Adult ; Colorectal Neoplasms, Hereditary Nonpolyposis ; genetics ; Humans ; Male ; Pedigree

Colorectal Neoplasms ; genetics ; Colorectal Neoplasms, Hereditary Nonpolyposis ; metabolism ; DNA Mismatch Repair ; Humans ; Microsatellite Instability

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominantly inherited disease associated with germ-line mutations in mismatch repair genes and microsatellite instability. This article reviews the molecular biology and clinical pathology of HNPCC.
Colorectal Neoplasms, Hereditary Nonpolyposis ; diagnosis ; genetics ; pathology ; DNA Mismatch Repair ; Humans ; Microsatellite Instability

OBJECTIVETo analyze the clinical and pathological features of patients with hereditary nonpolyposis colorectal cancer (HNPCC).

METHODSThe data of 8 HNPCC pedigrees according with Amsterdam standard II were collected and their pedigree trees were generated.

RESULTSThe morbidity of HNPCC was 1.59%. Thirty-one patients were found in the 8 HNPCC pedigrees including 25 with colorectal cancer and 6 with extraintestinal tumors. The 8 probands consisted of 6 female and 2 male patients, among whom 4 were younger than 40 years old, 2 had lesions in the right colon, 3 in the left colon, and 3 in the rectum. The tumors were histologically identified mainly as highly to moderately differentiated adenocarcinoma; all the patients were free of lymph node or distant metastasis. Of the 8 probands, 5 had abnormal expression of MMR protein and only 1 had normal expression.

CONCLUSIONThe HNPCC probands are characterized by early onset at a young age and high differentiation of the tumor. The members of the pedigrees show a high incidence of the malignancies, and regular examination and timely treatment can be effective in preventing the tumor occurrence and reducing the mortality. Detection of MMR gene mutation can be a crucial approach to raising the diagnostic rate of HNPCC.

Adult ; Aged ; Colorectal Neoplasms, Hereditary Nonpolyposis ; genetics ; pathology ; DNA Mismatch Repair ; genetics ; Female ; Humans ; Male ; Middle Aged ; Pedigree

OBJECTIVETo analyze the mutational features of adenomatous polyposis coli (APC) gene and to explore the effect of mismatch repair (MMR) deficiency on its mutations in hereditary non-polyposis colorectal cancers (HNPCC).

METHODSPCR-based in vitro synthesized protein test (IVSP) assay and sequencing analysis were used to confirm somatic mutations of whole APC gene in 19 HNPCC patients.

RESULTSEleven cases with thirteen mutations were determined. The frequency of APC mutation was 58%(11/19). The exhibiting mutations consisted of 9 frameshift mutations and 4 nonsense ones, indicating the existence of more frameshift mutations (69%). All of frameshift mutations were deletion or insertion of 1-2 bp and most of them (7/9) happened at simple nucleotide repeat sequences, particularly within (A) n tracts (5/9). All of four nonsense mutations resulted from C to T transitions at CpG sites.

CONCLUSIONMutational inactivations of APC gene were detected in more than half of HNPCC patients in this study, indicating that APC mutation is a common molecular event in the tumorigenesis of HNPCC. According to the location of frameshift mutations at simple nucleotide repeat sequences and point mutations at CpG sites, it was suggested that endogenous mechanisms like MMR deficiency might exert an effect on the nature of APC mutations in most HNPCC.

Adenomatous Polyposis Coli ; genetics ; Adenomatous Polyposis Coli Protein ; genetics ; metabolism ; Carcinoma ; genetics ; Colorectal Neoplasms ; genetics ; pathology ; Colorectal Neoplasms, Hereditary Nonpolyposis ; genetics ; Genes, APC ; physiology ; Humans

Hereditary syndromes cause approximately 5 to 15% of overall colorectal cancer (CRC) cases. Hereditary CRC is conventionally divided into two major categories: hereditary non-polyposis colorectal cancer (HNPCC) and those related to polyposis syndromes including familial adenomatous polyposis (FAP), Peutz-Jegher syndrome (PJS), and juvenile polyposis (JP). The screening for the cancer and methods of treatment applied to patients with hereditary CRC are quite different from those applied to the general population. The genes responsible for these syndromes has recently identified, as a result, genetic testing has become the most important determining factor in clinical decisions. Germ-line mutation of the APC gene induces FAP, an autosomal dominant disorder, characterized by the development of hundreds to thousands of colonic adenomas. CRC appears in almost all affected individuals by the time they are 50 years of age. An affected individual should undergo colectomy by his/her late teens. Furthermore, according to the findings of genetic testing, at-risk family members also need endoscopic surveillance and surgery. Recently, a mutation on the MYH gene is increasingly being investigated in patients with multiple polyps, and autosomal recessive MYH polyposis is considered to be a new category of polyposis. More common than FAP, HNPCC is caused by germ-line mutations in DNA mismatch repair genes, mainly MLH1 and MSH2. Although there is no polyposis, polyps seem to be more villous and dysplastic and appear to grow rapidly into CRCs. The aggregate lifetime risk of CRC is about 80% for mutation carriers. The risk for other types of cancer, such as endometrial, ovarian, small bowel, and transitional cell cancer, is also increased. The Amsterdam criteria and Bethesda guidelines are the best-known tools for diagnosis and genetic testing, and colectomy followed by endoscopic follow-up is the standard treatment. PJS and JP are reported to be characterized by hamartomatous polyps throughout the GI tract and germ-line mutations in the STK11 gene (PJS) and the DPC4/BMPR1A gene (JP).
Adenomatous Polyposis Coli/*genetics ; Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis/*genetics ; Genetic Predisposition to Disease ; Germ-Line Mutation ; Humans ; Intestinal Polyposis/diagnosis/*genetics ; Peutz-Jeghers Syndrome/diagnosis/*genetics

Lynch syndrome (LS), an autosomal dominantly inherited disease previously known as hereditary non-polyposis colorectal cancer (HNPCC), leads to a high risk of colorectal cancer (CRC) as well as malignancy at certain sites including endometrium, ovary, stomach, and small bowel (Hampel et al., 2008; Lynch et al., 2009). Clinically, LS is considered the most common hereditary CRC-predisposing syndrome, accounting for about 3% of all CRC cases (Popat et al., 2005). LS is associated with mutations of DNA mismatch repair (MMR) genes such as MLH1, MSH2, MSH6, PMS2, and EPCAM (Ligtenberg et al., 2009; Lynch et al., 2009), which can trigger a high frequency of replication errors in both microsatellite regions and repetitive sequences in the coding regions of various cancer-related genes. Immunohistochemistry (IHC) tests followed by genetic analysis of these mutations play a significant role in diagnosis, treatment determination, and therapeutic response prediction of LS (Lynch et al., 2009; Alex et al., 2017; Ryan et al., 2017). Here, we report substitution of one base-pair in exon 1 of MLH3 (c.1397C>A) and a frameshift mutation in exon 19 of MLH1 (c.2250_2251ins AA) in a 43-year-old Chinese male with an LS pedigree.
Adult ; Asian People/genetics* ; China ; Colorectal Neoplasms, Hereditary Nonpolyposis/genetics* ; Exons ; Female ; Frameshift Mutation ; Germ-Line Mutation ; Humans ; Male ; MutL Protein Homolog 1/genetics* ; MutL Proteins/genetics* ; Pedigree

OBJECTIVETo investigate cyclooxygenase-2 (COX-2) expression and its relationship with mismatch repair (MMR) protein expression and microsatellite instability (MSI) in hereditary nonpolyposis colorectal cancer (HNPCC).

METHODSA total of 28 cases of colorectal adenoma and 14 cases of colorectal carcinoma were collected between July 2003 and July 2007 from 33 HNPCC families. Sporadic colorectal adenoma (n=32) and carcinoma patients (n=24) served as controls. With samples of tumor tissues and normal colonic mucosa collected from the patients, the protein expressions of COX-2 and MMR (hMLH1, hMSH2, and hMSH6) were examined with immunohistochemical assay. Frequency of MSI in five standard MSI loci BAT25, BAT26, D2S123, D5S346, and D17S250 were analyzed by means of polymerase chain reaction.

RESULTSThe rate of COX-2 high-expression was 53.6% (15/28) and 42.9% (6/14) in HNPCC adenoma and carcinoma; 62.5% (20/32) and 91.7% (22/24) in sporadic adenoma and carcinoma, respectively. That rate was lower in HNPCC carcinoma than in sporadic carcinoma (Pü0.05). MMR-deletion rate and percentage of high-frequency MSI (MSI-H) in HNPCC carcinoma were higher than those in sporadic colorectal carcinoma [both 71.4% (10/14) vs. 12.5% (3/24), both Pü0.01]. Among the 10 MMR-deficient HNPCC carcinoma patients, COX-2 low-expression was observed in 8 cases (80.0%), while COX-2 high-expression was observed in all of the 4 MMR-positive HNPCC carcinoma cases (Pü0.05). In comparison to MMR positive HNPCC carcinoma, HNPCC adenoma, and sporadic carcinoma, COX-2 expression was significantly lower in corresponding MMR-deficient cases (all Pü0.05). The rates of COX-2 low-expression in HNPCC adenoma, HNPCC carcinoma, and sporadic carcinoma with MSI-H were significantly higher than those in the cases with microsatellite stability (all Pü0.05).

CONCLUSIONCOX-2 is expressed at a low level in HNPCC carcinoma, different from the high COX-2 expression in sporadic carcinoma.

Adult ; Aged ; Base Pair Mismatch ; Base Sequence ; Colorectal Neoplasms, Hereditary Nonpolyposis ; genetics ; Cyclooxygenase 2 ; genetics ; DNA Primers ; DNA Repair ; Female ; Humans ; Immunohistochemistry ; Male ; Microsatellite Repeats ; genetics ; Middle Aged

OBJECTIVE: To establish a genetic diagnosis method for a novel MSH2 mutation. METHODS: A specific primer on the mutated site of MSH2 was synthesized and PCR was conducted using the specific primer and another downstream primer. PCR products were electrophoresed and then the carriers with the novel gene mutation of the carriers or non-carriers were identified. RESULTS: MSH2 in a hereditary nonpolyposis colorectal cancer family were successfully found. CONCLUSION The method is effective and simple for genetic diagnosis of the novel mutation in MSH2.
Base Sequence ; Colorectal Neoplasms, Hereditary Nonpolyposis ; genetics ; DNA Mutational Analysis ; methods ; Female ; Humans ; Male ; Molecular Sequence Data ; MutS Homolog 2 Protein ; genetics ; Pedigree ; Point Mutation ; Polymerase Chain Reaction

Pseudomyxoma peritonei (PMP) is a rare tumor that usually originates in the appendix, but a small number of cases originate in the ovary. Lynch syndrome (LS) is an autosomal dominant hereditary condition that increases the risk of cancer, particularly in the colon and endometrium. Mutations in the mismatch repair genes (MSH2, MLH1, MSH6, and PMS2) increase the risk of LS. Reported PMP cases with hereditary gene mutations of unknown significance are also rare. Here, we investigated a PMP patient and her family members, who have an MSH2 variant of unknown significance. Physicians have an important role in counseling, management, and surveillance based on genetics and pathogenicity.
Appendix ; Colon ; Colorectal Neoplasms, Hereditary Nonpolyposis ; Counseling ; DNA Mismatch Repair ; Endometrium ; Female ; Genetics ; Germ-Line Mutation ; Humans ; Ovary ; Pseudomyxoma Peritonei* ; Virulence