Hereditary Nonpolyposis Colorectal Cancer Families Research Articles

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

382 Background: Hereditary non-polyposis colorectal cancer (HNPCC) is the most common hereditary colorectal cancer (CRC). At least five mismatch repair genes, majorly hMLH1and hMSH2 gene mutations, are associated with this syndrome. Given the geographical and racial differences, Chinese HNPCC patients have some special characteristics compared with patients in West countries. Based on our former studies, we developed a criteria, the Fudan Criteria, for clinical diagnosis of Chinese HNPCC. The aim of this study is (1) to understand the relationship between genotype and phenotype in Chinese HNPCC; and (2) to investigate the clinical value of Fudan Criteria. Methods: 116 unrelated probands of HNPCC or suspected HNPCC families from the Fudan Colorectal Registry were studied. 32 families fulfilled the Amsterdam criteria (AC group), 28 families fulfilled the Fudan Criteria (FD group). 56 families met the revised Bethesda guideline (BG Group). Direct DNA sequencing of all exons of hMSH2 and hMLH1 genes were performed. Mutation and clinicalpathological features were compared between the groups. Results: 32 pathological germline mutations were identified. 16/32 mutations were located at hMLH1 and 16/32 located 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%. In AC group, there were no significant clinicopathological differences in patients with or without mutation. However, families with hMSH2 mutation had a higher ratio of synchronous and metachronous CRC than families with hMLH1 mutation (33% vs. 6%; P=0.04). Families in AC group share the same clinicopathological features with families in FD group, except multiple relative tumors (21.6% vs.6%; P=0.001). Conclusions: There seems no close relation between genotype and phenotype, except patients with hMSH2 mutation more frequently harbor synchronous and metachronous CRC. Fudan Criteria had a little higher sensitivity and accuracy than Amsterdam Criteria for identification of Chinese HNPCC. No significant financial relationships to disclose.

Genetic profiles of hereditary nonpolyposis colorectal cancer.

469 Background: With the aim to identify genetic markers of hereditary nonpolyposis colorectal cancer (HNPCC), we applied tiling BAC array-based comparative genomic hybridization (aCGH) to 46 HNPCC-associated colorectal cancer. Methods: 32 k iling BAC arrays were used to generate high-density genomic profiles. Tumors were selected through a case-control design with half of the tumors derived from individuals with disease-predisposing mismatch repair gene mutations and the reminder from phenotypic HNPCC families without identified mutations. In addition, an equal number of sporadic tumors were used for comparison. Results: Tumors with disease-predisposing germline mutations showed frequent gains of chromosomes 1p (39%), 17 (43%), 19 (57%) and 22q (30%). HNPCC associated tumors without mutations did as a group have more complex alterations with the most frequent changes being gains of 20q (70%), 19 (35%), 17 (26%) and loss of 18 (39%). Gains of 1p and 20q and loss of chromosome 18 were identified as significant discriminators between HNPCC tumors with/without germline MMR gene mutations. Conclusions: The aCGH profiles of HNPCC-associated colorectal cancer suggest that specific gains and losses may be used to distinguish between tumors with/without germline mismatch repair gene mutations. No significant financial relationships to disclose.

Expression of Cyclooxygenase-2 and Its Relationship with Mismatch Repair and Microsatellite Instability in Hereditary Nonpolyposis Colorectal Cancer

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

Endoscopic surveillance for hereditary non-polyposis colorectal cancer (HNPCC) family members in a Southern Italian region

Background Surveillance in hereditary non-polyposis colorectal cancer (HNPCC) family members recommends baseline colonoscopy starting at age 20 and then surveillance colonoscopy every 1–2 years. Aims To verify adherence to the guidelines for HNPCC family members enrolled in endoscopic surveillance. Methods Data regarding 11 HNPCC families was retrieved from our database. Excluding 11 probands, 106 family members were evaluated and 40 underwent surveillance. Results At baseline colonoscopy, 7 colorectal cancers (CRC), 14 polyps (PO) [1 inflammatory, 2 hyperplastic, 10 adenomas with low grade dysplasia (LGD-AD) and 1 adenoma with high-grade dysplasia (HGD-AD)] were diagnosed in sixteen individuals. Twenty-eight HNPCC family members underwent endoscopic surveillance, with a total of 94 surveillance colonoscopies. Of these, 45 were positive (4 CRC, 3 inflammatory PO, 34 hyperplastic PO, 21 LGD-AD and 5 HGD-AD). Mean time between two consecutive surveillance colonoscopies was 24.6 months (range 4–168). Median time to first positive surveillance colonoscopy was 84 months for HNPCC family members with negative baseline colonoscopy, and 60 months for those with positive baseline colonoscopy ( p = 0.21). Conclusions Our data suggests that surveillance colonoscopy every 2 years is adequate to diagnose advanced lesions in HNPCC family members, and improves their compliance with surveillance.

CHEK2 mutations and HNPCC‐related colorectal cancer

Recently, the 1100delC variant of cell cycle checkpoint kinase 2 (CHEK2) has been reported to confer a colorectal cancer risk in hereditary non-polyposis-colorectal cancer (HNPCC) and HNPCC-related families in the Netherlands. To investigate whether CHEK2 mutations confer increased cancer risk in HNPCC and HNPCC-related families in Poland, we genotyped 463 probands from HNPCC and HNPCC-related families, and 5,496 controls for 4 CHEK2 alleles (1100delC, IVS2+1G>A, del5395, I157T). All 463 probands were screened for mutations in the HNPCC-related genes MSH2, MLH1 and MSH6. A positive association was observed for HNPCC-related cancer and the I157T missense CHEK2 mutation (OR = 1.7; p = 0.007), but not for the truncating alleles (OR = 1.0; p = 1.0). The association with the I157T was seen both for the 117 cases who fulfill Amsterdam criteria (OR = 1.9; p = 0.1) and for the 346 cases who do not fulfill the criteria (OR = 1.6; p = 0.03). One hundred forty-five of the 463 families had a mutation in MSH2, MLH1 or MSH6 (MMR-positive families). A positive association between the CHEK2 I157T mutation and HNPCC-related cancer was observed only for MMR-negative cases (OR = 2.1; p = 0.0004), but not for MMR-positive cases (OR = 0.8; p = 0.9). The association with I157T was particularly strong for MMR-negative cases with familial colorectal cancer (2 or more first-degree relatives affected) (OR = 2.5; p < 0.0001). We conclude that the I157T variant of CHEK2 increases the risk of colorectal cancer among MMR-negative, HNPCC/HNPCC-related families in Poland.

Abstract B39: Molecular diagnostics strategy to identify hereditary non-polyposis colorectal cancer patients

Abstract Introduction: Hereditary non-polyposis colorectal cancer (HNPCC), also called Lynch syndrome, is an autosomal dominantly inherited syndrome predisposing to the early development of cancers of colon, rectum, endometrial, small bowel and urinary tract and accounts for ∼5% of all colon cancer cases. Molecular investigations have shown that most HNPCC families are associated with constitutional mutations in a class of genes (called MLH1, MSH2, MSH6, PMS2 and probably others) involved in DNA mismatch repair. MLH1 and MSH2 genes account for approximately 90% of HNPCC families identified germline mutations. Most of these mutations are point mutations and small insertions or deletions. The large genomic deletions in MMR genes and germline epimutations in MLH1 explain a proportion of point mutation-negative families suspected of Lynch syndrome. At the same time the methylation in promoter of MLH1 gene in colon tissue frequently causes MLH1 protein loss in sporadic tumors. The aim of the study is to characterize the mismatch repair gene mutations of Estonian hereditary non-polyposis colorectal cancer families and to improve the screening strategy. Methods: A systematic analysis of 75 unrelated patients from suspected HNPCC families in Estonia was performed by immunohistochemistry, microsatellite instability, and gene mutation and methylation detection. Results. The study is still continuing. Systematic and comprehensive analysis of samples from 75 HNPCC-suspected patients is proceeding using various methods. Conclusion: Based on traditional molecular genetics, combined with epigenetics, multiple detection methods can accurately diagnose HNPCC. As the results of the study, the precise molecular diagnostic scheme for diagnosing HNPCC will be worked out for clinical use in Estonia. Citation Information: Clin Cancer Res 2010;16(7 Suppl):B39

Microsatellite instability in the peripheral blood leukocytes of HNPCC patients

Most hereditary nonpolyposis colorectal cancer (HNPCC) patients inherit a defective allele of a mismatch repair (MMR) gene, usually MLH1 or MSH2, resulting in high levels of microsatellite instability (MSI-H) in the tumors. Presence of MSI in the normal tissues of mutation carriers has been controversial. Here we directly compare MSI in the peripheral blood leukocyte (PBL) DNA of seven HNPCC patients carrying different types of pathogenic MMR mutations in MLH1 and MSH2 genes with the PBL DNA of normal age-matched controls and of patients with sporadic colorectal cancer (SCRC). Small pool PCR (SP-PCR) was used studying three microsatellite loci for at least 100 alleles each in most samples. The average frequencies of mutant microsatellite fragments in each HNPCC patient (0.04-0.24) were significantly higher (p<0.01) relative to their age-matched normal controls with mutant frequencies (MF) from 0.00 to 0.06, or SCRC patients (MF from 0.01-0.03). The data support the conclusions that higher MF in the PBL DNA of HNPCC patients is real and reproducible, may vary in extent according to the type of germline MMR mutation and the age of the individual, and provide a possible genetic explanation for anticipation in HNPCC families.

Germline mutation analysis ofhPMS2gene in Chinese families with hereditary nonpolyposis colorectal cancer

To study the germline mutation of hPMS2 gene in 26 unrelated Chinese hereditary nonpolyposis colorectal cancer (HNPCC) probands and to fulfill the screening strategy for HNPCC in Chinese. Genomic DNA was extracted from the peripheral blood. To avoid the interference of pseudogene in detection of the remaining 11 exons (exon 1-5, 9, 11-15), long-range polymerase chain reaction (PCR) was conducted to amplify the complete coding region of hPMS2 gene firstly. Then 1/8 of the PCR products were used as template to amplify the individual exon respectively and DNA sequencing was done. Direct DNA sequencing of the conventional PCR products of exon 6, 7, 8 and 10 of hPMS2 gene was performed. The same analysis was made in 130 healthy persons without family histories of HNPCC to further investigate the pathological effects of the detected missense mutation. One HNPCC proband fulfilled Bethesda guidelines and was found to carry the germline mutation of hPMS2 gene, which has not been reported in Chinese HNPCC families. It was a missense mutation at c.1532C>T of exon 11. It was detected in three controls as well with an occurrence rate of 2.3% (3/130). Since it could not be found in the PMS2-single nucleotide polymorphism (SNP) database, this missense mutation is a new SNP unreported up to date. Meanwhile, 260 reported SNPs of hPMS2 gene were detected in the 26 HNPCC probands. The 2nd and 5th exons were probably the hot SNP regions of hPMS2 gene in Chinese HNPCC families involving 53.1% of all reported SNP. The germline mutation of hPMS2 gene may be rare in Chinese HNPCC families. The 2nd and 5th exons are hot SNP regions of hPMS2 gene.

Partial loss of heterozygosity events at the mutated gene in tumors from MLH1/MSH2 large genomic rearrangement carriers

BackgroundDepending on the population studied, large genomic rearrangements (LGRs) of the mismatch repair (MMR) genes constitute various proportions of the germline mutations that predispose to hereditary non-polyposis colorectal cancer (HNPCC). It has been reported that loss of heterozygosity (LOH) at the LGR region occurs through a gene conversion mechanism in tumors from MLH1/MSH2 deletion carriers; however, the converted tracts were delineated only by extragenic microsatellite markers. We sought to determine the frequency of LGRs in Slovak HNPCC patients and to study LOH in tumors from LGR carriers at the LGR region, as well as at other heterozygous markers within the gene to more precisely define conversion tracts.MethodsThe main MMR genes responsible for HNPCC, MLH1, MSH2, MSH6, and PMS2, were analyzed by MLPA (multiplex ligation-dependent probe amplification) in a total of 37 unrelated HNPCC-suspected patients whose MLH1/MSH2 genes gave negative results in previous sequencing experiments. An LOH study was performed on six tumors from LGR carriers by combining MLPA to assess LOH at LGR regions and sequencing to examine LOH at 28 SNP markers from the MLH1 and MSH2 genes.ResultsWe found six rearrangements in the MSH2 gene (five deletions and dup5-6), and one aberration in the MLH1 gene (del5-6). The MSH2 deletions were of three types (del1, del1-3, del1-7). We detected LOH at the LGR region in the single MLH1 case, which was determined in a previous study to be LOH-negative in the intragenic D3S1611 marker. Three tumors displayed LOH of at least one SNP marker, including two cases that were LOH-negative at the LGR region.ConclusionLGRs accounted for 25% of germline MMR mutations identified in 28 Slovakian HNPCC families. A high frequency of LGRs among the MSH2 mutations provides a rationale for a MLPA screening of the Slovakian HNPCC families prior scanning by DNA sequencing. LOH at part of the informative loci confined to the MLH1 or MSH2 gene (heterozygous LGR region, SNP, or microsatellite) is a novel finding and can be regarded as a partial LOH. The conversion begins within the gene, and the details of conversion tracts are discussed for each case.

Prognostic relevance of MLH1 and MSH2 mutations in hereditary non-polyposis colorectal cancer patients.

Colorectal carcinoma patients from hereditary non-polyposis colorectal cancer families are suggested to have a better prognosis than sporadic colorectal carcinoma cases. Since the majority of hereditary non-polyposis colorectal cancer-related colorectal carcinomas are characterized by microsatellite instability due to germline mutations in DNA mismatch repair genes, this is consistent with the prolonged survival observed in sporadic microsatellite instability-positive colorectal carcinoma compared to microsatellite stable cases. However, a fraction of colorectal carcinoma cases belongs to families that, despite fulfilling the clinical criteria for hereditary non-polyposis colorectal cancer, do not carry mismatch repair gene mutations. Our aim was to verify to what extent the genotypic heterogeneity influences the prognosis of hereditary non-polyposis colorectal cancer patients. A survival analysis was performed on 526 colorectal carcinoma cases from 204 Amsterdam Criteria-positive hereditary non-polyposis colorectal cancer families. Enrolled cases were classified as MLH1-positive, MSH2-positive and mutation-negative, according to the results of genetic testing in each family. Five-year survival rates were 0.73 (95% CI, 0.66-0.80), 0.75 (95% CI, 0.66-0.84) and 0.62 (95% CI, 0.55-0.68) for MLH1-positive, MSH2-positive and mutation-negative groups, respectively (logrank test, P = 0.01). Hazard ratio, computed using Cox regression analysis and adjusted for age, sex, tumor site and stage, was 0.71 (95% CI, 0.51-0.98) for the mutation-positive compared to the mutation-negative group. Moreover, in the latter group, patients with microsatellite instability-positive colorectal carcinomas showed a better outcome than microsatellite stable cases (5-year survival rates, 0.81 and 0.60, respectively; logrank test, P = 0.006). Our results suggest that the prognosis of hereditary non-polyposis colorectal cancer-related colorectal carcinoma patients depends on the associated constitutional mismatch repair genotype.

Prognostic Relevance of MLH1 and MSH2 Mutations in Hereditary Non-Polyposis Colorectal Cancer Patients

Colorectal carcinoma patients from hereditary non-polyposis colorectal cancer families are suggested to have a better prognosis than sporadic colorectal carcinoma cases. Since the majority of hereditary non-polyposis colorectal cancer-related colorectal carcinomas are characterized by microsatellite instability due to germline mutations in DNA mismatch repair genes, this is consistent with the prolonged survival observed in sporadic microsatellite instability-positive colorectal carcinoma compared to microsatellite stable cases. However, a fraction of colorectal carcinoma cases belongs to families that, despite fulfilling the clinical criteria for hereditary non-polyposis colorectal cancer, do not carry mismatch repair gene mutations. Our aim was to verify to what extent the genotypic heterogeneity influences the prognosis of hereditary non-polyposis colorectal cancer patients. A survival analysis was performed on 526 colorectal carcinoma cases from 204 Amsterdam Criteria-positive hereditary non-polyposis colorectal cancer families. Enrolled cases were classified as MLH1-positive, MSH2-positive and mutation-negative, according to the results of genetic testing in each family. Five-year survival rates were 0.73 (95% CI, 0.66-0.80), 0.75 (95% CI, 0.66-0.84) and 0.62 (95% CI, 0.55-0.68) for MLH1-positive, MSH2-positive and mutation-negative groups, respectively (logrank test, P = 0.01). Hazard ratio, computed using Cox regression analysis and adjusted for age, sex, tumor site and stage, was 0.71 (95% CI, 0.51-0.98) for the mutation-positive compared to the mutation-negative group. Moreover, in the latter group, patients with microsatellite instability-positive colorectal carcinomas showed a better outcome than microsatellite stable cases (5-year survival rates, 0.81 and 0.60, respectively; logrank test, P = 0.006). Our results suggest that the prognosis of hereditary non-polyposis colorectal cancer-related colorectal carcinoma patients depends on the associated constitutional mismatch repair genotype.

A study on MSH2 and MLH1 mutations in hereditary nonpolyposis colorectal cancer families from the Basque Country, describing four new germline mutations

Hereditary non-polyposis colorectal cancer (HNPCC) or Lynch syndrome underlies between 2 and 5% of all colorectal cancer. It is inherited as an autosomal dominant condition due to mutations in the mismatch repair genes. Fifty-four non-related index cases, 21 of them fulfilling Amsterdam criteria I or II, were studied. Ten (10/21 = 47.6%) different pathological mutations were found in this group, two of which had not previously been reported--one in MLH1 and the other in MSH2-. In the remaining patients, we also found another family with one of these new mutations, and four additional changes, two of which were also new--a pathological change in MSH2 and a second change of uncertain significance in MLH1-, while the other two changes had already been reported. Of all mutations, eight were found in MSH2 (8/15 = 53.3%) and seven in MLH1 (7/15 = 46.6%), suggesting a slightly greater involvement of MSH2 in HNPCC than MLH1 in our population, in contrast to the results reported by other authors.

An effect from anticipation also in hereditary nonpolyposis colorectal cancer families without identified mutations

Optimal prevention of hereditary cancer is central and requires initiation of surveillance programmes and/or prophylactic measures at a safe age. Anticipation, expressed as an earlier age at onset in successive generations, has been demonstrated in hereditary nonpolyposis colorectal cancer (HNPCC). We specifically addressed anticipation in phenotypic HNPCC families without disease-predisposing mismatch repair (MMR) defects since risk estimates and age at onset are particularly difficult to determine in this cohort. The national Danish HNPCC register was used to identify families who fulfilled the Amsterdam criteria for HNPCC and showed normal MMR function and/or lack of disease-predisposing MMR gene mutation. In total, 319 cancers from 212 parent–child pairs in 99 families were identified. A paired t-test and a bivariate statistical model were used to assess anticipation. Both methods demonstrated an effect from anticipation with cancer diagnosed mean 11.4 years ( t-test, p < 0.0001) and mean 5.9 (bivariate model, p = 0.02) years earlier in children than in parents. This observation suggests that anticipation may apply also to families without identified mutations and serves as a reminder to initiate surveillance programmes at young age also in HNPCC families with undefined genetic causes.

Four novel germline mutations in the MLH1 and PMS2 mismatch repair genes in patients with hereditary nonpolyposis colorectal cancer

Hereditary nonpolyposis colorectal cancer (HNPCC) is the most common cause of early onset hereditary colorectal cancer. In the majority of HNPCC families, microsatellite instability (MSI) and germline mutation in one of the DNA mismatch repair (MMR) genes are found. The entire coding sequence of MMR genes (MLH1, MLH2, MLH6, and PMS2) was analyzed using direct sequencing. Also, tumor tests were done as MSI and immunohistochemistry testing. We were able to find three novel MLH1 and one novel PMS2 germline mutations in three Iranian HNPCC patients. The first was a transversion mutation c.346A>C (T116P) and happened in the highly conserved HATPase-c region of MLH1 protein. The second was a transversion mutation c.736A>T (I246L), which caused an amino acid change of isoleucine to leucine. The third mutation (c.2145,6 delTG) was frameshift and resulted in an immature stop codon in five codons downstream. All of these three mutations were detected in the MLH1 gene. The other mutation was a transition mutation, c.676G>A (G207E), which has been found in exon six of the PMS2 gene and caused an amino acid change of glycine to glutamic acid. MSI assay revealed high instability in microsatellite for two patients and microsatellite stable for one patient. In all patients, an abnormal expression of the MMR proteins in HNPCC was related to the above novel mutations.

A novel germline mutation of hMLH1 in a Korean hereditary non-polyposis colorectal cancer family

Hereditary non-polyposis colorectal cancer (HNPCC) is an inherited disease caused by a germline mutation of the mismatch repair (MMR) genes, and the distinctive feature is that colorectal and extracolonic malignancies occur early in life. We report on the case of a Korean HNPCC family with endometrial cancer, with the goal of elucidating the involvement of an MMR deficiency. Although the family history did not fulfill the Amsterdam criteria II, blood samples were subjected to genetic testing by the revised Bethesda guidelines. Immunohistochemistry and direct sequencing of the genomic DNA identified a C insertion at the 1780th base in exon 16 of hMLH1, a pathogenic mutation that has not been reported before. By this mutation, premature termination at codon 592 resulted with an estimated deletion of 21% of the C-terminus of the hMLH1 protein. For early detection of the disease, the family was examined by colonoscopy and a gynecologic examination. The expression of hMLH1 in colon tissues was analyzed by Western blot analysis. We observed that the C-terminus portion of the hMLH1 protein was truncated in the HNPCC family members. Two young family members with no clinical symptoms were newly diagnosed with colorectal cancer by colonoscopy and a pathological examination. Hereby, we identified a novel pathogenic germline mutation of hMLH1 in a Korean HNPCC family. The loss of C-terminus of hMLH1 protein was thus considered to possibly play a role in the development of HNPCC with other tumors. Our findings might be useful for early diagnosis and management of the HNPCC family.

Knowledge about hereditary nonpolyposis colorectal cancer; mutation carriers and physicians at equal levels

BackgroundIdentification and adequate management of individuals at risk for hereditary nonpolyposis colorectal cancer (HNPCC) is crucial since surveillance programmes reduce morbidity and mortality. We investigated knowledge about key features of HNPCC in at risk individuals and physicians in surgery, gynecology and oncology.MethodsData were collected using a questionnaire which was answered by 67 mutation carriers and 102 physicians from the southern Swedish health care region. The statements were related to colorectal cancer, heredity and surveillance and the physicians were also asked questions about cancer risks and surveillance strategies.ResultsBoth groups answered questions on colorectal cancer risk, surveillance and genetic testing well, whereas answers about inheritance and risks for HNPCC associated cancer were less accurate. Only half of the family members and one third of the physicians correctly estimated the risk to inherit an HNPCC predisposing mutation. Among family members, young age (<57 years), female sex and recent genetic counseling significantly correlated with better results. Physicians generally underestimated the risk of HNPCC associated cancers and three out of four suggested a later starting age for surveillance than recommended.ConclusionThe finding of similar levels of knowledge about key features of HNPCC in at risk individuals and physicians reflect the challenge physicians face in keeping up to date on hereditary cancer and may have implications for the clinical management and professional relations with HNPCC family members.

Sarcomas associated with hereditary nonpolyposis colorectal cancer: broad anatomical and morphological spectrum

Hereditary nonpolyposis colorectal cancer (HNPCC) is primarily linked to colorectal and endometrial cancer, but is associated with a broad tumor spectrum. Though not formally part of the syndrome, occasional sarcomas have been reported in individuals with HNPCC. We used the national Danish HNPCC-register to identify HNPCC families in which sarcomas had been diagnosed. Fourteen sarcomas were identified in families with mutations in MSH2, MSH6, and MLH1. The median age at sarcoma diagnosis was 43 (15-74) years. Soft tissue sarcomas predominated followed by uterine sarcomas and eight histopathological subtypes were represented with recurrent diagnoses of liposarcoma, leiomyosarcoma, and carcinosarcoma. Tumor tissue from eight cases was available for analysis of mismatch-repair (MMR) status using immunohistochemical staining and analysis of microsatellite instability, which revealed MMR defects in six of the eight tumors investigated. This suggests that sarcomas may be part of the HNPCC tumor spectrum and that colorectal cancer should be considered in the family history of sarcoma patients.

Breast cancer immunohistochemistry can be useful in triage of some HNPCC families

Immunohistochemistry of tumour samples is increasingly used in the triage of families where hereditary non-polyposis colorectal cancer (HNPCC) due to mismatch repair defects is suspected. Usually, this is undertaken in tumours that are a recognised part of the spectrum of HNPCC-related cancers e.g. colon or endometrial cancers. Although breast cancers are not classed as part of this spectrum, this study examined the extent to which some breast tumours do arise by the mismatch repair pathway in these families. This may have clinical utility in families where an individual with a 'classic HNPPC-related' tumour is not available for evaluation. Immunohistochemistry of a breast tumour may identify an individual in whom germline mutation testing is worthwhile.

Genetic diagnosis strategy of hereditary non-polyposis colorectal cancer

To study the characteristics of mismatch repair gene mutation of Chinese hereditary non-polyposis colorectal cancer (HNPCC) and hMLH1 gene promoter methylation, and to improve the screening strategy and explore the pertinent test methods. A systematic analysis of 30 probands from HNPCC families in the north of China was performed by immunohistochemistry, microsatellite instability (MSI), gene mutation and methylation detection. High frequency microsatellite instability occurred in 25 probands (83.3%) of HNPCC family. Loss of hMLH1 and hMSH2 protein expression accounted for 88% of all microsatellite instability. Pathogenic mutation occurred in 14 samples and 3 novel mutational sites were discovered. Deletion of exons 1-6, 1-7 and 8 of hMSH2 was detected in 3 samples and no large fragment deletion was found in hMLH1. Of the 30 probands, hMLH1 gene promoter methylation occurred in 3 probands. The rate of gene micromutation detection combined with large fragment deletion detection was 46.7%-56.7%. The rate of the two methods in combination with methylation detection was 63.3%. Scientific and rational detection strategy can improve the detection rate of HNPCC. Based on traditional molecular genetics and combined with epigenetics, multiple detection methods can accurately diagnose HNPCC.

Risk of gynecologic cancers in Danish hereditary non‐polyposis colorectal cancer families

Women in hereditary non-polyposis colorectal cancer (HNPCC) families have an elevated risk of endometrial and ovarian cancer. The risk in Lynch syndrome families with known mutations in mismatch repair genes (MMR genes) seems to be higher than in familial colorectal cancer (CRC) families. Data in the Danish HNPCC register on the frequency and lifetime risk of gynecologic cancers were analyzed and the actual surveillance strategy discussed in relation to the results. Register-based retrospective study. A total of 1,780 at-risk women were identified and epidemiological, clinical and MMR gene mutation data were retrieved. In a total of 105 cases of endometrial cancer, there was no significant difference in MSH2, MSH6 and MLH1 mutation carrier frequency. Compared to the general population, mutation carriers had a 20 times increase in lifetime risk of endometrial cancer. Lifetime risk was elevated four times in familial CRC families. In these families, frequency was correlated to the pedigree phenotype, with significantly higher frequency demonstrated in Amsterdam II families compared to Amsterdam I families and families suspected of HNPCC. A total of 39 cases of ovarian cancer were identified with a lifetime risk of three to four times the general population. No significant correlation was found between the frequency of ovarian cancer and MMR gene mutation status in the families. The benefit of surveillance concerning gynecological cancers seems to be less well founded in familial CRC families than in Lynch syndrome families. Modifying the surveillance strategy may be relevant in the future, but before changing existing guidelines concerning surveillance, further research is recommended.