Humans ; Genetic Predisposition to Disease ; Neoplastic Syndromes, Hereditary/genetics* ; Mutation

OBJECTIVE: To analyze clinical phenotype and genetic variants in a Chinese pedigree of hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome. METHODS: Whole exome sequencing was carried out for the proband from the pedigree. Suspected FH gene variants were validated by Sanger sequencing. Clinical manifestation and histopathological examination were used to analyze the pedigree comprehensively. RESULTS: The pedigree met the clinical diagnostic criteria for HLRCC syndrome. The whole exome sequencing showed that the FH gene of the proband had a heterozygous missense variant of c.1490T>C (p.F497S), which was consistent with the Sanger sequencing. The mother, daughter and son of the proband all had the heterozygous missense variant of c.1490T>C (p.F497S). According to the American Society of Medical Genetics and Genomics Classification Standards and Guidelines for Genetic Variations, c.1490T>C (p.F497S) (PM2+PP1-M+PP3+PP4) was a possible pathogenic variant. Based on our literature search, this variant was a new variant that had not been reported. CONCLUSION The FH gene missense variant of c.1490T>C (p.F497S) may be the cause of the HLRCC syndrome pedigree, which provides a basis for the genetic diagnosis and genetic counseling of the HLRCC syndrome.
Carcinoma, Renal Cell/genetics* ; Humans ; Kidney Neoplasms/genetics* ; Leiomyomatosis/pathology* ; Mutation ; Neoplastic Syndromes, Hereditary ; Pedigree ; Phenotype ; Skin Neoplasms ; Uterine Neoplasms

OBJECTIVETo evaluate the frequency and nature of E-cadherin gene (CDH1) germline mutations in familial gastric cancer kindreds of china.

METHODSFive familial gastric cancer kindreds of Chinese origin were screened for germline CDH1 mutations, all of them meeting the clinical criteria for hereditary diffuse gastric cancer (HDGC), by PCR-DHPLC and direct sequencing.

RESULTSA new truncating mutation in exon 10 in B family was identified, producing a stop codon at position 503 (Q503X), resulting in a truncated protein. The proband of this family had metachronous development of lobular breast and diffuse type gastric carcinoma. No protein expression was detected in the lobular breast carcinoma, indicating complete inactivation of the gene.

CONCLUSIONSA Chinese gastric cancer family with CDH1 germline truncating mutation is described for the first time, and our findings suggest that lobular breast carcinoma might be part of the tumor spectrum of HDGC.

Adult ; Breast Neoplasms ; genetics ; Cadherins ; genetics ; Female ; Humans ; Male ; Middle Aged ; Mutation ; Neoplasms, Multiple Primary ; genetics ; Neoplastic Syndromes, Hereditary ; genetics ; Pedigree ; Polymerase Chain Reaction ; Stomach Neoplasms ; genetics

Familial juvenile polyposis (FJP) is a rare autosomal dominant hereditary disorder that is characterized by the development of multiple distinct juvenile polyps in the gastrointestinal tract and an increased risk of cancer. Recently, germline mutations, including mutations in the SMAD4, BMPR1A, PTEN and, possibly, ENG genes, have been found in patients with juvenile polyps. We herein report a family with juvenile polyposis syndrome (JPS) with a novel germline mutation in the SMAD4 gene. A 21-year-old man presented with rectal bleeding and was found to have multiple polyps in his stomach, small bowel, and colon. His mother had a history of gastrectomy for multiple gastric polyps with anemia and a history of colectomy for colon cancer. A review of the histology of the polyps revealed juvenile polyps in both patients. Subsequently, mutation screening in DNA samples from the patients revealed a germline mutation in the SMAD4 gene. The pair had a novel mutation in exon 10 (stop codon at tyrosine 413). To our knowledge, this mutation has not been previously described. Careful family history collection and genetic screening in JPS patients are needed to identify FJP, and regular surveillance is recommended.
Exons ; Female ; Gastrointestinal Neoplasms/*genetics/pathology ; Germ-Line Mutation ; Humans ; Intestinal Polyposis/*congenital/genetics/pathology ; Male ; Middle Aged ; Neoplastic Syndromes, Hereditary/*genetics/pathology ; Smad4 Protein/*genetics ; Young Adult

Pancreatic cancer is currently the major leading cause of cancer-related deaths in the Western countries with an overall 5-year survival rate of less than 3. The key aim of investigation is to identify the cellular population in which some of the earliest molecular events occur, presumably the ultimate target for carcinogenic insult. Advances in pathological classification and genetics have improved our descriptive understanding of this disease. However, important aspects of pancreatic cancer biology remain poorly understood. Factors associated with the increased risk of pancreatic cancer include smoking, chronic pancreatitis, diabetes, prior gastric surgery, and exposure to radiation or chemicals. A number of syndromes have been identified with the increased incidence of pancreatic cancer, including familial atypical multiple-mole melanoma syndrome, hereditary nonpolyposis colorectal cancer, and hereditary pancreatitis, etc. Recently, there have been growing evidences that stem cell biology could provide new insights into the understanding of cancer biology. Three postulates regarding the relationship between stem and tumor cells have been proposed. First, the similarities in the mechanims that regulate self-renewal of normal stem cells and cancer cells. Second, the possibility that tumor cells might arise from normal stem cells and third, the notion that tumors might contain 'cancer stem cells' - rare cells with indefinite proliferative potential which drive the formation and growth of tumors. New insights for the cancer stem cells and their possible markers in pancreatic cancer have been suggested recently. Further observations of molecular and cellular events in the early stage of pancreatic carcinogenesis may have important implications regarding the cellular lineage responsible for pancreatic ductal metaplasia and neoplasia, and provide further support for the presence of stem cell capabilities within mature pancreatic epithelium.
Carcinoma, Pancreatic Ductal/*etiology/genetics/pathology ; Disease Progression ; Humans ; Mutation ; Neoplasm Proteins/genetics ; Neoplastic Syndromes, Hereditary/genetics ; Oncogenes ; Pancreatic Neoplasms/diagnosis/*etiology/genetics ; Risk Factors ; Tumor Markers, Biological

Adolescent ; Adult ; Child ; Deubiquitinating Enzyme CYLD ; Female ; Humans ; Male ; Neoplastic Syndromes, Hereditary ; genetics ; Pedigree ; Skin Neoplasms ; genetics ; Tumor Suppressor Proteins ; genetics ; Young Adult

INTRODUCTIONThe Singapore Polyposis Registry (SPR) was established in 1989 in Singapore General Hospital (SGH). The aims were to provide a central registry service to facilitate identification, surveillance and management of families and individuals at high risk of colorectal cancer.

MATERIALS AND METHODSThis is a review of published literature in the department.

RESULTSThe registry currently has 253 families with several genetic conditions-93 familial adenomatous polyposis (FAP) families, 138 Amsterdam-criteria positive presumed Lynch syndrome (LS) families, 12 families with Peutz Jeghers syndrome, 2 families with Cowden's syndrome, and 8 families with hereditary mixed polyposis syndrome (HMPS). There are also 169 families with a strong family history of colorectal cancer but no abnormal genes yet identified. In FAP, a diagnostic tool developed has allowed a 94% local APC germline detection rate in FAP families. Knowledge obtained studying the phenotype of FAP patients has allowed better choice of surgery between ileal pouch anal anastomosis (IPAA) against an ileal-rectal anastomosis (IRA). In LS, our review has noted a highly heterogenous mutational spectrum and novel variants made up 46.7% (28/60) of all variants identified in this cohort. This may suggest that our Southeast Asian ethnic groups have distinct mutational variants from Western populations. Pathogenic mutations were only confined to MLH1 and MSH2, and identified in 28.8% of families.

CONCLUSIONThe impact of predictive gene testing for hereditary cancer risk in clinical practice has allowed evolution of care. Risk-reducing surgery and aggressive surveillance allows reduction in morbidity and mortality of patients. The SPR will continue to grow and improve outcomes in hereditary colorectal cancer patients and families.

Adaptor Proteins, Signal Transducing ; genetics ; Colorectal Neoplasms ; diagnosis ; ethnology ; genetics ; surgery ; Disease Management ; Female ; Genetic Testing ; methods ; Humans ; Male ; MutL Protein Homolog 1 ; MutS Homolog 2 Protein ; genetics ; Mutation ; Neoplastic Syndromes, Hereditary ; classification ; diagnosis ; ethnology ; genetics ; surgery ; Nuclear Proteins ; genetics ; Registries ; statistics & numerical data ; Singapore ; epidemiology

Antibodies, Monoclonal ; therapeutic use ; Antibodies, Monoclonal, Humanized ; Antineoplastic Agents ; therapeutic use ; Cadherins ; genetics ; metabolism ; Carcinoma, Papillary ; pathology ; Cetuximab ; Colorectal Neoplasms ; drug therapy ; genetics ; pathology ; Consensus ; Dissent and Disputes ; Drug Delivery Systems ; Epithelial-Mesenchymal Transition ; Gastrointestinal Neoplasms ; classification ; pathology ; Genes, ras ; Humans ; Mutation ; Neoplasm Invasiveness ; Neoplastic Syndromes, Hereditary ; genetics ; metabolism ; pathology ; Neuroendocrine Tumors ; classification ; pathology ; Precancerous Conditions ; pathology ; Stomach Neoplasms ; genetics ; metabolism ; pathology

Biallelic inactivation of fumarate hydratase(FH) causes type 2 papillary renal cell carcinoma (PRCC2), uterine fibroids, and cutaneous leimyomas, a condition known as hereditary leiomyomatosis and renal cell cancer(HLRCC). The most direct effect of FH inactivation is intracellular fumarate accumulation. A majority of studies on FH inactivation over the past decade have focused on the theory that intracellular fumarate stabilizes hypoxia-inducible factor 1α(HIF1A) through competitive inhibition of HIF prolyl hydroxylases. Recently, a competing theory that intracellular fumarate activates nuclear factor (erythroid-derived 2)-like 2(NRF2) through post-translational modification of its negative regulator. Kelch-like ECH-associated protein 1(KEAP1) has emerged from a computational modeling study and mouse model studies. This review dissects the origin of these two governing theories and highlights the presence of chromatin-structure-regulated targets of transcription factors, which we refer to as "cryptic targets" of transcription factors. One such cryptic target is heme oxygenase I(HMOX1), the expression of which is known to be modulated by the gene product of SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4 (SMARCA4, also known as BRG1).
Animals ; DNA Helicases ; metabolism ; Fumarate Hydratase ; genetics ; metabolism ; Fumarates ; metabolism ; Heme Oxygenase-1 ; metabolism ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit ; genetics ; metabolism ; Intracellular Signaling Peptides and Proteins ; metabolism ; Kelch-Like ECH-Associated Protein 1 ; Kidney Neoplasms ; genetics ; metabolism ; Leiomyomatosis ; genetics ; metabolism ; NF-E2-Related Factor 2 ; genetics ; metabolism ; Neoplastic Syndromes, Hereditary ; genetics ; metabolism ; Nuclear Proteins ; metabolism ; Procollagen-Proline Dioxygenase ; metabolism ; Protein Processing, Post-Translational ; Skin Neoplasms ; Transcription Factors ; metabolism ; Uterine Neoplasms

The NCCN has recently released its 2017 version 1.0 guideline for colorectal cancer. There are several updates from this new version guideline which are believed to change the current clinical practice. Update one, low-dose aspirin is recommended for patients with colorectal cancer after colectomy for secondary chemoprevention. Update two, biological agents are removed from the neoadjuvant treatment regimen for resectable metastatic colorectal cancer (mCRC). This update is based on lack of evidence to support benefits of biological agents including bevacizumab and cetuximab in the neoadjuvant setting. Both technical criteria and prognostic information should be considered for decision-making. Currently biological agents may not be excluded from the neoadjuvant setting for patients with resectable but poor prognostic disease. Update three, panitumumab and cetuximab combination therapy is only recommended for left-sided tumors in the first line therapy. The location of the primary tumor can be both prognostic and predictive in response to EGFR inhibitors in metastatic colorectal cancer. Cetuximab and panitumumab confer little benefit to patients with metastatic colorectal cancer in the primary tumor originated on the right side. On the other hand, EGFR inhibitors provide significant benefit compared with bevacizumab-containing therapy or chemotherapy alone for patients with left primary tumor. Update four, PD-1 immune checkpoint inhibitors including pembrolizumab or nivolumab are recommended as treatment options in patients with metastatic deficient mismatch repair (dMMR) colorectal cancer in second- or third-line therapy. dMMR tumors contain thousands of mutations, which can encode mutant proteins with the potential to be recognized and targeted by the immune system. It has therefore been hypothesized that dMMR tumors may be sensitive to PD-1 inhibitors.
Antibodies, Monoclonal ; pharmacology ; therapeutic use ; Antibodies, Monoclonal, Humanized ; therapeutic use ; Antineoplastic Agents ; therapeutic use ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Aspirin ; administration & dosage ; therapeutic use ; Bevacizumab ; therapeutic use ; Biological Products ; therapeutic use ; Brain Neoplasms ; drug therapy ; genetics ; Cetuximab ; therapeutic use ; Clinical Decision-Making ; methods ; Colorectal Neoplasms ; drug therapy ; genetics ; pathology ; prevention & control ; therapy ; Contraindications ; Humans ; Mutation ; physiology ; Neoadjuvant Therapy ; standards ; Neoplasm Metastasis ; drug therapy ; Neoplastic Syndromes, Hereditary ; drug therapy ; genetics ; Practice Guidelines as Topic ; Prognosis ; Secondary Prevention ; methods ; standards