Endometrial Cancer as a Familial Tumor: Pathology and Molecular Carcinogenesis (Review)

Some cases of endometrial cancer are associated with a familial tumor and are referred to as hereditary nonpolyposis colorectal cancer (HNPCC or Lynch syndrome). Such tumors are thought to be induced by germline mutation of the DNA mismatch repair (MMR) gene, but many aspects of the pathology of familial endometrial cancer are unclear and no effective screening method has been established. However, the pathology of endometrial cancer with familial tumor has been progressively clarified in recent studies. At present, about 0.5% of all cases of endometrial cancers meet the clinical diagnostic criteria for HNPCC. A recent analysis of the three MMR genes (hMLH1, hMSH2 and hMSH6) revealed germline mutations in 18 of 120 cases (15.0%) of endometrial cancer with familial accumulation of cancer or double cancer, with a frameshift mutation of the hMSH6 gene being the most common. Many cases with mutation did not meet the current clinical diagnostic criteria for HNPCC, indicating that familial endometrial cancer is often not diagnosed as HNPCC. The results suggest that the hMSH6 gene mutation may be important in carcinogenesis in endometrial cancer and germline mutations of the MMR gene may be more prevalent in cases associated with familial accumulation of cancer. An international large-scale muticenter study is required to obtain further information about the pathology of endometrial cancer as a familial tumor.Key Words: HNPCC, Endometrial cancer, DNA mismatch repair gene, hMLH1, hMSH6.     

Familiärer Darmkrebs

Up to 5% of colorectal cancer cases are caused by a monogenic inherited disposition. Among these, hereditary nonpolyposis colorectal cancer (Lynch syndrome, HNPCC) accounts for 2–3% and adenomatous polyposis syndromes (familial adenomatous polyposis, FAP and MUTYH-associated polyposis, MAP) for about 1% of cases. Hamartomatous polyposis syndromes (juvenile polyposis syndrome, Peutz-Jeghers syndrome and Cowden syndrome) are rare disorders that are also associated with an increased colorectal cancer risk. The genetic basis is largely known for the tumour syndromes mentioned above. The identification of the causative germline mutation in the respective DNA repair genes (e.g. in HNPCC and MAP) or tumour suppressor genes (FAP or hamartomatous polyposis syndromes) allows confirmation of the diagnosis in affected individuals and provides predictive diagnostics for their healthy relatives. To achieve a targeted and useful molecular diagnostics, it is important that the clinician provides a detailed characterisation of the clinical picture; moreover, family history may also give a hint of the underlying gene defect. The screening of tumour tissue for the presence of a mismatch repair defect should precede mutation analysis in suspected cases of HNPCC, as it is difficult to differentiate between this condition and sporadic colorectal cancer. In contrast, mutation analysis can be directly performed in polyposis syndromes provided the syndrome has been correctly classified by the histology of polyps.     

Risk reduction and health promotion behaviors following genetic testing for adult-onset disorders

Although clinical genetic testing is available for over 1,000 inherited disorders, consequences of predictive genetic testing have been most extensively examined for hereditary breast and ovarian cancer (HBOC), hereditary colon cancer, and Huntington disease (HD). These focus primarily on psychological, ethical, legal, and social aspects of genetic testing. Genetic testing may also provide information that can lead to behaviors that promote health and reduce risk for disease, reflecting options available for the disorder for which the person is at risk. However, regardless of condition, people completing a genetic test may inform relatives about the results of the test and implications for their risk to develop the condition. Literature on risk reduction behaviors and communication focuses on families with HBOC or colorectal cancer. Few reports document behaviors for other conditions. This paper presents a systematic review of the research literature on risk reduction and health promotion behaviors following clinical genetic testing for adult onset conditions, primarily HBOC, familial colon cancers, and HD. Insights gleaned from this review are discussed as a basis for planning monitoring of health promotion and risk-reduction behaviors for genetic testing for present and future use.     

Screening for an inherited susceptibility to colorectal cancer

The principal Mendelian disorders predisposing to colorectal cancer are familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC). FAP is caused by mutations in the adenomatous polyposis coli (APC) gene. HNPCC is caused by a mutation in one of at least five mismatch repair genes. It is important to identify individuals with these conditions because colon cancer will occur in at least 80% and onset is earlier than in the general population. Potential benefits of identification include improved compliance with recommended surveillance, early detection of polyps, reduction in cancer mortality, and reassurance for relatives found to be negative with attendant savings in the time and expense of surveillance. For classic FAP, the large number of polyps readily identifies affected persons. For HNPCC, identification of individuals meriting DNA sequencing requires either recognition of a suspect family history or finding high microsatellite instability in a tumor. Individuals accepting the offer of genetic counseling and DNA testing often have more cancers in their family, are motivated to inform relatives, have a larger social network, and have more confidence in their coping ability. Individuals who decline are often concerned about their own or their family's emotional reaction or fear discrimination.     

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.     

Genetic predictive testing for bowel cancer predisposition: the impact on the individual.

When considering the impact of a genetic diagnosis of hereditary predisposition to colon cancer, there are many similarities to other predictive genetic tests, but also many differences. The development and availability of such genetic diagnoses, and the concept of testing being linked to effective prevention, have advanced rapidly, opening up not only unique opportunities but also unique psychosocial situations for the affected families-and unusual ethical issues for the professional. Compared to a diagnosis of sporadic colorectal cancer for a patient, hereditary colorectal cancer requires an understanding of genetics, heredity, and the attendant mathematics of risk calculation, but, most importantly, there must be a belief that it is possible to remain healthy whilst having an increased risk. This paper outlines the possible impact of a genetic diagnosis of hereditary non-polyposis colorectal cancer (HNPCC) or familial adenomatous polyposis (FAP) on both the individual and the family and concludes that genetic testing should be accompanied by genetic counseling. Relevant ethical issues are also introduced, with the opinion presented suggesting that if primary considerations are always for the individual rather than the family or society, then unethical or eugenic decisions are likely to be avoided.     

Hereditary nonpolyposis colorectal cancer: causative role of a germline missense mutation in the hMLH1 gene confirmed by the independent occurrence of the same somatic mutation in tumour tissue

Evaluation of the causative role of germline mutations in DNA mismatch repair genes in hereditary nonpolyposis colorectal cancer (HNPCC) families can be difficult. Whereas nonsense, frameshift or splice-site mutations are presumed to lead to dysfunctional gene products and thus are generally considered to be causative, the evaluation of missense mutations often remains uncertain. We observed a novel germline mutation in the hMLH1 gene (His→Pro at codon 329) in an HNPCC family. The same missense mutation also occurred as a somatic event in the colonic tumours of two other HNPCC patients who had germline mutations at different sites of the hMLH1gene. Thus, the H329P mutation present in the germline can be considered as having an aetiological role in this HNPCC family. Received: 1 April 1997 / Accepted: 13 May 1997     

Genetic susceptibility to prostate cancer

Prostate cancer is the most frequent malignant tumor among men over 50 years old. Its incidence varies according to countries and ethnic group. Known risk factors are race and positive family history of the disease. Familial aggregation (at least 2 cases in the family) is observed in about 20% of cases and an hereditary form of prostate cancer in 5%. This proportion increases with younger age at diagnosis. Six putative loci are already identified but undoubtedly, others will be found in forthcoming studies. The genetic heterogeneity observed in hereditary prostate cancer reflects variety of origins of the studied families. In some families, aggregation of prostate cancer and other cancers suggests the involvement of common predisposing genes. In other familial and in sporadic cases, the genetic component should be polygenic: prostate cancer wouldn't result to segregation of a major gene mutations transmitted according to a monogenic inheritance, but rather to sharing of alleles at many loci, each contributing to a small increase in cancer risk. Indeed, several genetic polymorphism were associated with an increased risk of developing prostate cancer and could explain the variations of prostate cancer incidence observed between populations.     

Do MSH6 mutations contribute to double primary cancers of the colorectum and endometrium?

Mismatch repair (MMR) gene mutations cause hereditary nonpolyposis colorectal cancer (HNPCC), a common form of familial colorectal cancer. Among MMR genes, germline MSH6 mutations are often observed in HNPCC-like families with an increased frequency of endometrial cancer. We have previously shown that a proportion of women affected with double primary cancers of the colorectum and endometrium carry germline MSH2 or MLH1 mutations and, thus, belong to HNPCC families. In this study, we have investigated the specific contribution of MSH6 defects to such double primary patients. By sequence analysis of the entire coding region of MSH6, three putative missense mutations were identified in patients with atypical family histories that do not meet HNPCC criteria. Moreover, one of these mutations, a novel substitution Arg901 His, was found in a patient previously shown to carry a truncating germline MLH1 mutation. Thus, MSH6 mutations are likely to contribute to the etiology of double primary cancers of the colorectum and endometrium.     

Determining carrier probabilities for breast cancer-susceptibility genes BRCA1 and BRCA2.

Breast cancer-susceptibility genes BRCA1 and BRCA2 have recently been identified on the human genome. Women who carry a mutation of one of these genes have a greatly increased chance of developing breast and ovarian cancer, and they usually develop the disease at a much younger age, compared with normal individuals. Women can be tested to see whether they are carriers. A woman who undergoes genetic counseling before testing can be told the probabilities that she is a carrier, given her family history. In this paper we develop a model for evaluating the probabilities that a woman is a carrier of a mutation of BRCA1 and BRCA2, on the basis of her family history of breast and ovarian cancer in first- and second-degree relatives. Of special importance are the relationships of the family members with cancer, the ages at onset of the diseases, and the ages of family members who do not have the diseases. This information can be elicited during genetic counseling and prior to genetic testing. The carrier probabilities are obtained from Bayes's rule, by use of family history as the evidence and by use of the mutation prevalences as the prior distribution. In addressing an individual's carrier probabilities, we incorporate uncertainty about some of the key inputs of the model, such as the age-specific incidence of diseases and the overall prevalence of mutations. There is some evidence that other, undiscovered genes may be important in explaining familial breast cancer. Users of the current version of the model should be aware of this limitation. The methodology that we describe can be extended to more than two genes, should data become available about other genes.     

Tumorigenesis in colorectal tumors from patients with hereditary non-polyposis colorectal cancer

Tumorigenesis of colorectal cancer in patients with hereditary non-polyposis colorectal cancer (HNPCC) has been postulated to follow a different pathway from that of sporadic colorectal tumors. A characteristic of HNPCC-associated tumors is the replication error phenotype. We studied tumorigenesis in 8 fresh-frozen and 67 paraffin-embedded colorectal tumors derived from 29 families with HNPCC or a familial aggregation of colorectal cancer. By using intragenic markers, inactivation of the wild-type allele of hMLH1 was shown to occur through loss of heterozygosity and not through a somatic point mutation. Microsatellite instability is very common and occurs early in almost all colorectal tumors from HNPCC patients. Transforming growth factor β type II receptor (TβRII) mutations occur in these tumors at a high frequency. Of colorectal cancers from families with HNPCC, 63% have frameshift mutations in TβRII, compared with 10% of sporadic colorectal cancers. APC and K-RAS mutations appear to be as frequent in the HNPCC tumors as in the sporadic counterpart. Received: 3 March 1997 / Accepted: 23 June 1997     

Hereditary nonpolyposis colorectal cancer families not complying with the Amsterdam criteria show extremely low frequency of mismatch-repair-gene mutations.

Hereditary nonpolyposis colorectal cancer (HNPCC) is a common autosomal dominant cancer-susceptibility condition characterized by early onset colorectal cancer. Germ-line mutations in one of four DNA mismatch repair (MMR) genes, hMSH2, hMLH1, hPMS1, or hPMS2, are known to cause HNPCC. Although many mutations in these genes have been found in HNPCC kindreds complying with the so-called Amsterdam criteria, little is known about the involvement of these genes in families not satisfying these criteria but showing clear-cut familial clustering of colorectal cancer and other cancers. Here, we applied denaturing gradient-gel electrophoresis to screen for hMSH2 and hMLH1 mutations in two sets of HNPCC families, one set comprising families strictly complying with the Amsterdam criteria and another set in which at least one of the criteria was not satisfied. Interestingly, hMSH2 and hMLH1 mutations were found in 49% of the kindreds fully complying with the Amsterdam criteria, whereas a disease-causing mutation could be identified in only 8% of the families in which the criteria were not satisfied fully. In correspondence with these findings, 4 of 6 colorectal tumors from patients belonging to kindreds meeting the criteria showed microsatellite instability, whereas only 3 of 11 tumors from the other set of families demonstrated this instability. Although the number of tumors included in the study admittedly is small, the frequencies of mutations in the MMR genes show obvious differences between the two clinical sets of families. These results also emphasize the practical importance of the Amsterdam criteria, which provide a valid clinical subdivision between families, on the basis of their chance of carrying an hMSH2 or an hMLH1 mutation, and which bear important consequences for genetic testing and counseling and for the management of colorectal cancer families.     

A large family with hereditary MTC: role of RET genetic analysis in differential diagnosis between MEN 2A and FMTC.

Germline mutations of the RET proto-oncogene cause three different cancer syndromes: multiple endocrine neoplasia type 2A (MEN 2A), multiple endocrine neoplasia type 2B (MEN 2B) and familial medullary thyroid carcinoma (FMTC). In the absence of biochemical and/or clinical evidence of pheochromocytoma and hyperparathyroidism, patients with MEN 2A disease display the same phenotype of FMTC disease, although prognosis and clinical management in both affected and unaffected familial members are quite different. We studied a family with hereditary MTC, whose proband was referred to us because of enlarged cervical nodes and increased calcitonin serum levels 28 years after the total thyroidectomy for MTC. Cervical node dissection was carried out and subsequently the presence of MTC metastasis was histologically confirmed. A RET genomic mutation at codon 634 (TGC-->TTC) was identified in the proband and in seven out of 19 familial members studied. Accordingly, a hereditary disease was suggested. However, the strong association of RET mutation at codon 634 with the presence of pheochromocytoma in MEN 2 disease suggested a more rigorous management in all gene carriers. Indeed, during the follow-up pheochromocytoma was subsequently identified in the proband. This finding suggests that all families with a pedigree suggestive of FMTC should be regarded at risk from MEN 2A disease, at least when a critical mutation in the RET cysteine domain is detected.     

Voluntary disclosure of BRCA1 mutation test results

This study assessed the probability that individuals tested for a BRCA1 gene mutation share their test results with family members, co-workers, and insurers. Members of a large kindred known to be at-risk for carrying a BRCA1 gene mutation were tested and they learned their results from a genetic counselor. During a follow-up interview, 4 months later, subjects were asked with whom they had shared their results. Respondents were most likely to have communicated results to family members, followed by co-workers, and insurers. Carrier status affected their willingness to disclose results to insurers. High rates of disclosure to family members should promote awareness of hereditary cancer risk. Selective disclosure to co-workers and insurers may promote information asymmetries that could affect employment and insurance markets.     

Mutational analysis of the hMSH6 gene in familial and early-onset colorectal and endometrial cancer in Israeli patients

Familial colorectal cancer (CRC) is noted in about 15% of incident CRC cases, and at times is hallmarked by an age at diagnosis less than 50 years. Familial adenomatous polyposis (FAP) and hereditary non-polyposis colon cancer (HNPCC) account for about 40% of familial cases. Thus, the majority of familial and early-onset CRC remain genetically elusive. Similarly, the majority of familial and early onset endometrial cancer (EC), the most prevalent extracolonic tumor in HNPCC, are genetically undefined. An attractive candidate is the hMSH6 gene. Israeli patients with early onset (age under 50 years) (n = 44) and familial nonsyndromic (n = 23) CRC, and women with familial clustering of EC or CRC (n = 12), and those diagnosed with EC at, or under, the age of 50 years (n = 5) were genotyped for germ-line mutations within the hMSH6 gene. Exon-specific PCR was followed by denaturing gradient gel electrophoresis (DGGE) analysis, complemented by DNA sequencing of abnormally migrating fragments. No patients displayed a truncating mutation, and 1 CRC patient harbored a novel missense mutation (V878A). In addition, 6 previously described polymorphisms were detected. In conclusion, mutations in the hMSH6 gene occur uncommonly in Israeli patients with familial and early-onset CRC and EC.     

The value of MUTYH testing in patients with early onset microsatellite stable colorectal cancer referred for hereditary nonpolyposis colon cancer syndrome testing

MUTYH adenomatous polyposis (MAP) can mimic both the familial adenomatous polyposis (FAP) and hereditary nonpolyposis colon cancer (HNPCC) phenotypes. As a result of MAP's phenotypic overlap with FAP, some DNA diagnostic laboratories perform MUTYH testing in conjunction with APC testing in patients with suspected FAP or attenuated FAP (AFAP). In addition to testing FAP/AFAP samples for MUTYH mutations, we were interested whether there would also be value in testing samples referred for HNPCC testing. To determine this, we tested a consecutive series of 229 samples referred for HNPCC testing for the two most common MUTYH mutations in the Caucasian population. To enrich our study population with MAP cases, we only included samples from patients with early onset colorectal cancer (CRC diagnosed <50 years old) in whom HNPCC had been excluded by microsatellite instability testing (microsatellite stable or low microsatellite instability). Four biallelic (2%) and six monoallelic (3%) MUTYH mutation carriers were identified. No clinical factors predicted MUTYH mutation status. Specifically, a family history of vertical transmission of CRC or having few polyps (<15) did not rule out the possibility of biallelic MUTYH mutations. Thus, MUTYH mutation testing may be a reasonable cascade test in early onset CRC found to have proficient DNA mismatch repair, regardless of pattern of family history or number of polyps.     

Genetic support groups in the delivery of comprehensive genetic services.

This research sought information about the services provided by genetic support groups, their members' experiences in obtaining genetic and related services, and members' recommendations for improving services. Results from a survey of 43 directors of genetic support groups showed that these organizations not only provide their members with a wide range of informational and supportive services but also address the need for education of both the public and health professionals about genetic disorders. A second survey of 931 members of genetic support groups found that, although they obtained genetic information from a variety of professional and informal sources, many of them experienced barriers to obtaining sufficient genetic information. Respondents called for professionals to improve their interpersonal skills in working with clients and to assist families in obtaining a wider variety of services. On the basis of these findings, a service model and priorities are proposed to bring together genetic specialists, community professionals, and genetic support groups for the delivery of comprehensive services to individuals and families with genetic disorders.     

Attitudes toward genetic testing for cancer risk after genetic counseling and decision support: a qualitative comparison between hereditary cancer types

This study aimed to qualitatively assess individuals' attitudes toward genetic testing for cancer risk after genetic counseling and decision support. As part of a larger study, 78 women considering genetic testing for hereditary breast/ovarian cancer (HBOC) risk and 22 individuals considering genetic testing for hereditary nonpolyposis colorectal cancer (HNPCC) completed an open-ended table of their perceived pros and cons of genetic testing. The most frequently reported pros were "to help manage my risk of developing cancer," "to help my family," and "to know my cancer risk." With regards to risk management, the HBOC group perceived genetic testing as most helpful in informing their general risk management practices, while the HN-PCC group focused on the potential to clarify their need for bowel cancer screening, suggesting that patients' perceptions of the benefits of genetic testing may differ across cancer syndromes. Individuals in both groups expressed concern about the potential psychological impact of genetic testing. We also found that some affected individuals may not fully comprehend the meaning of their potential test results. Eliciting patients' perceived pros and cons during genetic counseling is likely to be a valuable tool for improving patient care. This data also provides an improved evidence base for the development of patient education tools.     

An intronic polymorphism of the hMLH1 gene contributes toward incomplete genetic testing for HNPCC

Hereditary non-polyposis colorectal cancer (HNPCC) is a common hereditary cancer. Genetic testing is complicated by the multiple DNA mismatch repair genes that underlie the disorder. Many suspected HNPCC families have no germ-line mutation identified. We reassessed an unusual family that appeared to have 2 individuals homozygous for a germline mutation within exon 1 of the hMLH1 gene. A few rare individuals with two inherited mutations in one of the mismatch repair genes have been reported and appear to have a distinct clinical appearance. However, there were no clinical features in the family discussed here that were consistent with constitutive lack of hMLH1. Redesigning the intronic primers for exon 1 identified a common polymorphism located within the original intronic primer site. The polymorphism prevented amplification of the wild-type allele, giving the erroneous appearance of homozygous inheritance of the mutated allele. Likewise, common intronic polymorphisms, if located within primer sequences on the chromosome harboring the HNPCC germ-line mutation could restrict amplification to only the wild-type allele, which may contribute significantly to the low success rate of identifying mutations in HNPCC families.     

Mismatch Repair Genes on Chromosomes 2p and 3p Account for a Major Share of Hereditary Nonpolyposis Colorectal Cancer Families Evaluable by Linkage

Two susceptibility loci for hereditary nonpolyposis colo-rectal cancer (HNPCC) have been identified, and each contains a mismatch repair gene: MSH2 on chromosome 2p and MLH1 on chromosome 3p. We studied the involvement of these loci in 13 large HNPCC kindreds originating from three different continents. Six families showed close linkage to the 2p locus, and a heritable mutation of the MSH2 gene was subsequently found in four. The 2p-linked kindreds included a family characterized by the lack of extracolonic manifestations (Lynch I syndrome), as well as two families with cutaneous manifestations typical of the Muir-Torre syndrome. Four families showed evidence for linkage to the 3p locus, and a heritable mutation of the MLH1 gene was later detected in three. One 3p-linked kindred was of Amerindian origin. Of the remaining three families studied for linkage, one showed lod scores compatible with exclusion of both MSH2 and MLH1, while lod scores obtained in the other two families suggested exclusion of one HNPCC locus (MSH2 or MLH1) but were uninformative for markers flanking the other locus. Our results suggest that mismatch repair genes on 2p and 3p account for a major share of HNPCC in kindreds that can be evaluated by linkage analysis.