and Genomics (ACMG) standard guideline, Clinvar and Intervar databases. The clinicopathological characteristics and responses to castration treatment were compared among patients with MMR gene mutation (MMR+ group), patients with DNA damage repair (DDR) gene germline pathogenic mutation without MMR gene (DDR+MMR－ group) and patients without DDR gene germline pathogenic mutation (DDR－ group).@*RESULTS@#Thirteen (1.52%) MMR+ patients were identified in 855 prostate cancer patients, including 1 case with MLH1 gene mutation, 6 cases with MSH2 gene mutation, 4 cases with MSH6 gene mutation and 2 cases with PMS2 gene mutation. 105 (11.9%) patients were identified as DDR gene positive (except MMR gene), and 737 (86.2%) patients were DDR gene negative. Compared with DDR－ group, MMR+ group had lower age of onset (P<0.05) and initial prostate-specific antigen (PSA) (P<0.01), while no significant differences were found between the two groups in Gleason score and TMN staging (both P>0.05). The median time to castration resistance was 8 months (95%CI: 6 months-not achieved), 16 months (95%CI: 12-32 months) and 24 months (95%CI: 21-27 months) for MMR+ group, DDR+MMR－ group and DDR－ group, respectively. The time to castration resistance in MMR+ group was significantly shorter than that in DDR+MMR－ group and DDR－ group (both P<0.01), while there was no significant difference between DDR+MMR－ group and DDR－ group (P>0.05).@*CONCLUSIONS@#MMR gene mutation testing is recommended for prostate cancer patients with early onset, low initial PSA, metastasis or early resistance to castration therapy.

Germline pathogenic variants in Mexican patients with hereditary triple-negative breast cancer / Variantes patóge nas de línea germinal en mexicanas con cáncer de mama triple negativo hereditario

Abstract: Objective: Describe the prevalence of breast cancer (BC)-associated germline pathogenic variants (PVs) among Mexican patients with triple-negative BC (TNBC). Materials and methods: The spectrum of PVs identified among patients with TNBC who were enrolled in a prospective registry and underwent genetic testing was analyzed. Results: Of 387 patients with invasive TNBC and a median age at diagnosis of 39 years (range 21-72), 113 (29%) were carriers of PVs in BC-susceptibility genes: BRCA1 (79%), BRCA2 (15%), and other (6%: ATM, BRIP1, PALB2, PTEN, RAD51C, and TP53). PV carriers were younger at BC diagnosis (37 vs. 40 years, p=0.004) than non-carriers. Conclusion: A large proportion of TNBC in Mexican patients is associated with germline PVs, the vast majority in BRCA. The incremental yield of PVs in other BC-susceptibility genes was modest, and a stepwise approach starting with BRCA testing may be justified if it is more cost-effective than multigene panel testing.

Resumen: Objetivo: Describir la prevalencia de variantes patógenas (VPs) germinales en genes asociados con cáncer de mama (CM) en pacientes mexicanos con CM triple negativo (CMTN). Material y métodos: Se analizó el espectro de VPs identificadas en pacientes con CMTN que fueron incluidos prospectivamente en un registro y se realizó un estudio genético. Resultados: Se analizó un total de 387 pacientes con una mediana de edad al diagnóstico de 39 años; 113 (29%) eran portadores de VPs en genes de susceptibilidad a CM: BRCA1 (79%), BRCA2(15%), y otros (6%: ATM, BRIP1, PALB2, PTEN, RAD51C y TP53). Los portadores de VPs eran más jóvenes al diagnóstico de CM (37 vs. 40 años, p=0.004). Conclusiones: Existe una alta prevalencia de VPs en pacientes mexicanos con CMTN y la mayoría se encuentra en genes BRCA. La realización de pruebas genéticas se puede optimizar mediante la adopción de un proceso escalonado para la detección de VPs.

Familial aggregation myelodysplastic syndromes/acute myeloid leukemia: report of 3 pedigrees and review of literature / 白血病·淋巴瘤

Objective:To investigate the clinical characteristics, gene mutation, treatment and prognosis of familial aggregation myelodysplastic syndromes/acute myeloid leukemia (MDS/AML).Methods:The 3 familial aggregation MDS/AML admitted to Shanghai Yangpu District Hospital from August 2012 to March 2019 were collected. The bone marrow examination, gene mutation detection, therapeutic effect and prognosis of the patients were retrospectively analyzed, and the relevant literature was reviewed.Results:In pedigree 1, the survival time of 2 AML patients was 8 months and 1 month, respectively. In pedigree 2, the transformation time of 2 patients diagnosed MDS to AML/high-risk MDS was 4 and 3 months, the survival time was 5 and 8 months, respectively. TP53 and RUNX1 mutations were detected in the older brother. In pedigree 3, the survival time of the AML patient was 13 months, and the MDS patient was stable.Conclusions:Familial aggregation MDS/AML has rapid progression and short survival time, and its diagnosis needs to be combined with family history, cytogenetics, and molecular biology.

Abiraterone for treatment of germline mutation in BRCA1 gene with low age, high tumor burden and rapid progression of prostate cancer: a case report / 中华泌尿外科杂志

The incidence of prostate cancer is increasing year by year in China. People with BRCA mutation are at high risk of prostate cancer. However, there is no clear and effective treatment for mHSPC with high metastatic load carrying BRCA mutation. In this study, we report a mHSPC patient with high metastatic burden and germline BRCA1 gene mutation who rapidly progressed to mCRPC after traditional CAB therapy and then received ADT combined with abiraterone and achieved significant PSA response, suggesting that ADT combined with abiraterone may be an effective therapy for mHSPC patients with BRCA1 germline mutation.

Germline and Somatic mutations in postmenopausal breast cancer patients

OBJECTIVES: In breast cancer (BC) patients, the frequency of germline BRCA mutations (gBRCA) may vary according to the ethnic background, age, and family history of cancer. Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) is the second most common somatic mutated gene in BC; however, the association of mutations in both genes with cancer has not been thoroughly investigated. Thus, our aims were to investigate gBRCA mutation frequency in a cohort of postmenopausal Brazilian BC patients and the association of gBRCA1/BRCA2 and PIK3CA somatic mutations. METHODS: Forty-nine postmenopausal (>55 years) and forty-one young (≤35 years) BC patients were included in this study. The postmenopausal group included patients who reported a positive family history of cancer. For these patients, gBRCA1/BRCA2 were sequenced using next-generation sequencing (NGS) or Sanger sequencing. Data for gBRCA in young patients were already available from a previous study. DNA from formalin-fixed, paraffin-embedded (FFPE) tumors was obtained from 27 postmenopausal and 41 young patients for analyzing exons 9 and 20 of PIK3CA. The association between gBRCA1/BRCA2 and somatic mutations in PIK3CA was investigated. RESULTS: The overall frequency of gBRCA1/BRCA2 among the 49 postmenopausal patients was 10.2%. The frequencies of somatic mutations in PIK3CA in the postmenopausal and young patients were 37% and 17%, respectively (ns). The most common PIK3CA mutation was found to be E454A. Nonsense and frameshift mutations, which may counteract the oncogenic potential of PIK3CA were also detected. Regardless of age, 25% of BRCA1/BRCA2 mutation carriers and non-carriers , each, had PIK3CA somatic mutations. CONCLUSIONS: Data obtained indicate that BRCA1/BRCA2 gene testing may be considered for postmenopausal patients with BC who have a family history of cancer. Although some of them are not considered pathogenic, somatic variants of PIK3CA are frequently observed in BC patients, especially in postmenopausal patients.

Deviation of paradigmatic mutations found in Shprintzen-Goldberg syndrome

Shprintzen-Goldberg (S-G) Syndrome known as rare congenital connective tissue disorder where craniosynostosis and marfanoid habitus found to be the usual presentation. Craniofacial dysmorphism with multi-organ involvement documented to be amongst prominent features of this syndrome. Case characteristics is five-month-old male infant with craniosynostosis, and motor developmental delay was evaluated for congenital connective tissue disorder. Dysmorphic craniofacial features like dolichocephaly, triangular forehead, ocular hypertelorism, micrognathia and retrognathia were noticed besides congenital umbilical hernia, empty scrotal sac, clinodactyly with long slender fingers, hyper-mobile joints, hypotonia. Subsequent investigations revealed normal male karyotype (46, XY) while genetic analysis depicted missense mutations in six different genes. Conventionally, mutation in SKI gene reported for its' associated with S-G syndrome where dysregulation of TGF-? signaling was discussed as the primary reason. In the present case discussed here, it was found to have polygenic mutational association where few novel genetic mutations were seen.

Clinical practice of prophylactic nipple- sparing mastectomy and immediate reconstruction in Chinese healthy women with BRCA1/BRCA2 germline mutation / 中国肿瘤临床

Objective: To explore the possibility of prophylactic nipple-sparing mastectomy and immediate reconstruction in healthy Chinese women with BRCA1/BRCA2 germline mutation. Methods: From January 2018 to February 2019, three healthy Chinese women with a BRCA1/ BRCA2 germline pathogenic mutation were treated at the Department of Breast Surgery, Peking University International Hospital (2 cases of BRCA1 mutation and 1 case of BRCA2 mutation); these three women (aged 34-36 years) had a strong family history of breast cancer. Thus, they underwent prophylactic nipple-sparing mastectomy and immediate reconstruction. Results: The operations were successfully completed, and no complications occurred. After a median 18-month follow-up, no breast cancer occurred in the three women; they were satisfied with the reconstructed breast's shape, and their anxiety also significantly reduced. Conclusions: Healthy Chinese women with a BRCA1/ BRCA2 germline mutation and a strong family history of breast cancer can possibly consider prophylactic nipple-sparing mastectomy and immediate reconstruction as options.

Pheochromocytoma and paraganglioma: implications of germline mutation investigation for treatment, screening, and surveillance

ABSTRACT Objective Paraganglioma (PGL) and pheochromocytoma (PCC) are rare neuroendocrine tumors that were considered to be predominantly sporadic. However, with the identification of novel susceptibility genes over the last decade, it is currently estimated that up to 40% of cases can occur in the context of a hereditary syndrome. We aimed to characterize PGL/PCC families to exemplify the different scenarios in which hereditary syndromes can be suspected and to emphasize the importance for patients and their families of making an opportune genetic diagnosis. Materials and methods Retrospective analysis of patients diagnosed with PGL/PCC. Germline mutations were studied using next-generation sequencing panels including SDHA, SDHB, SDHC and SDHD. Clinical data were collected from clinical records, and all patients received genetic counseling. Results We describe 4 families with PGL/PCC and germline mutations in SDH complex genes. 2 families have SDHB mutations and 2 SDHD mutations. The clinical presentation of the patients and their families was heterogeneous, with some being atypical according to the literature. Conclusions PGL/PCC are more commonly associated with a germline mutation than any other cancer type, therefore, all individuals with these types of tumors should undergo genetic risk evaluation. NGS multigene panel testing is a cost-effective approach given the overlapping phenotypes. Individuals with germline mutations associated with PGL/PCC should undergo lifelong clinical, biochemical and imaging surveillance and their families should undergo genetic counseling. For all these reasons, it is critical that all medical staff can suspect and diagnose these inherited cancer predisposition syndromes.

Appolication of next-generation sequencing for the screening of hereditary gastrointestinal cancer / 中国肿瘤临床

Objective: To explore the significance of next-generation sequencing for the screening of high-risk hereditary gastrointesti-nal cancer patients and the value of high-risk factors in screening. Methods: Twenty-five hereditary high-risk gastrointestinal cancer pa-tients from March 2016 to April 2016 in Peking University Cancer Hospital were enrolled. They received detection of 42 hereditary can-cer syndrome related genes by next-generation sequencing. Results: Out of 25 patients enrolled, 24% (6/25) patients had pathological germline mutations. The expression of mismatch repair protein was absent in 50% (3/6) patients. There were 83% (5/6) patients with family history of malignant tumors and were diagnosed when younger than 50 years. Six patients had hereditary cancer syndrome re-lated gene mutation, 1 patient had MYH gene missense mutation, 1 patient had APC gene deletion mutation, 4 patients had heredi-tary colorectal cancer related gene mutation, including MLH1, MLH3, and TGFBR2 germline missense mutations as well as MSH6 non-sense mutation. Conclusions: Out of 25 patients with high-risk factors of hereditary gastrointestinal cancer, 6 (24%) had pathological germline mutations. Given the high frequency and wide spectrum of mutations, the application of next-generation sequencing for screening of hereditary high-risk gastrointestinal cancer patients has the clinical value for improving the positive rate of diagnosis.

Familial aggregation myelodysplastic syndromes/acute myeloid leukemia: report of one pedigree and review of literature / 白血病·淋巴瘤

Objective To investigate the diagnosis, clinical characteristics, gene mutation and treatment of familial aggregation myelodysplastic syndromes/acute myeloid leukemia (MDS/AML). Methods Bone marrow morphocytology, immunophenotype, cytogenetics, gene mutation, therapeutic effects and prognosis of the brothers in the line of MDS/AML patients were analyzed, and the related literature was reviewed. Results The prover developed AML after the diagnosis of MDS-refractory anemia with excess blasts-Ⅰ (MDS-RAEB Ⅰ) for 4 months. With elder brother developed MDS RAEB-Ⅱ after the diagnosis of MDS-refractory cytopenia with multilineage dysplasia for 3 months. The survival period was 5 and 8 months. Conclusion Familial aggregation MDS/AML is rare with poor prognosis, and its diagnosis needs to be combined with family history, cytogenetics and molecular biology.

Germline TP53 Mutation and Clinical Characteristics of Korean Patients With Li-Fraumeni Syndrome

BACKGROUND: Little is known of the mutation and tumor spectrum of Korean patients with Li-Fraumeni syndrome (LFS). Owing to the rarity of LFS, few cases have been reported in Korea thus far. This study aimed to retrospectively review the mutations and clinical characteristics of Korean patients with LFS. METHODS: TP53 mutation was screened in 89 unrelated individuals at the Samsung Medical Center in Korea, from 2004 to 2015. Six additional mutation carriers were obtained from the literature. RESULTS: We identified nine different mutations in 14 Korean patients (male to female ratio=0.3:1). Two such frameshift mutations (p.Pro98Leufs*25, p.Pro27Leufs*17) were novel. The recurrent mutations were located at codons 31 (n=2; p.Val31Ile), 175 (n=3; p.Arg175His), and 273 (n=4; p.Arg273His and p.Arg273Cys). The median age at the first tumor onset was 25 yr. Ten patients (71%) developed multiple primary tumors. A diverse spectrum of tumors was observed, including breast (n=6), osteosarcoma (n=4), brain (n=4), leukemia (n=2), stomach (n=2), thyroid (n=2), lung (n=2), skin (n=2), bladder (n=1), nasal cavity cancer (n=1), and adrenocortical carcinoma (n=1). CONCLUSIONS: There was considerable heterogeneity in the TP53 mutations and tumor spectrum in Korean patients with LFS. Our results suggest shared and different LFS characteristics between Caucasian and Korean patients. This is the first report on the mutation spectrum and clinical characteristics from the largest series of Korean LFS patients.

A Case of Medullary Thyroid Carcinoma with de novo V804M RET Germline Mutation

Many cases of RET proto-oncogene mutations of hereditary medullary thyroid carcinoma (MTC) have been reported in Korea. However, MTC with V804M RET proto-oncogene germline mutations have not been reported in Korea. A 33-yr-old man was diagnosed with a 0.7-cm sized thyroid nodule. Laboratory testing revealed serum calcitonin was elevated. The patient underwent total thyroidectomy with central compartment neck dissection for the thyroid tumor. RET gene analysis was performed in both the index patient and his family. There were no V804M RET mutation and abnormal laboratory findings within his family except the index patient. Therefore, this patient was a de novo V804M RET germline mutation.

Mutation analysis in two Chinese families with multiple endocrine neoplasia type 1 / Análise de mutações em duas famílias chinesas com neoplasia endócrina múltipla tipo 1

OBJECTIVE: This study aimed at identifing mutations in two Chinese genealogies with MEN1. SUBJECTS AND METHODS: Three members of two Chinese families with MEN1 were enrolled in this study, and all of the coding regions and adjacent sequences of the MEN1 gene were amplified and sequenced. RESULTS: A recurrent mutation of heterozygous change T>A at IVS 4+1 was found in family I, and a novel insGAGGTGG mutation (c.703-709dup7bp) resulted in a frameshift (p.A237Gfsx13) in family II. CONCLUSION: We are able to add a new mutation of MEN1 gene in Chinese patients with MEN1 that will be useful for the diagnosis and treatment of the disease.

OBJETIVO: O objetivo deste estudo foi identificar as mutações em duas famílias chinesas com NEM1. SUJEITOS E MÉTODOS: Três membros das duas famílias chinesas foram estudados. Em todos eles, as regiões codificadoras e sequências adjacentes do gene MEN1 foram amplificadas e sequenciadas. RESULTADOS: Uma alteração heterozigota recorrente de T>A em IVS 4+1 foi encontrada na família I, e uma nova mutação insGAGGTGG (c.703-709dup7bp) levou a um frameshift (p.A237Gfsx13) na família II. CONCLUSÃO: Adicionou-se uma nova mutação ao gene MEN1 em pacientes chineses com diagnóstico de NEM1 que vai ser útil no diagnóstico e tratamento da doença.

Genetic progression of familial gastric cancer / 国际肿瘤学杂志

The hereditary diffuse gastric cancer (HDGC) is associated with CDHI (E-cadherin gene)germline mutations, and accounts for about one-third of the familial gastric cancer (FGC) cases. The other two thirds FGC cases which are not fit the diagnosis standard of HDGC remain lack of clear molecular diagnosis basis. The current disposal of prophylactic gastrectomy in FGC according to E-cadherins genetic counseling, has clinical significance only in part of HDGC.

Characteristics of the RET Oncogene Germline Mutations in Korean Medullary Thyroid Carcinoma: A Literature Review / 대한내분비외과학회지

PURPOSE: Germline mutation of the RET oncogene results in multiple endocrine neoplasia (MEN) types 2A and 2B and familial medullary thyroid cancer (FMTC). We reviewed the literature to determine the mutation patterns of the RET oncogene in Koreans with MEN-2A, 2B and FMTC. METHODS: We retrieved the relevant literature using the PubMed (http://www.pubmed.org/) and KoreaMed (http://www.koreamed.org/) databases concerning the RET germline mutations in Korea from 1998 to 2010. We evaluated the pedigree of the patients to exclude the same, repeated families. We collected all the data on the types of mutations and the clinical syndromes. RESULTS: There were 21 studies with a total of 25 families. In the patients with MEN-2A and FMTC, there were 14 mutations (56%) in codon 634, 6 mutations (24%) in codon 618, 2 mutations (8%) in codon 631 and one mutation (4%) in codon 768. In the patients with MEN-2B, there were 2 mutations (8%) in codon 918. D631Y is an extremely rare mutation, but two families with such a mutation existed in Korea. The frequency of codon 634 mutations in the patients with MEN-2A was relatively lower than that of the previously reports from western countries and the frequency of codon 618 mutations was relatively higher than that in the western countries. CONCLUSION: This study shows there are hot spots and genotype- phenotype correlations for the RET oncogene mutations in Koreans.

Analysis of clinical and pathological features of familial gastric cancer / 中国现代普通外科进展

Objective:To explore the clinical and pathological features of familial gastric cancer, and to get the early discovery and early treatment of it.Methods:Two kindreds of familial gastric cancer were followed up and their clinical and pathological features were analyzed.Results:Six patients with gastric cancer were found in the 2 kindreds.Autosomal dominant inheritance was observed in these cases.clinical and pathological features of familial gastric cancer were showed according to the document analysis:early onset;poor prognosis;patients suffer simultaneous or metachronous carcinoma;CDH1 germline mutation carriers had higher penetrance;pathologically, tumors are mostly diffuse infiltrative type with lower differentiated degree and earlier metastasis to lymphnodes;in one kindred,the sites of the lesions were relatively consistent.Conclusion:Familial gastric cancer has particular clinical and pathological features:early onset;poor prognosis;patients suffer simultaneous or metachronous carcinoma;CDH1 germline mutation carriers have higher penetrance; pathologically,tumors are mostly diffuse infiltrative type with lower differentiated degree and earlier metastasis to lymphnodes.

Germline Genetic Alterations in Intraductal Papillary Neoplasms Associated with Extrapancreatic Tumors

PURPOSE: IPMN (Intraductal papillary mucinous neoplasm) is frequently reported in combination with a variety of extrapancreatic tumors. The IPMN in these patients might represent the phenotypes of genes associated with multiple tumor syndrome. The aim of this study was to confirm the presence of germline mutations in the p53, MLH1, MSH2, BRCA1/2, and E-cadherin genes known to be associated with gastrointestinal malignancies in hereditary tumor syndromes such as Li-Fraumeni syndrome, HNPCC, Hereditary Breast/Ovarian cancer, and Hereditary diffuse gastric cancer. METHODS: 14 patients with IPMN with extrapancreatic tumors (6 gastric cancers, 5 colorectal cancers, 1 gastric GIST, 2 hepatocellular carcinomas, 1 AoV cancer) who underwent resection were enrolled in this study. We performed PCR (Polymerase chain reaction) and direct sequencing analysis for the p53, MLH1, MSH2 and CDH-1 genes. Multiplex PCR, F-CSGE (fluorescent conformation sensitive gel electrophoresis) and direct sequencing was performed for BRCA1/2 genes. RESULTS: We identified two novel mutations in the p53 gene (exon 1, codon 31, GTC>CTC, Glu-->Gln) and the CDH-1 gene (exon 14, codon 2218, CCC>TCC, Pro-->Ser). For BRCA1, we identified 11 identical coding SNP (exon 11, codon 3232, AAG>AGG, Glu-->Gly) among 13 patients with a high allele frequency (46.1%) compared with the 30.1% reported in Korean breast cancer patients. For BRCA2, we identified a coding SNP with an allele frequency of 2.6% (exon 11, codon 2578, AAG>AGG, Met-->Val). CONCLUSION: Germline alterations of the p53 and E-Cadherin genes in IPMN patients with extrapancreatic cancer suggest that IPMN could be a manifestation of multiple tumor syndrome.

Cáncer gástrico difuso hereditario (CGDH): presentación de una familia con una nueva mutación del gen CDH1 / Hereditary diffuse gastric Cancer (HDGC): presentation of a family with a new mutation of the CDH1 GENE

Introducción: el CGDH se hereda en forma autosómica dominante. Su sospecha se basa en los antecedentes familiares y su confirmación requiere estudios moleculares. En el 40% de las familias se logra identificar una mutación en el gen CDH1 de la caderina- E que permite discriminar a los portadores y no portadores. La prevención para los portadores de la mutación incluye la gastrectomía profiláctica o la vigilancia endoscópica cada 6 a 12 meses. Objetivo: presentar el caso de una familia con CGDH portadora de una mutación en gen CDH1 no previamente reportada. Caso: mujer de 28 años, gastrectomizada por cáncer gástrico de tipo difuso con antecedentes familiares de cáncer gástrico que mostraba un patrón de herencia autosómico dominante (afectación de 9 miembros en 5 generaciones). Con sospecha de CGDH se comenzó un plan de vigilancia endoscópica y se analizó el ADN purificado de la sangre periférica de la paciente afectada mediante la secuenciación directa del gen CDH1, en la cual se dentificó una mutación sin sentido (non-sense) en la posición 1913 G>A (W638X) del exón 12. Conclusión: la recolección detallada de los antecedentes familiares permitió sospechar una entidad hereditaria muy poco frecuente. Los estudios moleculares confirmaron el diagnóstico, lo que posibilitará la estimación del riesgo individual en los familiares consanguíneos.

Introduction: HDGC is a hereditary cancer syndrome with an autosomic dominant pattern. It may be clinically diagnosed by family background, and confirmed by genetic testing. In 40% of the families, a mutation in the CDH1 gene (E-cadherin) can be identified. Furthermore, the identification of the pathogenic mutation enables the segregate non-carriers (having population risk) and carriers. Prevention for the latter group includes prophylactic gastrectomy or surveillance endoscopy every 6 to 12 months. Objective: to present the case of an HDGC family with identified CDH1 mutation. CASE: 28 yearold woman who underwent gastrectomy for a diffuse ype gastric cancer. Her family background showed multiple gastric cancers with inherited autosomaldominant pattern (affectation of 9 members in 5 generations). Suspecting HDGC, a plan of surveillance endoscopy was iniciated, and a her DNA sample was sequenced for CDH1 gene finding a non-sense mutation in position 1913 G>A (W638X) of exon 12. Conclusion: the detailed recollection of the family background allowed to identify a rare inherited entity. The molecular testing confirmed the diagnosis and will allow future tailored counselling among relatives.

A Case of Type 1 von Hippel-Lindau (VHL) Disease associated with VHL Germline Mutation / 대한내분비학회지

Von Hippel-Lindau (VHL) disease is an autosomal dominant neoplasia syndrome that result from a germline mutation in the VHL gene. Germline mutation in the VHL gene lead to the development of hemangioblastomas of the central nervous system and retina, cysts and clear cell carcinoma of the kidney, cyst adenomas of other organs, and pheochromocytoma. VHL is a tumor suppressor gene on the short arm of chromosome 3. VHL disease has been classified into two main clinical subtypes depending on the presence (type 2) or absence (type 1) of pheochromocytoma. Type 2 has been subdivided into three categories depending on the presence (type 2B) or absence (type 2A) of renal cell carcinoma, with type 2C being a rare subtype in which pheochromocytoma is the sole manifestation of VHL disease. Recently we experienced a family with VHL type 1 who carry C to T (Q73X) transition in codon 217 nonsense germline mutation in exon 1 of VHL gene. The authors report this case with literature review.

Germline Mutations and polymorphisms of BRCA1 and BRCA2 in Sporadic Ovarian Carcinoma / 대한산부인과학회지

OBJECTIVE: Mutations in the BRCA1 and BRCA2 genes predispose women to ovarian and/or breast cancer. The purposes of this study were firstly to investigate the presence of BRCA1 and BRCA2 mutations in women with non-hereditary ovarian cancer and secondly to evaluate the relationship between ovarian cancer susceptibility gene polymorphism and clinicopathological features. METHODS: We studied 37 women who received a diagnosis of sporadic ovarian epithelial cancer and were treated at our hospital between August 2002 and March 2004. Genomic DNA was analyzed for BRCA mutations using PCR-DHPLC-sequencing method. And we examined the relationship between ovarian cancer susceptibility gene polymorphism and clinicopathological features using a high- throughput SNP scoring methods. RESULTS: Most mutations of BRCA1 and BRCA2 associated with ovarian and/or breast cancer resulted in truncated proteins. We found one frameshift mutation in BRCA1 (3746insA) led to premature termination. She has no family history of breast and ovarian cancer. There was no relationship between ovarian cancer susceptibility gene polymorphisms and clinicopathological features. CONCLUSION: Our results were consistent with the concept that there was a limited role of BRCA1 and BRCA2 mutations in ovarian carcinogenesis in Korean population and polymorphisms of some selected ovarian cancer susceptibility genes were not associated with the clinicopathological phenotypes of ovarian cancer.