Hereditary Nonpolyposis Colorectal Cancer Families Research Articles

BAT25, ACVR2, and TGFBR2 Mononucleotide STR Markers: A Triplex Panel for Microsatellite Instability Testing in Colorectal Tumors.

Microsatellite instability (MSI) in colorectal cancer (CRC) patients is considered as a diagnostic and prognostic marker. MSI is a consequence of mismatch repair deficiency which is evaluated using the different microsatellite markers on the whole genome. In this pilot study, the diagnostic value of a novel triplex panel including three mononucleotide markers has been evaluated in comparison to the standard Promega kit for MSI testing in CRC patients with Amsterdam II criteria. DNA extracted from tumors and normal Formalin-Fixed Paraffin-Embedded (FFPE) tissues of index cases from 37 HNPCC (Hereditary non-polyposis colorectal cancer) families were evaluated for MSI state. Primer design for three markers, including BAT25, ACVR2, and TGFBR2, was performed using 19 nucleotides of the M-13 phage. The instability of each marker was assessed through fragment analysis in comparison with Promega kit markers for all patients. The sensitivity and specificity of each marker have been calculated. The comparative evaluation of MSI in both tumors and normal adjacent FFPE tissues demonstrated a separate sensitivity as 100%, 83.3%, and 76.9% for BAT25, ACVR2, and TGFBR2, respectively, and 100% sensitivity in the form of a triplex. Moreover, the specificity for each of these three markers in MSI testing was estimated as 100%, separately and in the form of the triplex in comparison with the Promega pentaplex standard Kit. A high sensitivity and specificity for the novel triplex panel in MSI-testing were estimated among Iranian patients. More studies are recommended to confirm this panel as a diagnostic kit for MSI testing.

Frequent Novel Variations Within MSH2 and MLH1 Genes in a Subset of Iranian Families With Hereditary Non-Polyposis Colorectal Cancer Shadi

Abstract- Hereditary non-polyposis colorectal cancer (HNPCC) is the most frequent autosomal dominant predisposition for development of colorectal cancer (CRC) caused by germline defects in mismatch repair (MMR) genes. Current study was aimed to find genetic variations in MSH2 and MLH1 genes and their correlation with the serum levels of Carcinoembryonic Antigen (CEA) in seven Iranian HNPCC families. Seven unrelated Iranian families including 11 HNPCC patients and 7 affected family members were selected. They were initially screened for mutations in exons 7 of MSH2 and exon 15 of MLH1 gene through polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP). Positive PCR results were further analyzed through exon sequencing. Serum CEA level was determined using the ELISA test. PCRSSCP was positive in 8 out of 18 patients (44%) for exons 7 of MSH2 gene, whereas two samples (11%) demonstrated to bear a mutation in exon 15 of the MLH1 gene. Sequencing analysis of both amplified exons in positive and negative samples have confirmed no mutation in negative samples while revealed 5 and 7 novel mutations in exons 7 and 15, respectively. The mean serum concentration of CEA had a significant difference between HNPCC patients and their healthy family members. Our results demonstrated that the PCR-SSCP method has high specificity and sensitivity in the first step of mutation screening of HNPCC families. High frequency of novel alterations found in the current assay may revise the mutation screening of MSH2 and MLH1 genes and abet further assessment of their frequency among individual HNPCC patients.

Genetic epidemiology of colorectal cancer and associated cancers.

We review here data on familial risk in colorectal cancer (CRC) generated from the Swedish Family-Cancer Database, the largest resource of its kind in the world. Although the concordant familial risk for CRC (i.e. CRC risk in families of CRC patients) has been reasonably well established, the studies on discordant familial risks (i.e. CRC risk in families with any other cancers) are rare. Because different cancers could be caused by shared genetic susceptibility or shared environment, data of associations of discordant cancers may provide useful information for identifying common risk factors. In analyses between any of 33 discordant cancers relative risks (RRs) for discordant cancers were estimated in families with increasing numbers of probands with CRC; in the reverse analyses, RRs for CRC were estimated in families with increasing numbers of probands with discordant cancers. In separate analyses, hereditary non-polyposis colorectal cancer (HNPCC) families were excluded from the study, based on HNPCC related double primary cancers, to assess the residual familial RRs. We further reviewed familial risks of colon and rectal cancers separately in search for distinct discordant associations. The reviewed data suggested that colon cancer was associated with a higher familial risk for CRC compared to rectal cancer. The previous data had reported associations of CRC with melanoma, thyroid and eye cancers. Nervous system cancer was only associated with colon cancer, and lung cancer only associated with rectal cancer. The reviewed data on discordant association may provide guidance to gene identification and may help genetic counseling.

Familial Associations of Colon and Rectal Cancers With Other Cancers.

Many studies have indicated that colon and rectal cancers differ in etiology and histology. The aim of this study was to investigate whether the associations of colon and rectal cancers with any other (discordant) cancer were site specific. A novel approach was implemented in which cancer risks were analyzed in families with increasing numbers of family members diagnosed with defined cancers. The novel assumption was that, for a true familial association, the risk should increase by the number of affected family members. In separate analyses, familial risks were calculated after the exclusion of putative families with hereditary nonpolyposis colorectal cancer. The study was conducted using the Swedish Family-Cancer Database. The outcome measure was relative risk. Relative risks of colorectal cancer and colon cancer were higher when family members were diagnosed with colon cancer than when family members were diagnosed with rectal cancer (incidence rate ratio for colorectal: 1.82 (95% CI, 1.74-1.90) vs 1.61 (95% CI, 1.51-1.71); incidence rate ratio for colon: 1.92 (95% CI, 1.83-2.02) vs 1.56 (95% CI, 1.45-1.69)). Relative risks for 10 discordant cancers were increased in colon or rectal cancer families, whereas none of the relative risks differed significantly between colon and rectal cancers. After deleting hereditary nonpolyposis colorectal cancer families, the relative risks of endometrial and ovarian cancers were no longer significant. Genetic data are unavailable in the database. Our results suggested that familial risks for colon cancer were higher than risks for rectal cancer in families of patients with colorectal cancer and colon cancer. The relationships of lung cancer and nervous system cancer with colorectal cancer were site specific. The associations of colon and rectal cancers with lung cancer, myeloma, and cancer of unknown primary appeared not to point out known syndromes and may suggest involvement of a novel predisposition. See Video Abstract at http://links.lww.com/DCR/A791.

MLH1 and MSH2 Gene Mutations and Polymorphisms in Six Malay Families with Hereditary Nonpolyposis Colorectal Cancer

Background: Hereditary nonpolyposis colorectal cancer (HNPCC) also known as Lynch syndrome is commonly caused by genetic alterations in any of the four mismatch repair (MMR) genes; MLH1, MSH2, MSH6 and PMS2. This is the first study aimed to investigate genetic variants in Malay HNPCC families. Methods: Six Malay HNPCC families who fulfilled any of the Bethesda criteria were recruited into this study. A total of 3 ml of blood was withdrawn from each patient in the families. The samples were further analyzed using polymerase chain reaction and direct sequencing of the selected exons of MLH1 and MSH2 genes. Results: Two missense mutations and four single nucleotide polymorphisms (SNPs) were identified in six patients. These variants in the MLH1 and MSH2 genes were identified in four families who met the revised Bethesda guidelines. In two families, no mutation and polymorphism was identified in both the exon and intron of the respective genes. Of the mutations and polymorphisms identified, five have never been reported in Malay HNPCC families before. A missense mutation was detected in exon 5 of the MLH1 gene, c.394G>C (p.Asp132His) and four mutations and polymorphisms were detected in the MSH2 gene; heterozygous c.211+98T>C and c.211+9C>G and homozygous c.211+98T>C and c.211+9C>G, c.367-86A>C and c.382C>G. Conclusion: The results represented a new spectrum of mutations and polymorphisms in the Malay HNPCC families. However, a larger study involving additional families and analysis is required to determine the impact and nature of the identified mutations and polymorphisms.

Familial Associations of Colorectal Cancer with Other Cancers

Colorectal cancer (CRC) has a strong familial component which extends to discordant cancers (ie non-CRC tumors). This is best seen in cancer syndromes such as hereditary non-polyposis colorectal cancer (HNPCC) which predisposes to several tumor types. Population-based family studies have also found discordant associations for CRC but they have included cancers which manifest in HNPCC, and there is no convincing evidence of discordant associations beyond the known syndromes. We address familial associations of non-CRC tumors with CRC using the resources of the Swedish Family-Cancer Database and applying a powerful approach of assessing familial relative risks in families of increasing numbers of patients with discordant cancers. Among 1.8 million cancer patients and over 200,000 CRC cases consistent familial associations of CRC was observed for several HNPCC related cancers. However, for small intestinal, pancreatic and nervous system cancers RRs remained essentially unchanged when potential HNPCC families were excluded, suggesting involvement of genes not related to HNPCC. Two independent associations of CRC were found for melanoma, thyroid and eye cancers and these appeared not to be related to known syndromes. A number of other cancers associated with CRC in single analyses and independent studies are required to assess the relevance of such findings.

Hereditary non-polyposis colorectal cancer/Lynch syndrome in three dimensions.

Hereditary non-polyposis colorectal cancer (HNPCC) is defined by family history, and Lynch syndrome (LS) is defined genetically. However, universal tumour testing is now increasingly used to screen for patients with defective mismatch repair. This mixing of the results of family history, tumour testing and germline testing produces multiple permutations and combinations that can foster confusion. We wanted to clarify hereditary colorectal cancer using the three dimensions of classification: family history, tumour testing and germline testing. Family history (Amsterdam I or II criteria versus not Amsterdam criteria) was used to define patients and families with HNPCC. Tumour testing and germline testing were then performed to sub-classify patients and families. The permutations of these classifications are applied to our registry. There were 234 HNPCC families: 129 had LS of which 55 were three-dimensional Lynch (family history, tumour testing and germline testing), 66 were two-dimensional Lynch and eight were one-dimensional Lynch. A total of 10 families had tumour Lynch (tumours with microsatellite instability or loss of expression of a mismatch repair protein but an Amsterdam-negative family and negative germline testing), five were Lynch like (Amsterdam-positive family, tumours with microsatellite instability or loss of expression of a mismatch repair protein on immunohistochemistry but negative germline testing), 26 were familial colorectal cancer type X and 95 were HNPCC. Hereditary colorectal cancer can be confusing. Sorting families in three dimensions can clarify the confusion and may direct further testing and, ultimately, surveillance.

Epidemioclinical Feature of Early-Onset Colorectal Cancer at-Risk for Lynch Syndrome in Central Iran

Colorectal cancer (CRC) is becoming one of the most complicated challenges of human health, particularly in developing countries like Iran. In this paper, we try to characterize CRC cases diagnosed < age 50 at-risk for Lynch syndrome within central Iran. We designed a descriptive retrospective study to screen all registered CRC patients within 2000-2013 in Poursina Hakim Research Center (PHRC), a referral gastroenterology clinic in central Iran, based on being early-onset (age at diagnosis ≤50 years) and Amsterdam II criteria. We calculated frequencies and percentages by SPSS 19 software to describe clinical and family history characteristics of patients with early-onset CRC. Overall 1,659 CRC patients were included in our study of which 413 (24.9%) were ≤50 years at diagnosis. Of 219/413 successful calls 67 persons (30.6%) were reported deceased. Family history was positive for 72/219 probands (32.9%) and 53 families (24.2%) were identified as familial colorectal cancer (FCC), with a history of at-least three affected members with any type of cancer in the family, of which 85% fulfilled the Amsterdam II Criteria as hereditary non-polyposis colorectal cancer (HNPCC) families (45/219 or 20.5%). Finally, 14 families were excluded due to proband tumor tissues being unavailable or unwillingness for incorporation. The most common HNPCC-associated extracolonic- cancer among both males and females of the families was stomach, at respectively 31.8 and 32.7 percent. The most common tumor locations among the 31 probands were rectum (32.3%), sigmoid (29.0%), and ascending colon (12.9%). Given the high prevalence of FCC (~1/4 of early-onset Iranian CRC patients), it is necessary to establish a comprehensive cancer genetic counseling and systematic screening program for early detection and to improve cancer prognosis among high risk families.

POLYMORPHISM OF DNA MISMATCH REPAIR GENES IN ENDOMETRIAL CANCER

Endometrial cancer (EC) is the second most common malignancy associated with hereditary non-polyposis colorectal cancer (HNPCC) family. The development of HNPCC is associated with defects in DNA mismatch repair (MMR) pathway resulting in microsatellite instability (MSI). MSI is present in a greater number of EC than can be accounted for by inherited MMR mutations, therefore alternative mechanisms may underline defective MMR in EC, including polymorphic variation. We checked the association between EC occurrence and two polymorphisms of MMR genes: a 1032G>A (rs4987188) transition in the hMSH2 gene resulting in a Gly22Asp substitution and a -93G>A (rs1800734) transition in the promoter of the hMLH1 gene. These polymorphisms were genotyped in DNA from peripheral blood lymphocytes of 100 EC patients and 100 age-matched women by restriction fragment length polymorphism PCR. A positive association (OR 4.18; 95% CI 2.23-7.84) was found for the G/A genotype of the -93G>A polymorphism of the hMLH1 gene and EC occurrence. On the ot-her hand, the A allele of this polymorphism was associated with decreased EC occurrence. The Gly/Gly genotype slightly increased the effect of the -93G>A-G/A genotype (OR 4.52; CI 2.41-8.49). Our results suggest that the -93G>A polymorphism of the hMLH1 gene singly and in combination with the Gly322Asp polymorphism of the hMSH2 gene may increase the risk of EC.

Clinicopathological and genetic features of Chinese hereditary nonpolyposis colorectal cancer (HNPCC)

The aim of this study was to investigate the clinical value of different criteria and to understand the relationship between genotype and phenotype in Chinese hereditary nonpolyposis colorectal cancer (HNPCC). A total of 116 unrelated probands of suspected HNPCC families from the Fudan Colorectal Registry were studied. A total of 32, 28, and 56 families fulfilled the Amsterdam criteria, the Fudan criteria and the revised Bethesda guideline, respectively. Direct DNA sequencing of all exons of hMSH2 and hMLH1 genes were performed on all 116 samples. Mutations and clinicopathological features were compared between the groups. Thirty-two pathological germline mutations were identified. Out of 32 mutations, 16 were located at hMLH1 and 16 at hMSH2. The sensitivity of Amsterdam criteria was 50 %, specificity was 81 %, and Youden’s index was 31 %. The sensitivity of Fudan criteria was 75 %, specificity was 58 %, and Youden’s index was 33 %. Among all the 32 families with mutations, families with hMSH2 mutation had a higher ratio of synchronous and metachronous colon cancers than families with hMLH1 mutation (33 vs. 6 %, P = 0.04). Patients with hMSH2 mutation more frequently harbour synchronous and metachronous colon cancers. Fudan criteria had a little higher sensitivity and accuracy than Amsterdam criteria for identification of Chinese HNPCC.

The results of gynecologic surveillance in families with hereditary nonpolyposis colorectal cancer

ObjectiveWe aimed to estimate the incidence rate of endometrial cancer (EC) and to evaluate the results of EC-surveillance in hereditary nonpolyposis colorectal cancer (HNPCC) families. MethodsAll at-risk women recommended for EC-surveillance by the HNPCC-register—2959 women (19,334women years)—were included. Data on EC-surveillance were available for 871 women (6894women years), who had performed 1945 surveillance visits. The average surveillance period was 7.9 (range 0.1−21.7) years and 46% of the women had had less than 3years between their visits. ResultsDuring 19,334women years, 60 women with gynecological malignancies or premalignancies were diagnosed. Thirty-nine women had EC. Of these, 31 were from families with identified MMR gene mutations with the median age at diagnosis of 54 (39–83) years (Incidence Rate, IR=0.63 per 100women years) and four women from each Amsterdam (AMS)-positive and AMS-like families (median age 64 (55–73) years, IR=0.06 and 0.05 per 100women years, respectively, p<.0001).Among the 871 surveilled women, 13 EC were found: 7/13 cases were diagnosed by surveillance examination—two as prevalent cancers, diagnosed at the first visit—and 6/13 based on symptoms. In addition, five complex atypical hyperplasias and four ovarian cancers (OCs) were diagnosed. All these women were MMR mutation carriers. ConclusionBased on 19,334women years of EC-surveillance, our analysis provides a thorough estimation of the EC risk in women with an MMR mutation, or suspected of having Lynch syndrome. We conclude that EC surveillance should only be targeted at MMR-mutation carriers.

Germline mutation analysis, microsatellite instability and clinical pathology in Hazakh in China hereditary nonpolyposis colorectal cancer pedigree

Objective To study the significance of mismatch repair (MMR) gene and microsatellite instability (MSI) in Hazakh in China hereditary nonpolyposis colorectal cancer (HNPCC) pedigree.Methods The tumor tissues and normal intestine mucosa of the 105 members of this family were immunohistochemically examined for hMLH1 and hMSH2.The mutation of BAT25,BAT26,D2S123,D5S346 and D17S250 were analyzed with polymerase chain reaction-single-stmded conformation polymorphism (PCR-SSCP) in tissue paraffin imbedding in all cases of the family.Results MSI-positive rate of 17tumor in HNPCC families group was 100 ％,in which there are 16 patients (94.1％) with high frequency microsatellite instability (MSI-H),1 patients with low frequency microsatellite instability (MSI-L)(5.9％).The negative expression of hMLH1 or hMSH2 rate of 17 tumor in HNPCC families group was 100％.There are 44 patients (50.0％) in the other 88 members of the HNPCC family with MSI-H.There are 40 patients with hMLH1 or hMSH2 MMR protein expression absence in the 44 patients with MSI-H.Conclusion HNPCC patients with MSI-H and hMLH1 or hMSH2 MMR protein expression absence have a better consistency with earlier age of onset,right colon cancer incidence and the occurrence of poorly differentiated carcinoma. Key words: Hereditary nonpolyposis colorectal cancer; Microsatellite instability; Mismatch repair gene; Hazakh

Germline mutation and protein expression analysis of mismatch repair genes MSH6 and PMS2 in Malaysian Lynch syndrome patients

Dear Editor: Hereditary non-polyposis colorectal cancer (HNPCC) or Lynch syndrome is the most common hereditary form of colorectal cancer (CRC). The diagnosis of HNPCC or Lynch syndrome represents a major challenge because of its genotype and phenotype heterogeneity. Although Amsterdam criteria and Bethesda criteria might be useful for the diagnosis assessment of HNPCC family, there will be clinical situations involving families that may be wholly uninformative for the application of these criteria. The genetic basis of Lynch syndrome has been associated with potentially pathogenic mutations in a group of DNA MMR genes (MLH1 , MSH2 , MSH6 , PMS1 , and PMS2). Germline mutation analysis of DNA MMR genes is the most crucial process for the confirmation of the clinical diagnosis of Lynch syndrome cases. The mutation spectrum of DNA MMR genes appear to be diverse in both distribution and nature of mutations. Although mutation data is available from different parts of the world in varying frequencies, reports on Malaysian patients are scarce. This study was undertaken to unravel the spectrum of germline mutation in DNA MMR genes in Malaysian Lynch syndrome patients. Due to the minor role of germline MSH6 and PMS2 mutations, we adapted the Lynch syndrome detection strategy for the Malaysian population of CRC patients, whereby germline mutations were first sought for MLH1 and MSH2 genes, to be followed byMSH6 and PMS2 genes. The choice about which gene should be tested first was guided by immunohistochemical (IHC) analysis of protein expression of MMR genes. Earlier, we did germlinemutation analysis ofMLH1 and MSH2 genes in 50 Lynch syndrome patients, out of which the data for 34 Lynch syndrome patients has already been reported [1]. In addition to and continuation of the previous report, this report specifically focus on the protein expression profile and germline mutations of MSH6 and PMS2 genes in 50 Malaysian Lynch syndrome suspected patients.

Abstract 4229: Study on the germline mutation and protein expression of hMLH1 and hMSH2 gene in Chinese HNPCC probands.

Abstract BACKGROUND&amp;AIMS: Compare with sporadic colorectal cancer (SCRC), Hereditary nonpolyposis colorectal cancer (HNPCC) shows its own characteristcs associated with the molecular mechanism,clinical features,the methods for treatment and management of HNPCC kindreds. The molecular genetics basis of HNPCC was the mutation of mismatch repair (MMR) gene. Some HNPCC families which can found the mutation of MMR gene didn't fulfil any clinical criteria while more than fifty percent suspected HNPCC patients can't found mutation of MMR gene. Therefore, the tumorigenesis of HNPCC must be associated with other disease genes which have not been credited. The expression of hMLH1 and hMSH2 protein in 50 HNPCC probands fulfilling defferent clinical criteria and the germline mutation of hMLH1 and hMSH2 gene in 26 probands were analysed. Methods: The peripheral blood was collected from the probands of 26 HNPCC families fulfilling different clinical criterial, of which 7 families fulfilled AC, 19 kindreds fit BG. Genomic DNA was extracted following the manafacturer's protocol and used as the template to amplify 35 exons of the 2 genes by PCR. PCR products were purified and used as the template for direct DNA sequencing. The results of sequencing were analysed by different bioanalysis software. To further investigate the pathological effects of detected missense mutations, we analyse the same exon of hPMS2 gene using PCR-based sequencing in 130 healthy persons without family history. IHC envision two step method was performed.Results: 8 germline mutation of hMLH1 and hMSH2 was found in 26 HNPCC probands families. 4 fulfilled AC and 4 fulfilled BG..17 probands was found to be hMLH1 and hMSH2 protein deficient. Conclusion: The rate of germline mutation and protein expression was 30.8% and 34%. AC are the most sensitve clinical creteria to predict mutations. Immunohistochemical staining are reliable screening method with high predictive value for the detection of mutation. Some suspected HNPCC patients can't found mutation of MMR gene. Citation Format: Xia Sheng. Study on the germline mutation and protein expression of hMLH1 and hMSH2 gene in Chinese HNPCC probands. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4229. doi:10.1158/1538-7445.AM2013-4229

MSH6 Mutations are Frequent in Hereditary Nonpolyposis Colorectal Cancer Families With Normal pMSH6 Expression as Detected by Immunohistochemistry

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant condition accounting for 2% to 4% of all colorectal cancer cases worldwide. Families with germ line mutations in 1 of 6 mismatch repair genes are known as Lynch syndrome families. The largest number of mutations has been detected in the mismatch repair genes MLH1 and MSH2, but several mutations in MSH6 have also been demonstrated. : Whether HNPCC families are screened for mutations in mismatch repair genes often relies on their immunohistochemical profile. The aim of the present study was to evaluate this approach in Lynch families carrying mutations in MSH6. Results of the screening of the MSH6 gene in HNPCC families were compared with those obtained on immunohistochemical protein analysis. In 56 (7%) of 815 families, at least 1 MSH6 mutation, 23 definitively pathogenic mutations and 38 missense mutations or unclassified variants, and several polymorphisms in the MSH6 gene were detected. In families carrying a pathogenic MSH6 mutation, 69.6% of 23 colon adenocarcinomas showed absence of pMSH6 in tumor tissue by immunohistochemical analysis. In 34.5%, all proteins could be detected, whereas in 34.5% pMSH6 was present and pMLH1/pPMS2 was absent. If genetic screening of HNPCC families depended on immunohistochemical results, a substantial number of families harboring a pathogenic mutation in MSH6 and the vast majority of families harboring an MSH6 unclassified variant would not be detected.

Mo1446 Is Noncathartic Computed Tomographic Colonography With Fecal Tagging Useful for the Surveillance of Hereditary Non-Polyposis Colorectal Cancer Family Members? Preliminary Data of a Single Center Study

Mo1446 Is Noncathartic Computed Tomographic Colonography With Fecal Tagging Useful for the Surveillance of Hereditary Non-Polyposis Colorectal Cancer Family Members? Preliminary Data of a Single Center Study

Two novel mutations in hMLH1 gene in Iranian hereditary non-polyposis colorectal cancer patients

Hereditary non-polyposis colorectal cancer (HNPCC) is one of the most common forms of hereditary colorectal cancer. It is an autosomal dominant disorder resulting from germline mutations in DNA mismatch repair genes. In this study, we screened hMLH1 gene in a group of Iranian HNPCC patients using polymerase chain reaction-single strand conformational polymorphism and direct sequencing methods. Here we report two novel frameshift mutations in this gene in our studied population. One of them results from a deletion of "T" at codon 36, exon 1 which causes premature stop codon and a truncated protein. The other results from a deletion of "T" at codon 753, exon 19 causing a delayed stop codon. There are a variety of the reported novel mutations in hMLH1 gene studies. Identification of these mutations is necessary in different populations and can help the management of colorectal cancer in these populations by screening, by prevention strategies, and by following up the suspected HNPCC families.

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.

A cost-effectiveness analysis of prophylactic surgery versus gynecologic surveillance for women from hereditary non-polyposis colorectal cancer (HNPCC) Families

Women at risk for Lynch Syndrome/HNPCC have an increased lifetime risk of endometrial and ovarian cancer. This study investigates the cost-effectiveness of prophylactic surgery versus surveillance in women with Lynch Syndrome. A decision analytic model was designed incorporating key clinical decisions and existing probabilities, costs, and outcomes from the literature. Clinical forum where risk-reducing surgery and surveillance were considered. A theoretical population of women with Lynch Syndrome at age 30 was used for the analysis. A decision analytic model was designed comparing the health outcomes of prophylactic hysterectomy with bilateral salpingo-oophorectomy at age 30 versus annual gynecologic screening versus annual gynecologic exam. The literature was searched for probabilities of different health outcomes, results of screening modalities, and costs of cancer diagnosis and treatment. Cost-effectiveness expressed in dollars per discounted life-years. Risk-reducing surgery is the least expensive option, costing $23,422 per patient for 25.71 quality-adjusted life-years (QALYs). Annual screening costs $68,392 for 25.17 QALYs; and annual examination without screening costs $100,484 for 24.60 QALYs. Further, because risk-reducing surgery leads to both the lowest costs and the highest number of QALYs, it is a dominant strategy. Risk-reducing surgery is the most cost-effective option from a societal healthcare cost perspective.

A systematic review of gynecological cancer surveillance in women belonging to hereditary nonpolyposis colorectal cancer (Lynch syndrome) families

We performed a systematic review of studies that evaluate the role of gynecological cancer surveillance in women who carry a hereditary nonpolyposis colorectal cancer (HNPCC) mutation or belong to a family that fulfills the criteria for HNPCC. The PubMed database and a clinical trials database were used to identify relevant studies. We included studies that reported results of gynecological cancer surveillance in women who carry a HNPCC mutation, belong to a family in which a HNPCC mutation was detected or belong to a family fulfilling the Amsterdam II criteria. Number and stage of cancers, interval cancers and cancer precursor states detected at screening. Five studies fulfilled our review criteria. Surveillance modalities for endometrial cancer included transvaginal ultrasound combined with endometrial sampling when indicated, or transvaginal ultrasound with a routine endometrial biopsy, and, in certain studies, the tumor marker CA-125. The highest yield of pathological findings in surveillance visits, from 5 to 6.5%, occurred in studies that included routine endometrial biopsies. Without a routine sampling, 7/14 cancers and 11/18 hyperplasias would have been missed. One case of advanced ovarian cancer was detected at surveillance. Currently available published studies on gynecological cancer surveillance in women with HNPCC do not adequately allow for evidence-based clinical decisions. Detection of endometrial cancer or hyperplasia in nonsymptomatic women belonging to an HNPCC family is improved by adding routine endometrial sampling along with transvaginal ultrasound for surveillance visits. No benefit was shown for ovarian cancer surveillance.