Hereditary Nonpolyposis Research Articles

Correlation Between Body Mass Index and Prevalence of Hereditary Nonpolyposis Colorectal Cancer in Korean Patients With Endometrial Cancer

The purpose of the study was to investigate the relationship between body mass index (BMI) and hereditary nonpolyposis colorectal cancer (HNPCC) in Korean women with endometrial cancer. Among 227 patients with endometrial cancer in the study population, 20 patients (8.8%) had HNPCC. The patients were divided into 2 groups based on the BMI: nonobese (BMI ≤25 kg/m) and obese (BMI >25 kg/m); then the nonobese group was subdivided into 2 groups: normal weight (BMI <23 kg/m) and overweight (BMI, 23-25 kg/m). The distributions of BMI categories were compared between patients with sporadic endometrial cancer and with HNPCC-related endometrial cancer. Among 207 patients with sporadic endometrial cancer, 119 (57.5%) were nonobese and 88 patients (42.5%) were obese. Of 20 patients with endometrial cancer related to HNPCC, 10 (50.0%) were nonobese and 10 (50.0%) were obese. In a subgroup analysis of only nonobese patients, 68 patients with sporadic endometrial cancer had normal weight and 51 were overweight. On the other hand, all 10 patients with HNPCC related to endometrial cancer had normal weight. There was no significant difference between the group with HNPCC-related endometrial cancer and the group with sporadic endometrial cancer according to BMI (P = 0.221). However, BMI proportions in HNPCC related to endometrial cancer were significantly different from those in sporadic endometrial cancer (P = 0.016). Among a subgroup of nonobese patients, the proportion of normal weight was significant higher in patients with HNPCC-related endometrial cancer compared to those in sporadic endometrial cancer (P = 0.006). Body mass index was not different between sporadic endometrial cancer and HNPCC-related endometrial cancer in Koreans. However, BMI proportions in the patients with HNPCC related to endometrial cancer was significantly different from those in sporadic endometrial cancer. Specifically, among nonobese patients, the proportion of normal weight was significantly high in Korean women with HNPCC.

Family History As a Positive Prognostic Factor in Gastric Cancer

Family History As a Positive Prognostic Factor in Gastric Cancer

‘PREMM 1,2,6 MODEL’ as a new gene specific prediction model for Lynch Syndrome: retrospective review of mutation positive cases

Lynch Syndrome, also called Hereditary NonPolyposis Colorectal Cancer (HNPCC), occurs as a consequence of germline mutations in the mismatch repair (MMR) system (Stoffel et al., 2009), mainly in MLH1 and MSH2 (>90% of cases), but also in MSH6 and PMS2 [1]. Kastrinos et al., (2011) developed a new web-based multivariable polytomous logistic regression model for Providing gene specific Risk Estimates (Model) (PREMM 1,2,6) that uses genotype-phenotype data from MLH1, MSH2, and MSH6 mutation carriers to generate individualized predictions for each gene based on personal and family history characteristics [1] recommends that a gene prediction of >5% should be a threshold for a referral for further genetic risk assessment. A search was performed to obtain a list of patients seen at the Prince of Wales Hereditary Cancer Clinic who were sequenced for mutations in MLH1, MSH2 or MSH6 from 1994 to 2011 with 78% occurring after 2005. A total of 40 patient pedigrees were obtained and used for the PREMM 1,2,6 model, 29 were mutation positive and 11 were tested inconclusive. 17% of probands were selected for testing based on tumour testing and the remainder were selected based on family history alone. The model included proband and first and second degree relative’s age and diagnosis of colorectal cancer and endometrial cancer. This model also used an inclusion for extra colonic Lynch-associated cancers. Each proband was also assessed by the Amsterdam II criteria and given a risk category according to the Australian Cancer Network Guidelines of average, 1, 2 or 3. A gene-specific mutation prediction cut off of 5% was instigative of a mutation for 21 probands (8/12 for MLH1, missing 33%, 11/13 for MSH2, missing 2% and 2/4 for MSH6). Based on this limited data, endometrial cancer was highly predictive for MSH6. The prevalence of extracolonic, nonendometrial HNPCC-associated cancers was higher among MSH2 carriers than MLH1 and MSH6 carriers, being weakly predictive. The specific gene estimates were not useful for when tumour analysis was unavailable, with 59% (17) mutation positive probands having a low Premm1,2,6 score, which would not have support a decision to pursue single gene testing. Amsterdam II criteria and Australian Network Guidelines have been previously found to be an ineffective strategy for triage for gene testing for Lynch Syndrome. Further study on a larger cohort is needed to determine if the PREMM 1,2,6 model is an effective triage tool for gene testing for Lynch Syndrome.

遺伝性非腺腫性大腸癌の１手術例

遺伝性非腺腫性大腸癌の１手術例

Hereditary nonpolyposis colorectal cancer (Lynch syndrome I) in a 15-year-old male

Hereditary nonpolyposis colorectal cancer (Lynch syndrome I) in a 15-year-old male

Characterization of New Founder Alu-Mediated Rearrangements in MSH2 Gene Associated with a Lynch Syndrome Phenotype

It has been reported that large genomic deletions in the MLH1 and MSH2 genes are a frequent cause of Lynch syndrome in certain populations. Here, a cohort has been screened and two new founder rearrangements have been found in the MSH2 gene. These mutations have been characterized by break point determination, haplotype analysis, and genotype-phenotype correlation. Mutations have been identified in the MLH1, MSH2, and MSH6 genes in 303 subjects from 160 suspected Lynch syndrome unrelated families. All subjects were tested using heteroduplex analysis by capillary array electrophoresis. Multiplex ligation-dependent probe amplification was used to detect rearrangements in mutation-negative index patients and confirmed by reverse transcriptase PCR. The break point of the deletions was further characterized by the array comparative genomic hybridization method. Immunohistochemical staining and microsatellite instability were studied in tumor samples. Hereditary nonpolyposis colorectal cancer-related phenotypes were evaluated. More than 16% (24 of 160) of the families had pathogenic mutations (8 MLH1, 15 MSH2, and 1 MSH6). Twelve of these families (50%) are carriers of a novel mutation. Seven of the 15 positive MSH2 families (47%) are carriers of a rearrangement. The exon 7 deletion and exon 4 to 8 deletion of MSH2 are new founder mutations. The segregation of a common haplotype, a similar phenotype, and anticipation effects were observed in these families. These findings will greatly simplify the diagnosis, counseling, and clinical care in suspected Lynch syndrome families and not just in specific geographic areas, so wide distribution may be explained by migration patterns.

Inherited Hematologic and Oncologic Syndromes

Inherited Hematologic and Oncologic Syndromes

Jejunal Adenocarcinoma as Part of Metachronous Triple Primary Cancers of the Digestive Tract in Patient with Hereditary Nonpolyposis Colorectal Cancer

Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea 󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏 Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant inherited disease characterized by onset at a relatively early age, an excess of synchronous and metachronous tumors, and a variety of extracolorectal malignancies. Small bowel carcinoma reported, is included in the tumor spectrum of HNPCC, but the frequency of occurrence of this tumor in HNPCC patients is comparatively rare. In Korea, several cases of multiple primary cancers in patients with HNPCC have been reported, however, primary jejunal adenocarcinoma in conjunction with multiple primary cancers in the digestive tract has rarely been reported. Recently, we evaluated a 61-year-old male diagnosed with metachronous triple primary cancers of the jejunum, stomach, and colon. We report this rare case of primary jejunal adenocarcinoma as a part of metachronous triple cancers along with a review of the relevant literature. (Intest Res 2011;9:158-161) 󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏

Pre- and postassessment of nurse practitioners' knowledge of hereditary colorectal cancer

This study was part of an educational program conducted to describe nurse practitioners' (NPs') knowledge and perceived comfort level regarding the identification of hereditary colorectal cancer (CRC), specifically Lynch syndrome, also referred to as hereditary nonpolyposis CRC. A 3-h workshop was developed that included a pretest to evaluate NPs' knowledge of hereditary CRC syndromes, educational program focusing on Lynch syndrome, and a posttest knowledge evaluation. Knowledge of hereditary CRC syndromes was assessed via a nine-item multiple choice self-report survey. Forty-two NPs participated in the study. Few NPs (39%) reported "comfortable" in identifying red flags "suspect" for Lynch syndrome. Percentage of NPs who responded correctly on each of the pretest items ranged from 17.0% to 57.1% (M = 26.2%; SD = 13.5%; 95% confidence intervals [CI] 14.9%, -37.5%). NPs who responded correctly to the same items after the educational program (posttest) ranged from 53.8% to 95% (M = 80.5%; SD = 15.3%; 95% CI 67.8%, -93.4%). Genetic testing is widely available for Lynch syndrome. It is important that NPs are cognizant of the syndrome and identify patients at risk for hereditary cancer syndromes so appropriate referral and management can be instituted.

Understanding Patterns of Health Communication in Families at Risk for Hereditary Nonpolyposis Colorectal Cancer: Examining the Effect of Conclusive Versus Indeterminate Genetic Test Results

In families meeting criteria for hereditary nonpolyposis colorectal cancer (HNPCC), genetic testing may or may not identify a mutation. Communication about genetic testing and risk in families with identified HNPCC mutations is associated with individual and relational factors. Similar communication patterns would be expected in families with similar clinical and pathological characteristics, but without an identified HNPCC mutation; however, previous studies have not included such families. Social network analysis was used to compare communication networks and associated individual and relational factors in families with and without identified HNPCC mutations. Respondents from families without identified mutations communicated about genetic counseling and testing and risk for HNPCC with a significantly smaller proportion of network members, compared to respondents from mutation-positive families. Members of families without identified mutations were also more likely to share thoughts about risk for HNPCC with network members whose advice they take, compared to members of families with known mutations. These findings extend our knowledge of communication in families at risk of HNPCC to include the many families in which a causative mutation has not yet been identified. Differences in the breadth of communication about genetics and risk for HNPCC, and the possibility that members of families without identified mutations may seek advice from those with whom they communicate about risk, provide new avenues for future research. Understanding existing communication patterns could help improve education and counseling processes, and facilitate the development of interventions designed to assist in family discussions of risk.

Lynch Syndrome

Almost 100 years ago Lynch syndrome was discovered by Dr Aldred Warthin. Initially, the syndrome was named Hereditary Nonpolyposis Colorectal Cancer as colorectal cancer seemed most prevalent. Over time uterine cancer and several other malignancies were recognized as part of the spectrum. This autosomal-dominant inherited cancer syndrome is characterized by a defect in mismatch repair genes and puts patients at a significantly increased risk for colorectal and uterine cancer. Recognition and diagnosis of Lynch syndrome is extremely important so that appropriate screening programs and/or risk-reducing surgery can be initiated to prevent development or promote early detection of cancers.

Distinct mutations in MLH1 and MSH2 genes in Hereditary Non-polyposis Colorectal Cancer (HNPCC) families from China

Hereditary non-polyposis Colorectal Cancer (HNPCC) is an autosomal dominant inheritance syndrome. HNPCC is the most common hereditary variant of colorectal cancer (CRC), which accounts for 2-5% CRCs, mainly due to hMLH1 and hMSH2 mutations that impair DNA repair functions. Our study aimed to identify the patterns of hMSH2 and hMLH1 mutations in Chinese HNPCC patients. Ninety-eight unrelated families from China meeting Amsterdam or Bethesda criteria were included in our study. Germline mutations in MLH1 and MSH2 genes, located in the exons and the splice-site junctions, were screened in the 98 probands by direct sequencing. Eleven mutations were found in ten patients (11%), with six in MLH1 (54.5%) and five in MSH2 (45.5%) genes. One patient had mutations in both MLH1 and MSH2 genes. Three novel mutations in MLH1 gene (c.157_160delGAGG, c.2157dupT and c.-64G>T) were found for the first time, and one suspected hotspot in MSH2 (c.1168C>T) was revealed.

Retrospective review of endometrial cancer (EC) specimens in individuals younger than age 50 for microsatellite instability (MSI) testing and DNA mismatch repair enzyme (MMR) expression.

e15565 Background: In women with Hereditary Non-Polyposis Colon Cancer (HNPCC), the incidence of EC is at least equal to that of colorectal cancer. Data from studies performed at referral centers s...

Epidemiology of Inherited Colon Cancer

Inherited colorectal cancer (CRC) represents 15-30% of all CRC cases. Hereditary nonpolyposis colorectal cancer and familial adenomatous polyposis are the 2 main syndromes that comprise this category, and both have a well-defined genetic defect. The introduction of immunohistochemistry and genetic testing has resulted in earlier and more sensitive diagnosis of these hereditary syndromes. The incidence of hereditary nonpolyposis colorectal cancer is estimated at 2-5% of all CRC cases and is due to a mutation of the DNA mismatch repair genes. Familial adenomatous polyposis comprises 1% of all CRC cases and is caused by a mutation in the APC tumor suppressor gene. Familial X CRC syndrome contains the remainder of the inherited CRC cases (10-25% of all CRC cases) and encompasses patients who clinically fit the Amsterdam criteria, but do not have an identifiable genetic abnormality. The implementation of rigorous screening guidelines for the primary disease and associated extracolonic tumors in these patients has resulted in significantly improved outcomes. However, the associated extracolonic tumors continue to represent the main cause of morbidity and mortality and demonstrate the ongoing need for further elucidation of the genetic interactions responsible for these syndromes.

Screening and Prevention of Extracolonic Cancers in Patients with Hereditary Nonpolyposis Colon Cancer

Hereditary nonpolyposis colon cancer is the most common cause of hereditary colon cancer and results from defects in mismatch repair genes that create the phenomenon of microsatellite instability. Apart from the high risk of colon cancer, these patients are at increased risk of multiple malignancies, including endometrial cancer, ovarian cancer, small bowel tumors, gastric cancer, pancreatic cancer, and multiple other extraintestinal tumors. Routine colonoscopy for patients with hereditary nonpolyposis colon cancer has become standard and is widely accepted, but screening regimens for other organs remain matters of debate. Inadequacies detected in attempted surveillance methods have led some authors to call for prophylactic surgery as an alternative strategy in cancer prevention.

Indication and Extent of Surgery in Hereditary Nonpolyposis Colorectal Cancer

The extent of surgical resection for patients with Lynch syndrome (ie, hereditary nonpolyposis colorectal cancer) remains controversial. More extensive than standard segmental resections reduce the risk of metachronous cancers and simplify surveillance, but a survival benefit has not been documented. The fact that even in hereditary nonpolyposis colorectal cancer these colorectal cancers follow an adenoma to carcinoma sequence, albeit accelerated, have brought to question the need for prophylactic risk-reducing surgery of normal bowel segments in addition to the cancer-bearing segment. It has been advocated that adequate endoscopic surveillance may curtail the development of malignancy by treating adenomas as they develop. The high risk of gynecologic malignancy in women adds an additional level of complexity to the surgical decision making and the need and timing of surgery in this subset of patients is in debate. This article reviews the literature to date regarding the extent of surgical resection, and addresses the approach to prophylactic measures to both colonic and gynecologic aspects of malignancy in hereditary nonpolyposis colorectal cancer.

Genetic testing of the mismatch repair genes in our clinical practice – Case report of two HNPCC families

Introduction: Occurrence of colorectal cancer is sporadic in significant number of cases, but we have to concentrate the familial and the autosomal dominant conditions, too. Hereditary Nonpolyposis Colorectal Cancer syndrome (HNPCC or Lynch-syndrome) is characterized by early onset CRC and endometrial cancer, although the incidence of other malignant tumours, e.g. cancers of the stomach, urothelium, small bowel and ovarium, is also increased in HNPCC patients. HNPCC is autosomal dominantly inherited and is associated with germline mutations in at least six mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS1 and PMS2, EPCAM). The identification of carriers is usually based on screening individuals from families fulfilling international criteria for the syndrome, namely Amsterdam criteria or less stringent criteria referred to as the Bethesda guidelines.

Abstract 3802: EWSR1: Identification and functional characterization of a novel target gene locus in Lynch syndrome

Abstract Background: Lynch syndrome (also Hereditary Non-Polyposis Colon Cancer, HNPCC) represents the most common, autosomal dominantly inherited cancer predisposition worldwide and accounts for 3-5% of the total colorectal cancer (CRC) burden. It is caused by germline mutations in DNA mismatch repair (MMR) genes (mainly MLH1 and MSH2). MMR deficiency results in microsatellite instability (MSI), i.e. genome-wide accumulation of somatic alterations at repetitive DNA sequence motifs, mostly non-coding microsatellite markers. MSI, used as a diagnostic tool to identify HNPCC-related CRCs, can also affect repeat tracts within or immediately adjacent to the coding sequence of so-called target genes (like TGFbRII, BAX, etc) which are thought to fuel carcinogenesis in HNPCC. In search for novel target gene loci we identified a large poly-T tract, (T)16, in the 3’ untranslated region (3’UTR) of the Ewing sarcoma breakpoint region 1 (EWSR1) gene. Aims: To determine i) type and frequency of instability at the EWSR1 (T)16 in 78 HNPCC and 85 sporadic colorectal cancers and ii) its possible effect on EWS expression Materials and methods: We determined the length of the EWSR1 3’UTR tract motif, (T)16, by PCR amplification and fragment analysis of 78 CRCs from HNPCC patients with identified germline mutation (MLH1: n=50; MSH2: n=28), 85 sporadic microsatellite-stable CRCs as well as 5 CRC cell lines (2 MMR proficient, 3 MMR deficient). EWS protein expression was assessed by immunohistochemistry (IHC) on a tissue microarray and immunoreactivity scored semi-quantitatively. Statistical comparisons were performed using Chi-square or Student's t test where appropriated (two-tailed p values, considering p&amp;lt;0.05 to be statistically significant). Results: Novel alleles at the EWSR1 3’UTR (T)16 tract were observed in all (n=78) HNPCC but none (0/85) of the sporadic CRCs. The type (insertion/deletion) and frequency of somatic alterations were: ins1-2 (2.5%), del1-3 (22.6%), del4 (34.4%), del5 (28.54%) and del&amp;gt;6 (11.92%). Similar observations were made for the MMR-deficient cell lines (HCT116/MLH1: del3/del4; LoVo/MSH2: del4) whereas the MMR-proficient ones were stable. RNA secondary structure prediction suggested gross structural alterations for deletions &amp;gt;4 Ts. IHC showed significant downregulation of EWS expression in sporadic CRCs (p&amp;lt;0.005), but no difference in HNPCC CRCs (p=0.7). Since the (T)16 tract may represent a binding site for AU-rich element binding proteins it could have an effect on EWSR1 mRNA stability/translation (currently being tested). Conclusion: The (T)16 tract in the 3’UTR of the EWSR1 gene represents a novel target gene locus in Lynch syndrome allowing for highly sensitive and specific identification of MMR-deficient CRCs. Moreover, IHC analysis suggests a regulatory role of this locus on EWS protein expression in HNPCC colorectal cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3802. doi:10.1158/1538-7445.AM2011-3802

The Genetic Etiology of Familial and Nonfamilial Colorectal Cancer

Colorectal cancer (CRC) is the third most frequently diagnosed cancer in the US and the second leading cause of cancer death. CRCs arise from a multistep carcinogenic process, beginning with early changes from normal to hyperproliferative epithelium, then to the development of adenomas, which in turn are believed to be precursors of carcinomas. These histological changes are associated with the accumulation of genetic and epigenetic changes involving the activation of oncogenes and the inactivation of tumor suppressor genes. Approximately two thirds of new cases of CRC appear to be sporadic (i.e., occur without a family history of the disease), and the necessary genetic changes seem to arise de novo, fueled by etiologic agents that can include age, environmental exposures, and lifestyle factors. Nearly one third of cases, however, tend to cluster in families, so that first-degree relatives of patients with newly diagnosed adenomas or invasive CRCs are at increased risk. While many of these familial clusters may be linked to shared behaviors or environmental exposures among family members, some are associated with germline mutations in specific genes. Although specific genetic mutations have been identified for a wide variety of syndromes that may involve CRC, screening is normally directed at the most common of these: hereditary nonpolyposis CRC (HNPCC), also known as Lynch syndrome, and familial adenomatous polyposis (FAP). Lynch syndrome is the most common hereditary cancer syndrome predisposing to CRC, accounting for approximately 3% of all cases. It is associated with mutations in four DNA-mismatch repair (MMR) genes: MSH2, MLH1, MSH6, and PMS2. Individuals with a germline mutation in any of these genes have a significant lifetime risk of developing CRC (70% for men, 40% for women), as well as a heightened risk for the development of cancers at other sites, including the endometrium, ovary, stomach, small bowel, urinary tract, and pancreas. FAP, about one tenth as common as Lynch syndrome, is associated with mutations in the APC gene, which is classified as a tumor suppressor gene. Individuals with FAP may have hundreds of adenomas, making this syndrome relatively straightforward to detect. Because so many adenomas develop at an early age, classic FAP carries a lifetime risk of nearly 100% for the development of CRC. Additional hereditary CRC syndromes that are not routinely tested for include Peutz-Jeghers syndrome, familial juvenile polyposis, Cowden's disease, Bannayan-Ruvalcaba-Riley syndrome, and Li-Fraumeni syndrome. For both sporadic and familial CRC, a key early change is the development of genetic and epigenetic instability, which increases the rate at which further changes can be accumulated. At least three patterns of instability can contribute to the development of CRC; typically, one type will predominate in a specific cancer. One common pattern, prominent in at least 50% of CRCs, is chromosome instability (CIN), which can result in genetic deletions, duplications, and rearrangements. CRCs with CIN are characterized by aneuploid tumor cells. A second pattern is microsatellite instability (MSI), which occurs in about 15% of CRCs (Figure ​(Figure11). Microsatellites are simple repeat sequences 1 to 6 base pairs in length that occur thousands of times across the genome. MSI occurs through the inactivation of the DNA mismatch repair (MMR) system, resulting in sequences that accumulate errors and become abnormally long or short. In some instances, this creates a frameshift mutation in a gene, such as a tumor suppressor gene. Unlike CIN, most CRCs with MSI are diploid or near diploid. More than 90% of the CRCs attributable to Lynch syndrome are associated with MSI. Figure 1 Two molecular pathways to the development of colorectal cancer with microsatellite instability. From Boland CR, Goel A. Microsatellite instability in colorectal cancer. Gastroenterology 2010;138(6):2073–2087.e3. Reprinted with permission from ... The third pattern seen in CRC is an epigenetic change that involves the methylation of promoters of human genes. This can lead to the silencing of certain tumor suppressor genes in CRC. About half of the promoters of human genes are embedded in CpG islands, so this phenotype in tumor DNA is called the CpG island methylator phenotype (CIMP). Overlap between MSI and CIMP occurs in about 12% of CRCs when the promoter of the MMR gene MLH1 is methylated (and inactivated), leading to MSI.

G-C heterozygosis in mutS homolog2 as a risk factor to hereditary nonpolyposis colon cancer in the absence of a family medical history

To detect the presence of point mutations in a small section of the mutS homolog2 (MSH2) gene in both healthy and affected persons treated at the General Hospital of the State of Sonora, a 353 base pair section of the MSH2 gene was amplified and sequenced from six persons affected by hereditary nonpolyposis colorectal cancer and from 19 healthy persons. The affected persons did not show the mutations reported in the scientific literature; however, six healthy persons were heterozygote and mutant-allele carriers. The heterozygote condition implies that carriers are candidates for the development of colorectal cancer. However, it is important to know the family medical history when investigating hereditary mutations.