Altered expression of hMSH2 and hMLH1 in tumors with microsatellite instability and genetic alterations in mismatch repair genes

To date, at least four genes involved in DNA mismatch repair (MMR) have been demonstrated to be altered in the germline of patients with hereditary nonpolyposis colon cancer: hMSH2, hMLH1, hPMS1, and hPMS2. Additionally, loss of MMR function has been demonstrated to lead to the phenomenon of microsatellite instability (MIN) in tumors from these patients. In this study, we have examined the protein expression pattern of hMSH2 and hMLH1 by immunohistochemistry in paraffin-embedded tumors from 7 patients with MIN+ sporadic cancer, 13 patients with familial colorectal cancer, and 12 patients meeting the strict Amsterdam criteria for hereditary nonpolyposis colon cancer. The relationship between the expression of these two gene products, the presence of germline or somatic mutations, and the presence of tumor MIN was examined. Nineteen of the 28 tumors studied demonstrated MIN, whereas mutations in hMLH1 and hMSH2 were detected in 6 and 2 patients, respectively. Of the eight MIN+/mutation+ cases, the absence of protein expression was observed for the corresponding gene product in all but one case (missense mutation in hMLH1). However, seven MIN+/mutation- cases also showed no expression of either hMLH1 (n = 5), hMSH2 (n = 1), or both (n = 1), whereas four MIN+/mutation- cases demonstrated normal expression for both. None of the MIN-/mutation- cases (n = 9) demonstrated an altered expression pattern for either protein. These data suggest that examination of protein expression by immunohistochemistry may be a rapid method for prescreening tumors for mutations in the MMR genes.     

Genetics of colonic cancer

Research in hereditary forms of colorectal cancer (CRC) has increased almost logarithmically thanks in a major way to momentous discoveries in molecular genetics during the past decade. Between 10 and 20% of the total CRC burden is due to Mendelian-inherited CRC syndromes. The paradigm for hereditary CRC is familial adenomatous polyposis (FAP), wherein the APC germ-line mutation has been identified. This has contributed to the elucidation of genomic and clinical heterogeneity within the syndrome, wherein an attenuated form of FAP has been identified as a result of intragenic mutations within this large APC gene. The most common form of hereditary CRC is hereditary nonpolyposis colorectal cancer (HNPCC). Several mutator genes, namely hMSH2, hMLH1, hPMS1, hPMS2 and, more recently, hMSH6/GTBP, have been identified. These molecular genetic discoveries are providing new insights into the pathogenesis of CRC. Individuals within these kindreds who are harbingers of these germ-line mutations will benefit from screening and, one day, chemoprevention.     

A naturally occurring hPMS2 mutation can confer a dominant negative mutator phenotype

Defects in mismatch repair (MMR) genes result in a mutator phenotype by inducing microsatellite instability (MI), a characteristic of hereditary nonpolyposis colorectal cancers (HNPCC) and a subset of sporadic colon tumors. Present models describing the mechanism by which germ line mutations in MMR genes predispose kindreds to HNPCC suggest a "two-hit" inactivation of both alleles of a particular MMR gene. Here we present experimental evidence that a nonsense mutation at codon 134 of the hPMS2 gene is sufficient to reduce MMR and induce MI in cells containing a wild-type hPMS2 allele. These results have significant implications for understanding the relationship between mutagenesis and carcinogenesis and the ability to generate mammalian cells with mutator phenotypes.     

Neuroendocrine synaptic vesicles are formed in vitro by both clathrin-dependent and clathrin-independent pathways

Hereditary nonpolyposis colorectal cancer (HNPCC) is a syndrome involving a predisposition to cancers of the colon, endometrium and several other extra-colonic sites, accounting for approximately 1-5% of all colorectal cancer cases. It is not easily recognized because of a lack of distinctive clinical markers, making diagnosis and management of this disease problematic. To provide a basis for uniformity in diagnosis of HNPCC, the Amsterdam criteria were proposed and are currently in use. More recently, the discovery of four human mismatch repair genes (hMSH2, hMLH1, hPMS1 and hPMS2) has provided novel insight into the genetic basis of this disease, and raised the possibility of genetic diagnosis for management of HNPCC patients and their family members. This report summarizes the clinicopathologic aspects of HNPCC, reviews the recent genetic findings and surveillance strategies, and suggests a novel designation of certain patients as suspected HNPCC.     

Optimisation of sample presentation for the near-infrared spectra of pharmaceutical excipients

The two most common forms of hereditary ovarian cancer are: the breast ovarian cancer syndrome, and ovarian cancer associated with HNPCC (hereditary nonpolyposis colorectal cancer) syndrome. Studies have shown that these diseases may be associated with mutations in a number of tumor suppressor genes, mainly BRCA1 and BRCA2. Malfunction of the protein products of these genes have also been found to be involved in sporadic ovarian cancer, which makes up the majority of ovarian cancer cases. HNPCC-ovarian cancer associated families reveal frequent mutations in at least four genes (hMSH2, hMLH1, hPMS1, and hPMS2) involved in the repair of mismatched DNA. With ovarian cancer being such an important health issue, the push is on to design reliable screening tests to detect defective inherited or somatic alleles in individual carriers. So far, most progress has been demonstrated in those patients with family histories of the disease who are at increased risk. The ramifications of such research may impact a variety of scientific, clinical, legal, ethical, and psychosocial issues. In addition to current treatment modalities, positive results of these tests may indicate the need for increased clinical surveillance, prophylactic treatment, and genetic counseling of patients on an individual basis. It remains to be seen whether the technology can be made reliable enough to not only benefit high-risk individuals but also the general population.     

Microsatellite instability in early onset and familial colorectal cancer

Hereditary non-polyposis colorectal cancer syndrome (HNPCC) is often considered to be the most common form of inherited colorectal cancer, although its precise incidence is unknown. The clinical diagnosis of HNPCC relies on a combination of family history and young age of onset of colorectal cancer, but as many familial aggregations of colorectal cancer do not fulfil the strict diagnostic criteria, HNPCC might be underdiagnosed. The majority of HNPCC families have germline mutations in mismatch repair (MMR) genes, such as MSH2 or MLH1, so that HNPCC cancers characteristically exhibit DNA replication errors (RERs) at microsatellite loci. Although an RER positive phenotype in tumours can also result from somatic mutations in an MMR gene, the prevalence of RER + tumours should provide a maximum estimate of the incidence of germline MMR gene mutations in patients with early onset and familial colorectal cancer. We investigated colorectal cancers for RERs from (1) a population based study of 33 patients with colorectal cancer aged 45 years or less, (2) 65 kindreds with familial colorectal cancer which only partially fulfilled the criteria for the diagnosis of HNPCC, and (3) 18 cancers from 12 HNPCC kindreds. Seven of 33 patients (21%) with colorectal cancer aged 45 years or less had an RER + cancer, with only two of these having a clear family history of HNPCC. A greater proportion of RER + tumours (5/7) occurred proximal to the splenic flexure than RER - tumours (4/26; chi2 = 6.14, p < 0.025). RERs were detected in all 18 cancers from HNPCC patients but in only six of 65 non-HNPCC familial colorectal cancer kindreds (9%; chi2 = 52.2, p < 0.0005). These findings suggest that most cancers in patients diagnosed at 45 years of age or less and familial aggregations of colorectal cancer which do not fulfil HNPCC diagnostic criteria do not have germline mutations in MSH2 and MLH1. Hence population screening for germline mutations in these genes is unlikely to be an efficient strategy for identifying people at high risk of developing colorectal cancer.     

MLH1 and MSH2 constitutional mutations in colorectal cancer families not meeting the standard criteria for hereditary nonpolyposis colorectal cancer

Genetic diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC) may have a significant impact on the clinical management of patients and their at-risk relatives. At present, clinical criteria represent the simplest and most useful method for the identification of HNPCC families and for the selection of candidates for genetic testing. However, reports of mismatch repair (MMR) gene mutations in families not fulfilling the minimal diagnostic criteria point out the necessity to identify additional clinical parameters suggestive of genetic predisposition to colorectal cancer (CRC) related to MMR defects. We thus investigated a series of 32 Italian putative HNPCC individuals selected on the basis of one of the following criteria: 1) family history of CRC and/or other extracolonic tumors; 2) early-onset CRC; and 3) presence of multiple primary malignancies in the same individual. These patients were investigated for the presence of MLH1 and MSH2 mutations by single-strand conformation polymorphism analysis. Pathogenetic truncating mutations were identified in 4 (12.5%) cases, 3 of them involving MSH2 and 1 MLH1. In addition, 2 missense MLH1 variants of uncertain significance were observed. All pathogenetic mutations were associated with early age (<40 years) at onset and proximal CRC location. Our results support the contention that constitutional MMR mutations can also occur in individuals without the classical HNPCC pattern. Moreover, evaluation of the clinical parameters associated with MMR mutations indicates that early onset combined with CRC location in the proximal colon can be definitely considered suggestive of MMR-related hereditary CRC and should be included among the guidelines for referring patients for genetic testing.     

Characterization of distinct human endometrial carcinoma cell lines deficient in mismatch repair that originated from a single tumor

The role of specific mismatch repair (MMR) gene products was examined by observing several phenotypic end points in two MMR-deficient human endometrial carcinoma cell lines that were originally isolated from the same tumor. The first cell line, HEC-1-A, contains a nonsense mutation in the hPMS2 gene, which results in premature termination and a truncated hPMS2 protein. In addition, HEC-1-A cells carry a splice mutation in the hMSH6 gene and lack wild-type hMSH6 protein. The second cell line, HEC-1-B, possesses the same defective hMSH6 locus. However, HEC-1-B cells are heterozygous at the hPMS2 locus; that is, along with carrying the same nonsense mutation in hPMS2 as in HEC-1-A, HEC-1-B cells also contain a wild-type hPMS2 gene. Initial recognition of mismatches in DNA requires either the hMSH2/hMSH6 or hMSH2/hMSH3 heterodimer, with hPMS2 functioning downstream of damage recognition. Therefore, cells defective in hPMS2 should completely lack MMR (HEC-1-A), whereas cells mutant in hMSH6 only (HEC-1-B) can potentially repair damage via the hMSH2/hMSH3 heterodimer. The data presented here in HEC-1-B cells illustrate (i) the reduction of instability at microsatellite sequences, (ii) a significant decrease in frameshift mutation rate at HPRT, and (iii) the in vitro repair of looped substrates, relative to HEC-1-A cells, illustrating the repair of frameshift intermediates by hMSH2/hMSH3 heterodimer. Furthermore, the role of hMSH2/hMSH3 heterodimer in the repair of base:base mismatches is supported by observing the reduction in base substitution mutation rate at HPRT in HEC-1-B cells (hMSH6-defective but possessing wild-type hPMS2), as compared with HEC-1-A (hMSH6/hPMS2-defective) cells. These data support a critical role for hPMS2 in human MMR, while further defining the role of the hMSH2/hMSH3 heterodimer in maintaining genomic stability in the absence of a wild-type hMSH2/hMSH6 heterodimer.     

Allelic losses and DNA methylation at DNA mismatch repair loci in sporadic colorectal cancer

Normal and tumor DNA samples of 35 patients with sporadic colorectal carcinoma were analyzed for microsatellite alterations at 12 markers linked to mismatch repair loci: hMLH1, hMSH2, hMSH3, hMSH6, hPMS1 and hPMS2. Remarkably, no correlation was observed between the replication error phenotype (RER+) and allelic losses at these loci. Hemizygous deletions, seen in 6/35 (17%) informative cases at hMLH1, 4/27 (15%) at hMSH2/hMSH6 and 6/34 (18%) at hMSH3, were rarely found in RER+ tumors. Since mismatch repair protein components act in molecular complexes of defined stoichiometry we propose that hemizygous deletion of the corresponding loci may be involved in colorectal tumorigenesis through defects in cellular functions other than replication error correction. The analysis of the methylation status of the promoter region of hMLH1 revealed that methylation might be an important mechanism of this locus inactivation in RER+ sporadic colorectal cancer.     

Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability

Recent studies have demonstrated the presence of microsatellite instability (MSI) in tumors from patients with hereditary nonpolyposis colon cancer and in a subset of patients with sporadic colorectal cancer (CRC). In sporadic CRC, three tumor phenotypes have been defined: microsatellite stable (MSS), low-frequency MSI, and high-frequency MSI (MSI-H). Although defective mismatch repair, consisting primarily of alterations in hMSH2 and hMLH1, is believed to be responsible for the MSI phenotype in the majority of patients with hereditary nonpolyposis colon cancer, the genetic defect responsible for this phenotype in sporadic CRC has yet to be clearly delineated. Somatic or germ-line alterations in these two genes have been identified in only a minority of these cases. Analysis of the protein expression patterns of hMSH2 and hMLH1 in unselected CRC, however, suggests that alterations in hMLH1 may account for a majority of the MSI-H cases. In an effort to explore the underlying molecular basis for these findings, we have examined the methylation status of the presumptive hMLHI promoter region in 31 tumors that vary in regard to their MSI status (MSI-H or MSS), their hMLH1 protein expression (MLH- or MLH+), and their gene mutation (Mut+ or Mut-) status. Hypermethylation of the hMLH1 promoter occurred in all 13 MSI-H/ MLH- tumors that did not have a detectable mutation within the hMLH1 gene. Of those MSI-H tumors containing germ-line or somatic alterations in hMLH1 (n = 7, including 3 frameshift, 1 nonsense, 2 missense mutations, and 1 tumor containing multiple mutations: missense, splice-site alteration, and a frameshift), four had a normal methylation pattern, whereas three others demonstrated hypermethylation of the hMLH1 promoter region. Two of these cases had a missense alteration, the other a frameshift alteration. The single MSI-H/Mut+ tumor that had normal hMLH1 and hMSH2 expression, as well as 9 of the 10 MSS cases, lacked methylation of the hMLH1 promoter. Hypermethylation of the hMSH2 promoter was not observed for any of the cases. These results suggest that hypermethylation of the hMLH1 promoter may be the principal mechanism of gene inactivation in sporadic CRC characterized by widespread MSI.     

A cost-effectiveness analysis of colorectal screening of hereditary nonpolyposis colorectal carcinoma gene carriers

BACKGROUND: It has been estimated that the prevalence of carriers of a mutated mismatch repair (MMR) gene among the general population in Western countries is between 5 and 50 per 10,000. These carriers have a risk of >85% of developing colorectal carcinoma (CRC) and therefore need careful follow-up. The objective of this study was to analyze the cost-effectiveness of CRC surveillance of carriers of a mutated MMR gene. METHODS: The authors constructed a model to estimate the potential health effects (life expectancy) and healthcare costs of two strategies: 1) surveillance, with colonoscopy every 2-3 years, and 2) no CRC surveillance. Estimates of the lifetime risk of developing CRC and the stage distribution of CRC for symptomatic patients were derived from the Dutch hereditary nonpolyposis colorectal carcinoma (HNPCC) registry. The CRC stage specific relative survival rates and the effectiveness of surveillance in preventing or detecting cancer early were based on Finnish studies. The costs of surveillance and treatment were derived from recent American studies. RESULTS: The results showed that 1) surveillance of gene carriers led to an increase in life expectancy of 7 years, and 2) the costs of surveillance under a wide range of assumptions are less than the costs of no CRC surveillance. CONCLUSIONS: CRC surveillance of HNPCC gene carriers appears to be effective and considerably less costly than no CRC surveillance and therefore deserves to be supported by governmental agencies and health insurance organizations.     

Aspirin suppresses the mutator phenotype associated with hereditary nonpolyposis colorectal cancer by genetic selection

Nonsteroidal anti-inflammatory drugs (NSAIDs) are well-known cancer preventives, which have been largely attributed to their antiproliferative and apoptosis-inducing activities. In this study, we show that microsatellite instability (MSI) in colorectal cancer cells deficient for a subset of the human mismatch repair (MMR) genes (hMLH1, hMSH2, and hMSH6), is markedly reduced during exposure to aspirin or sulindac [or Clinoril, which is chemically related to indomethacin (Indocin)]. This effect was reversible, time and concentration dependent, and appeared independent of proliferation rate and cyclooxygenase function. In contrast, the MSI phenotype of a hPMS2-deficient endometrial cancer cell line was unaffected by aspirin/sulindac. We show that the MSI reduction in the susceptible MMR-deficient cells was confined to nonapoptotic cells, whereas apoptotic cells remained unstable and were eliminated from the growing population. These results suggest that aspirin/sulindac induces a genetic selection for microsatellite stability in a subset of MMR-deficient cells and may provide an effective prophylactic therapy for hereditary nonpolyposis colorectal cancer kindreds where alteration of the hMSH2 and hMLH1 genes are associated with the majority of cancer susceptibility cases.     

Microsatellite instability in human solid tumors

BACKGROUND: Microsatellite instability (MIN) has been identified in a wide variety of human tumors, both familial and sporadic. In this study the authors attempted to correlate MIN with other biologic parameters to assess the significance of MIN in cancer. METHODS: The current literature up to May 1997 was reviewed critically. Comparative assessment and analysis of published MIN data in human solid tumors was addressed. RESULTS: Based on review of the current medical literature, the following conclusions can be drawn: 1) MIN associated with inherited mutations of the DNA mismatch repair genes (predominantly hMSH2/hMLH1) appears to characterize only the hereditary nonpolyposis colon carcinoma (HNPCC)/Muir-Torre family cancer syndrome category, and a subset of young colorectal carcinoma patients. Constitutional hMSH2/hMLH1 mutations rarely are reported in other than colon MIN+ tumor types; 2) MIN in non-HNPCC tumors generally is not associated with somatic mutations in the mismatch DNA repair genes most commonly involved in HNPCC; 3) loci of individual chromosomes containing microsatellite markers demonstrating high MIN frequency may be linked to particular tumor types (tumor specific MIN hot spots); 4) the gel banding patterns of MIN observed in noncolon tumors differ significantly from those reported previously in HNPCC; 5) although overall no association between MIN and histopathology is observed in the literature, a statistically higher MIN frequency has been noted in certain tumor subtypes; and 6) MIN in tumors can be associated with early or late stages of tumor progression, and also has been found in nontumor tissues. CONCLUSIONS: Molecular diagnosis using MIN analysis has been documented in at least two types of tumors (HNPCC and sporadic bladder carcinoma), suggesting a potential role of MIN in the diagnosis and/or prognosis of other solid human tumors as well.     

Evaluation of tryptamine in an impinger and on XAD-2 for the determination of hexamethylene-based isocyanates in spray-painting operations

We have investigated the relationship between immunohistochemically determined p53 status and outcome in 277 women with node-positive primary breast cancer who, following tumour excision and axillary clearance, were randomised to receive either 6 cycles of cyclophosphamide/methotrexate/S-fluorouracil (CMF) (n = 130) or no such post-operative treatment (n = 147). Follow-up data (median = 9 years) were available on all patients. A significant association was found between p53 status and survival. Patients with p53-positive tumours had a less favourable outcome than those with p53-negative disease. Women receiving adjuvant CMF chemotherapy had a significantly more favourable outcome compared to those who did not. The effect was seen both in women with p53-positive and p53-negative tumours; multivariate analysis showed relative risks for overall survival attributable to chemotherapy of 2.3 (95% CI 1.2-4.3) for women with p53-positive tumours and of 2.1 (95% CI 1.4-3.0) for those with p53-negative tumours. Thus, adjuvant chemotherapy with CMF is associated with a survival benefit in women with node-positive breast cancer irrespective of immunohistochemically determined p53 status.     

Drastic genetic instability of tumors and normal tissues in Turcot syndrome

Turcot syndrome is characterized by an association of malignant brain tumors and colon cancer developing in the patient's teens. Since the mechanism of carcinogenesis in Turcot syndrome is still unclear, we analysed genetic changes in tumors from a Turcot patient with no family history of the condition. All tumors, including one astrocytoma, three colon carcinomas, and two colon adenomas, exhibited severe replication error (RER), and all colon tumors showed somatic mutations at repeated regions of TGFbetaRII, E2F-4, hMSH3, and/or hMSH6 genes. Somatic APC mutations were detected in three of three colon carcinomas, and somatic p53 mutations were detected in the astrocytoma and two of three colon carcinomas, both of which showed two mutations without allele loss. We also found that normal colon mucosa, normal skin fibroblasts and normal brain tissue from this patient showed respective high frequencies of RER, in contrast to usual HNPCC patients in which RER was very rare in normal tissues. These results suggest that extreme DNA instability in normal tissues causes the early development of multiple cancer in Turcot syndrome. A missense mutation (GAG to AAG) at codon 705 of hPMS2 gene was detected in one allele of this patient, which was inherited from his mother without tumors. Additional unknown germline mutation may contribute to the genetic instability in normal tissues.     

Detection of Tn, sialosyl-Tn and T antigens in hereditary nonpolyposis colorectal cancer

The simple mucin-type carbohydrate antigens Tn, sialosyl-Tn, T and the 'cryptic' sialylated variant of the last represent the mucin core oligosaccharide structures that are produced in the initial steps of the mucin biosynthetic pathway. Utilizing monoclonal antibodies anti-Tn antigen (HB-Tn1), anti-sialosyl-Tn antigen (HB-STn1), anti-T antigen (HB-T1) and the biotinylated Amaranthus caudatus agglutinin (ACA), we have investigated the expression of the simple mucin-type carbohydrate antigens in hereditary nonpolyposis colorectal cancer (HNPCC; 15 cases) compared with sporadic colorectal cancer (CRC; 60 cases) and normal colonic mucosa (30 cases). A variable positivity of Tn, sialosyl-Tn, T and the cryptic sialylated form of this latter antigen was encountered in both HNPCC and sporadic CRC cases; in addition, in normal colonic mucosa a constant reactivity was encountered only for Tn and the cryptic sialylated form of T, while negative results were always obtained for sialosyl-Tn and T antigens. Statistical analysis, performed using a Chi-square test, showed significantly lower (P = 0.037) expression of sialosyl-Tn and higher (P = 0.022) expression of T in HNPCC than in sporadic CRC, suggesting a greater presence of beta 1,3 galactosyltransferase activity in HNPCC than in sporadic CRC. We were unable to identify a peculiar phenotype for HNPCC with simultaneous evaluation of reactivity for HB-Tn1, HB-STn1, HB-T1 and ACA; the biological significance of the preferential expression of T antigen in HNPCC remains to be investigated.     

Interactions of human hMSH2 with hMSH3 and hMSH2 with hMSH6: examination of mutations found in hereditary nonpolyposis colorectal cancer

Mutations in the human mismatch repair protein hMSH2 have been found to cosegregate with hereditary nonpolyposis colorectal cancer (HNPCC). Previous biochemical and physical studies have shown that hMSH2 forms specific mispair binding complexes with hMSH3 and hMSH6. We have further characterized these protein interactions by mapping the contact regions within the hMSH2-hMSH3 and the hMSH2-hMSH6 heterodimers. We demonstrate that there are at least two distinct interaction regions of hMSH2 with hMSH3 and hMSH2 with hMSH6. Interestingly, the interaction regions of hMSH2 with either hMSH3 or hMSH6 are identical and there is a coordinated linear orientation of these regions. We examined several missense alterations of hMSH2 found in HNPCC kindreds that are contained within the consensus interaction regions. None of these missense mutations displayed a defect in protein-protein interaction. These data support the notion that these HNPCC-associated mutations may affect some other function of the heterodimeric complexes than simply the static interaction of hMSH2 with hMSH3 or hMSH2 with hMSH6.     

A phase II trial of weekly infusional 5-fluorouracil in combination with low-dose leucovorin in patients with advanced colorectal cancer

We examined 59 breast cancers for p53 and bcl-2 protein expression by immunohistochemistry. The results were correlated with Ki-67 immunostaining. p53-negativity was noted in 40 cases and the remaining 19 tumours were p53-positive. Thirty-six tumours showed strong expression of bcl-2 and in 23 no staining for this protein was observed. We found statistically significant reverse correlation between expression of p53 and bcl-2 in majority of carcinomas: 31 cases were bcl-2 positive and p53-negative, and 14 tumours were bcl-2-negative and p53-positive. Six carcinomas showed no nuclear staining for Ki-67 and in the remaining 53 the percent of cancer cells positive for Ki-67 ranged from 1 to 60 (mean: 14.6). In these 53 cases we found that bcl-2-positive tumours were characterized by lower proliferation than bcl-2-negative tumours, the mean value of Ki-67 immunostaining being 10.7% and 23.0%, respectively. p53-negative tumours showed lower proliferation than p53-positive tumours: mean Ki-67 index was 10.2% and 23.9%, respectively. We conclude that immunohistochemically detected p53 and bcl-2 proteins show a significant inverse relationship in majority of breast carcinomas and their expression correlates with tumour proliferation (Ki-67 immunostaining).     

Complex genetic predisposition to cancer in an extended HNPCC family with an ancestral hMLH1 mutation

Hereditary non-polyposis colorectal cancer (HNPCC) is characterised by a genetic predisposition to develop colorectal cancer at an early age and, to a lesser degree, cancer of the endometrium, ovaries, urinary tract, and organs of the gastrointestinal tract other than the colon. In the majority of families the disease is linked to mutations in one of the two mismatch repair genes, hMSH2 or hMLH1. We have found a novel hMLH1 nonsense mutation in a Swiss family with Lynch syndrome, which has been transmitted through at least nine generations. A different tumour spectrum of neoplasms of the skin, soft palate, breast, duodenum, and pancreas was observed in three branches of this family, where there was a virtual absence of colonic tumours. The hMLH1 mutation could not be detected in members of these branches suggesting that at least a second genetic defect predisposing to cancer is segregating in part of the kindred.