Hereditary Nonpolyposis Colon Carcinoma Research Articles

Risk of urothelial bladder cancer in Lynch syndrome is increased, in particular among MSH2 mutation carriers

BackgroundColorectal, endometrial and upper urinary tract tumours are characteristic for Lynch syndrome (hereditary non-polyposis colon carcinoma, HNPCC). The aim of the present study was to establish whether carriers of mutations...

Synchronous lung tumours in a patient with metachronous colorectal carcinoma and a germline MSH2 mutation

Mutations of DNA mismatch repair genes are characterised by microsatellite instability and are implicated in carcinogenesis. This mutation susceptible phenotype has been extensively studied in patients with hereditary non-polyposis colon...

Significance of genetic instability in development and chemosensitivity of malignant tumors

Abstract Cellular responses to DNA damages have critical roles in tumor genesis. The mismatch repair system and the p53 protein are involved in the maintenance of the genomic integrity. We set the aim to examine the alterations of the main mismatch repair genes (hMLH1 and hMSH2) in the predisposition to hereditary colorectal cancer, and the influence of these genes on the therapeutic sensitivity of testicular germ-cell tumors. We investigated mutations of the p53 gene in primary head and neck tumors with the view to outline their prognostic values in the clinical outcome and the therapeutic responsiveness. Germline alterations of the MMR genes result in autosomal dominantly inherited predisposition to hereditary nonpolyposis colon carcinoma (HNPCC). We applied Bethesda guidelines to select patients not fulfilling Amsterdam criteria. Our findings demonstrated that causative mutations coupled with single nucleotide polymorphisms have worse prognostic values. The majority of testicular germ cell tumors (TGCT...

Hereditary breast cancer syndromes in a Turkish population. Results of molecular germline analysis

Breast cancer is the most common malignancy which affects women. In 5–10% of all cases, breast cancer presents as a hereditary cancer syndrome. Since 1996, 68 families with suspicion of familial breast cancer have been referred to our department. In 5 of the 68 families (7.4%), the clinical diagnosis was hereditary breast ovarian cancer syndrome. In 17 families (25%), two or more breast cancer cases were present. Mutation screening of BRCA1 and BRCA2 in these families revealed a BRCA1 mutation (185delAG) in one family. Three families (4.4%) had a diagnosis of Li–Fraumeni syndrome and germline mutations in TP53 (Lys292Ile, Pro278Ser and Pro278Thr). Breast cancer occurred in a family with hereditary nonpolyposis colon carcinoma (HNPCC; Lynch syndrome) carrying an MLH1 mutation (IVS17-3G>C). Most of our families (41 families; 60.2%) had only one case with breast cancer or cystic adenoma (or both) and did not need counseling and DNA testing. In summary, in 10 of the 68 families in our series (14.7%), a germline mutation in a breast cancer predisposing gene was detected. Our data show the importance of detailed examination of clinical data, pedigree analyses, and molecular germline diagnostics for the counseling of breast cancer cases.

Reduced expression of hMSH2 protein is correlated to poor survival for soft tissue sarcoma patients.

Deregulation of DNA mismatch repair is a common mechanism for the development of hereditary nonpolyposis colon carcinoma and related familiar cancers, but it also plays a role in the tumorigenesis of sporadic cancers. Although the protein expression of the two main components of DNA mismatch repair, hMSH2 and hMLH1, has been described in soft tissue sarcoma (STS) patients, its prognostic impact is yet to be determined. The authors investigated the expression of the DNA repair proteins hMSH2 and hMLH1 by Western blot analysis in tumor samples of 57 STS patients. The correlation between the expression of hMSH2/hMLH1 and survival was studied in a Cox proportional hazards regression model, which was adjusted for the prognostic effects of staging, tumor entity, and radicality of tumor resection. Nine of 57 STS (16%) showed reduced expression of hMSH2 and reduced expression of hMLH1 was detected in seven STS patients (12%). In a Kaplan-Meier analysis, the median survival for patients with reduced expression of the hMSH2 protein was 18 months, whereas the patients with a normal expression of hMSH2 survived for an average of 68 months. A multivariate Cox proportional hazards regression model revealed a significant correlation between the reduced expression of the hMSH2 protein and poor survival (relative risk = 4.7; 95% confidence interval [CI]: 1.3-17.2; P = 0.019). Reduced expression of the hMSH2 protein is an independent negative prognostic factor for STS patients.

Is reduced expression of mismatch repair genes MLH1 and MSH2 in patients with sporadic colorectal cancer related to their prognosis?

The majority of mutations in hereditary nonpolyposis colon carcinoma (HNPCC) patients affect the mismatch-repair genes (MMRG) MLHI and MSH2. In addition, mutations of these genes were found in about 15% of sporadic colorectal carcinomas which appear to be related to microsatellite instability (MSI). However, mutations in MMRG were not found in all MSI-positive carcinomas, but MMRG mutations may be relevant for the assessment of tumor characteristics and patients' prognosis. Therefore, we investigated the relationship between expression of MMRG, tumor biology and patients' survival. In 127 patients with sporadic colorectal carcinomas and a minimum of 5 years follow-up after curative surgery immunohistochemical detection of MLHI and MSH2 was analyzed semiquantitatively. Lost expression of MLHI has been found in tumor specimens from 10 patients, whereas MSH2 expression was missing in 5 patients. This reduced expression did not correlate with tumor stage, lymph node involvement, grading or tumor invasion into blood vessels. However, a significant correlation was found for lymphovascular invasion (P = 0.02) and localization within the colorectum (P = 0.003) in MLH1-negative carcinomas. In addition, although there was a clear tendency for longer overall survival (72 vs. 63 months) for patients with MLH1-negative carcinomas, significant differences for overall and recurrence-free survival were not seen. In conclusion of our results and a critical review of literature, the prognostic importance of the MMR genes in sporadic colorectal carcinomas remains controversial.

Microsatellite instability and hMLH1/hMSH2 expression in Barrett esophagus-associated adenocarcinoma.

Microsatellite instability (MSI) has been documented in malignancies associated with hereditary nonpolyposis colon carcinoma and in sporadic malignancies of the colon, stomach, and endometrium. In these malignancies, MSI is associated with defects in the DNA mismatch repair enzymes hMSH2 and hMLH1. Defects in these enzymes result in a phenotype characterized by instability of multiple microsatellite repeat sequences throughout the genome. This study sought to determine the prevalence of MSI in 80 primary Barrett esophagus-associated adenocarcinomas (BEAd) and to examine the relation of MSI with the clinical and pathologic features of the tumors. Eighty BEAd were evaluated for the presence of MSI by using the microsatellite markers BAT25, BAT26, D10S219, D10S541, and D10S551. These tumors also were evaluated for immunohistochemical expression of hMSH2 and hMLH1. High levels of MSI were not found in any of the tumors examined. Furthermore, immunohistochemical expression of hMSH2 and hMLH1 was retained in all cases evaluated. Evidence of low level MSI was found in 16% of tumors. In none of these tumors, however, was MSI present in more than two of five loci. The presence of MSI did not correlate with patient age, tumor stage, degree of differentiation, or with patient survival. High level MSI and loss of hMLH1/hMSH2 expression is uncommon in BEAd. A subset of BEAd demonstrate low level MSI. The presence of low level MSI was not associated with the clinicopathologic features of the tumors examined.

The xeroderma pigmentosum group D (XPD) gene: one gene, two functions, three diseases.

DNA, the genetic material in all living organisms, is continually exposed to agents that cause damage to its structure, resulting in the loss of vital genetic information. To counteract the potentially devastating effects of such damage, all organisms have evolved a series of different repair processes, with which many kinds of damage to the DNA can be corrected. The importance of DNA repair is shown by the existence of several human genetic disorders that are caused by defects in one of these repair processes. Thus, for example, most individuals with xeroderma pigmentosum (XP) are unable to repair damage generated in DNA by ultraviolet (UV) light from the sun, whereas patients with hereditary nonpolyposis colon carcinoma are defective in the repair of mismatched bases. XP was the first DNA-repair disorder to be identified. It is a rare autosomal recessive genetic disorder characterized by numerous skin abnormalities ranging from excessive freckling to multiple skin cancers (Fig. 1a) (Bootsma et al. 1998). The incidence of skin cancer is about 2000-fold greater than in normal individuals. All skin abnormalities result from exposure to sunlight and are caused by inability to repair DNA damage induced in the skin by sunlight. The more severely affected patients have neurological abnormalities caused by premature neuronal death. Cells from XP donors are hypersensitive to killing by UV irradiation, and this is caused, in the majority of cases, by defects in nucleotide excision repair (NER), the process with which UV-induced photoproducts in the DNA are removed and replaced (Friedberg et al. 1995). XP is genetically heterogeneous. There are eight complementation groups designated XP-A through G and XP-variant. The XPD gene, defective in XP individuals assigned to the XP-D complementation group, is the topic of this review.

Routine detection of the replication error phenotype in clinical tumor specimens using fluorescence-SSCP.

Almost all tumors from patients with hereditary non-polyposis colon carcinoma and approximately 10%-15% of sporadic colon and gastric carcinomas contain widespread deletions within mono- and dinucleotide repeat sequences in their DNA. This is referred to as the replication error (RER+) phenotype and, in the case of colon carcinoma, is often associated with an improved tumor prognosis and possibly also with response to chemotherapy. The RER+ status of tumors is usually determined by examining several dinucleotide and mononucleotide repeats for size variations when compared with the matching normal DNA. Alternately, the identification of deletions within BAT-26, a quasi-monomorphic polyadenine tract within the hMSH2 gene, has been shown to establish the RER+ status of tumors with greater than 99% accuracy and without the need for normal DNA. Here, we use fluorescent PCR in combination with single strand conformation polymorphism analysis to detect deletions in BAT-26. This technique provides a sensitive, rapid, reproducible and inexpensive assay suitable for the routine identification of RER+ status in clinical tumor specimens.

Integration of family history and medical management of patients with hereditary cancers.

The family histories of individuals affected by a wide variety of cancers have provided information about the principal features of hereditary cancer. Surveillance protocols, indicating the most appropriate modalities and the age at which to initiate them, have been derived from what has been learned about the age of onset and the cancer sites associated with specific cancer syndromes. Likewise, cancer management has been based on what is known of the natural history of the syndrome cancers from studying multiple affected families. Family history has even been an essential tool for molecular geneticists as they have mapped and eventually identified genes for such cancer syndromes as hereditary breast ovarian carcinoma (HBOC), familial adenomatous polyposis (FAP), and hereditary nonpolyposis colon carcinoma (HNPCC). Despite the rapid integration of molecular genetics into the diagnosis and management of individuals at high risk for hereditary cancer, family history remains an essential tool in all aspects of cancer genetic health services. Recognition of a hereditary cancer syndrome through a family's history offers a primary care provider an opportunity to intervene on behalf of not just one patient but an entire family. Once hereditary cancer is identified, the information that has been learned and the protocols developed from numerous family histories can be applied to one individual or family based on their specific family history.

Integration of family history and medical management of patients with hereditary cancers

The family histories of individuals affected by a wide variety of cancers have provided information about the principal features of hereditary cancer. Surveillance protocols, indicating the most appropriate modalities and the age at which to initiate them, have been derived from what has been learned about the age of onset and the cancer sites associated with specific cancer syndromes. Likewise, cancer management has been based on what is known of the natural history of the syndrome cancers from studying multiple affected families. Family history has even been an essential tool for molecular geneticists as they have mapped and eventually identified genes for such cancer syndromes as hereditary breast ovarian carcinoma (HBOC), familial adenomatous polyposis (FAP), and hereditary nonpolyposis colon carcinoma (HNPCC). Despite the rapid integration of molecular genetics into the diagnosis and management of individuals at high risk for hereditary cancer, family history remains an essential tool in all aspects of cancer genetic health services. Recognition of a hereditary cancer syndrome through a family's history offers a primary care provider an opportunity to intervene on behalf of not just one patient but an entire family. Once hereditary cancer is identified, the information that has been learned and the protocols developed from numerous family histories can be applied to one individual or family based on their specific family history.

Does a family history of cancer increase the risk for postmenopausal endometrial carcinoma?

As part of the hereditary nonpolyposis colon carcinoma (HNPCC) constellation of neoplasia caused by defects in mismatch repair genes, some endometrial carcinomas are known to have a genetic contribution to etiology. However, most endometrial carcinomas occur in postmenopausal women, presumably without the HNPCC defect. Consequently, the genetic contribution to these cases is unclear. The objective of this study was to determine whether family history of cancer is a risk factor for endometrial carcinoma in older women. The authors analyzed incident endometrial carcinoma data, as well as data on family history of various cancers in first-degree relatives, from a cohort of 24,848 postmenopausal Iowa women ages 55-69 years who were cancer free at baseline in 1986. Because a positive family history is dependent on many factors, including the age of the patient, the number of relatives, and the distribution of other risk factors in relatives, the authors also conducted a nested case-control study on family members of 95 patients with endometrial carcinoma diagnosed during 1988-1989 and 91 cancer free controls who were chosen randomly from subjects matched for age (+/-1 year). During 10 years of follow-up of the cohort, 322 incident endometrial carcinoma cases occurred. Women who reported a positive family history of cancer overall or at any specific site (e.g., the endometrium, colon, or breast) were not at increased risk for endometrial carcinoma. Adjustment for potential confounders, such as age, obesity, parity, oral contraceptive use, and estrogen replacement therapy, did not alter these results. Analysis of the family members of the cases and controls produced little evidence to suggest that this lack of association between family history and endometrial carcinoma could be explained by unequal distribution of known risk factors among relatives. Case family members were slightly older than control family members, but no significant differences were found in body mass index (kg/m2), age at menarche, age at menopause, or number of pregnancies. Relation to a case or control was not associated with increased risk of endometrial, ovarian, breast, or colon carcinoma for family members. Controlling for a variety of potential confounders did not alter the results. No evidence was found that genetics contribute to the risk of postmenopausal endometrial carcinoma for women with no personal cancer history.

Prediction-based threading of the hMSH2 DNA mismatch repair protein.

Mutations in the genes whose products participate in DNA mismatch repair underlie the increased risk of cancer in families with hereditary nonpolyposis colon carcinoma. Mutations in hMSH2 account for approximately 50% of the mutations found in these families. We sought to predict the 3-dimensional structure of hMSH2 by identifying structural homologues using prediction-based threading and by computer modeling using information from these putative structurally related proteins. Prediction-based threading identified three candidate structural homologues: glycogen phosphorylase (gpb), a 70 kDa soluble lytic transglycosylase, and ribonucleotide reductase protein R1. An independent approach utilizing a potential-based threading program also identified gpb as a structural homologue. The models based on the structures of these proteins suggest that the ATP binding domain and helix-turn-helix domain are exposed on the outside of the protein. All known bacterial MutS and hMSH2 mutations appear to be clustered in similar vicinities in the theoretical models of hMSH2; the major site is within the ATP binding domain and near the carboxyl-terminal end, whereas a smaller number map to the region coding for exon 5 and the amino-terminal domain. All point mutations also appear to affect amino acids that are exposed on the outside surface of the protein.

Microsatellite instability in human solid tumors.

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. The current literature up to May 1997 was reviewed critically. Comparative assessment and analysis of published MIN data in human solid tumors was addressed. 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. 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.

Assessment of microsatellite alterations in young patients with gastric adenocarcinoma.

Genetic factors are probably important in the development of gastric carcinoma in young patients (younger than 40 years). The authors investigated early onset primary gastric adenocarcinomas for the presence of microsatellite instability, which is a phenotypic marker for the hereditary nonpolyposis colon carcinoma syndrome. DNA was extracted from archival microdissected carcinoma and corresponding normal tissue from 10 British gastric carcinoma patients age 19 to 39 years at the time of diagnosis. A panel of 12 microsatellite loci were amplified by fluorescent polymerase chain reaction and analyzed using an automated DNA sequencer. There was no evidence of microsatellite instability. In contrast, allelic imbalance was recorded at D3S966, D3S1076, D10S197, D11S904, P53, NM23, and DCC microsatellite loci. The authors reported ten cases of early onset gastric carcinoma that demonstrated allelic imbalance but no evidence of instability at microsatellite loci. It is unlikely that defective DNA mismatch repair is important in this group of young patients.

Microsatellite instability at a single locus (D11S988) on chromosome 11p15.5 as a late event in mammary tumorigenesis.

Replication errors at microsatellite repeats are markers for genomic instability in hereditary nonpolyposis colon carcinoma and in some sporadic cancers. Microsatellite sequences may show alterations in one or both alleles in some tumors, suggesting an error in the DNA replication of dinucleotide repeats. We have investigated microsatellite instability (MSI) in sporadic breast tumors at several loci on the short arm of chromosome 11. Among microsatellites studied we found a high frequency of MSI at one specific locus, D11S988 on chromosome 11p15.5. Most colorectal tumors that exhibit MSI display abnormalities of at least one other locus and usually more. By contrast we have detected only one abnormal microsatellite in all the tumors examined. This marker lies between the TH and HBB genes, a subregion previously suggested to harbor a putative tumor suppressor gene for breast cancer. Loss of heterozygosity for chromosome markers at 11p15 has earlier been correlated with poor prognosis. In an unselected panel of primary breast tumors, we observed that 20 of 69 showed mobility shifts of D11S988 in tumor compared with corresponding normal DNA samples. Tumors with instability at D11S988 were rapidly proliferating compared with tumors without MSI. DNA aneuploidy, estrogen receptor positivity and moderate to poorly differentiated tumor phenotype were also characteristics of tumors with MSI at this locus and the majority also exhibited loss of heterozygosity at one or more of the six 11p loci analyzed. Taken together these data suggest that MSI at the D11S988 locus is a late event in mammary tumorigenesis and may be associated with progression of breast carcinomas.