Inherited Cancer Predisposition Syndrome Research Articles

Diffusion-weighted and dynamic contrast-enhanced imaging as markers of clinical behavior in children with optic pathway glioma

Optic pathway gliomas (OPGs) are common pediatric brain tumors that pose significant clinical challenges with regard to predicting which tumors are likely to become symptomatic and require treatment. These tumors can arise sporadically or in the context of the inherited cancer predisposition syndrome neurofibromatosis type 1 (NF1). Few studies have suggested biological or imaging markers that predict the clinical course of this disease. In this cross-sectional study, we hypothesized that the clinical behavior of OPGs in children can be differentiated by diffusion-weighted (DW) and dynamic contrast-enhanced (DCE) MRI. A total of 27 children with OPG were studied using DW and DCE MRI protocols. Diffusivity and permeability were calculated and correlated with the clinical behavior the OPG. Mean diffusivity values of 1.39 microm2/ms and mean permeability values of 2.10 ml/min per 100 cm3 of tissue were measured. Clinically aggressive OPGs had significantly higher mean permeability values (P = 0.05) than clinically stable tumors. In addition, there was a strong correlation between clinical aggressiveness and the absence of NF1 (P < 0.01). These results suggest that DCE MRI might be a useful biomarker for clinically aggressive OPG, which should be confirmed in larger prospective longitudinal studies.

Psychosocial impact of Peutz-Jeghers Syndrome

Peutz-Jeghers Syndrome (PJS) is an autosomal dominant inherited cancer predisposition syndrome and gastrointestinal hamartomatous polyposis syndrome characterized by the presence of distinct perioral freckling. To date, we have not found any tool that specifically assesses the psychosocial impact of PJS on patients. We developed a PJS quality of life questionnaire using expert opinions of 3 cancer genetic counselors and a survey of patients with PJS through recruitment of participants involved in a support group over the internet. We measured and compared our questionnaire results to the widely used Center for Epidemiologic Studies and Depression Scale (CES-D) and the Short Form 36 (SF-36). We recruited 38 patients for our study. Volunteers were mailed a consent form, the self-administered CES-D, SF-36 and our developed PJS questionnaire and were instructed to return the completed questionnaires by mail. Results showed that PJS patients suffer from mild depression even though physically they did not feel impacted by their condition compared to the general population. However, having PJS caused them to alter many important life decisions. The PJS Questionnaire correlated with data obtained from analysis of CES-D, as well as the SF-36. More uniquely, it provided specific information regarding the burden of disease and quality of life in patients affected with Peutz-Jeghers syndrome. Its ability to do so for other polyposis syndrome populations remains to be studied. These results are important in developing plan of care for these patients regarding genetic counseling and surveillance strategies for PJS patients.

Germline hMSH2 promoter mutation in a Chinese HNPCC kindred: evidence for dual role of LOH

Hereditary non-polyposis colorectal cancer (HNPCC) is a dominantly inherited cancer predisposition syndrome that is caused by germline mutations in mismatch repair genes. By screening the core promoters of hMSH2, hMLH1, and hMSH6 in 37 Chinese suspected HNPCC families, a novel germline mutation c.-78_-79delGT was found in the hMSH2 promoter. Its pathogenic effects were supported by the following findings: (a) it co-segregated with HNPCC-related cancers and was not present in the 220 control subjects, (b) tumors harboring the mutation lacked the expression of hMSH2 and showed high microsatellite instability, (c) it significantly decreased the promoter activity, and (d) it abolished the binding ability of the transcription factor E1A-F. Loss of heterozygosity (LOH) was found in three of the tumors studied. Intriguingly, in the tumors from patients II:1 and III:1, LOH occurred in the wild-type allele and agreed well with the traditional 'two-hit' model. In contrast, in the tumor from patient III:3, LOH occurred in the mutant allele. A pathogenic somatic mutation (c.2210+1G>A) was also found in this tumor; therefore, we proposed that the 'second hit' was inactivated by somatic mutation, and the mutant allele was lost during tumor progression; this provided evidence for the new hypothesis for the dual role of LOH.

Two TP53 germline mutations in a classical Li-Fraumeni syndrome family.

Li-Fraumeni syndrome (LFS) is an autosomal dominantly inherited cancer predisposition syndrome characterized by a combination of tumors including sarcoma, breast cancer, brain tumors, adrenocortical carcinoma and leukemia. Germline mutations in the tumor suppressor gene TP53 are associated with LFS. We present a family with LFS in which initially a novel germline TP53 intron 5 splice site mutation was found. A second germline TP53 mutation, the exon 7 Asn235Ser (704A-->G) mutation, was detected in this family through pre-symptomatic DNA testing. This latter mutation has been reported repeatedly in the literature as a pathogenic mutation involved in LFS. We provide evidence for pathogenicity of the novel intron 5 splice site mutation, whereas this evidence is lacking for the exon 7 Asn235Ser (704A-->G) mutation. Our findings emphasize the importance of performing additional tests in case of germline sequence variants with uncertain functional effects.

Broad tumor spectrum in a mouse model of multiple endocrine neoplasia type 1

Multiple endocrine neoplasia type 1 (MEN1) is an inherited cancer predisposition syndrome typified by development of tumors in parathyroid, pituitary and endocrine pancreas, as well as less common sites including both endocrine and nonendocrine organs. Deletion or mutation of the tumor suppressor gene MEN1 on chromosome 11 has been identified in many cases of MEN1 as well as in sporadic tumors. The molecular biology of menin, the protein encoded by MEN1, remains poorly understood. Here we describe a mouse model of MEN1 in which tumors were seen in pancreatic islets, pituitary, thyroid and parathyroid, adrenal glands, testes and ovaries. The observed tumor spectrum therefore includes types commonly seen in MEN1 patients and additional types. Pancreatic pathology was most common, evident in over 80% of animals, while other tumor types developed with lower frequency and generally later onset. Tumors of multiple endocrine organs were observed frequently, but progression to carcinoma and metastasis were not evident. Tumors in all sites showed loss of heterozygosity at the Men1 locus, though the frequency in testicular tumors was only 36%, indicating that a different molecular mechanism of tumorigenesis occurs in those Leydig tumors that do not show loss of the normal Men1 allele. Menin expression was below the level of detection in ovary, thyroid and testis, but loss of nuclear menin immunoreactivity was observed uniformly in all pancreatic islet adenomas and in some hyperplastic islet cells, suggesting that complete loss of Men1 is a critical point in islet tumor progression in this model.

Endoscopic Surveillance in Hereditary Nonpolyposis Colorectal Cancer

Hereditary nonpolyposis colorectal cancer (HNPCC) is an inherited cancer predisposition syndrome with a greatly increased risk of colorectal cancer and some other cancer types, especially endometrial cancer in women. The predisposition is caused by a pathogenic mutation in one of several DNA mismatch repair genes, eg, MLH1, MSH2, or MSH6. Identification of HNPCC families and successful detection of the specific mutation for the individual family enables predictive genetic testing for the at-risk members in the family. Mutation-negative family members can be relieved from increased cancer risk, whereas mutation-positive members should be enrolled in endoscopic surveillance for prevention or early detection of colorectal cancer. Regular colonoscopies reduce the colorectal cancer incidence to less than half, prevent colorectal cancer deaths, and improve overall survival compared with nonsurveillance. The optimal surveillance interval lies between 1 to 3 years beginning from the age of 25, at the latest. For women, endometrial vacuum biopsies are commonly recommended possibly added by endovaginal ultrasound examination even though firm evidence supporting this is lacking.

Hereditary cancer predisposition in children: Genetic basis and clinical implications

Although cancer predisposition syndromes are rare and malignancies arising in this context account for only 1-10% of childhood tumors, studies performed in affected patients and their families have been of unique value for the understanding of cancer development. Three classes of genes (tumor suppressor genes, oncogenes and stability genes) have been identified and shown to be involved in the pathogenesis of familial, as well as sporadic tumors. Cancer has long been recognized as a genetic disease of somatic cells. Despite improved understanding of the molecular basis of predisposition to cancer and better diagnostic tools, the care of these patients and their families remains a major challenge for the clinician. Medical, psychological, ethical and legal issues have to be considered. This review focuses on examples of each class of inherited cancer predisposition syndromes with special implications for patients in the pediatric age group, including retinoblastoma predisposition, Li-Fraumeni syndrome, multiple endocrine neoplasia disorders and Fanconi anemia. The genetic basis of cancer predisposition is discussed as well as the major concepts and controversies in the clinical management of these patients and their families.

Gene Conversion Is a Frequent Mechanism of Inactivation of the Wild-Type Allele in Cancers from MLH1/MSH2 Deletion Carriers

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominantly inherited cancer predisposition syndrome caused by germ line mutations in DNA mismatch repair genes, predominantly MLH1 and MSH2, with large genomic rearrangements accounting for 5% to 20% of all mutations. Although crucial to the understanding of cancer initiation, little is known about the second, somatic hit in HNPCC tumorigenesis, commonly referred to as loss of heterozygosity. Here, we applied a recently developed method, multiplex ligation-dependent probe amplification, to study MLH1/MSH2 copy number changes in 16 unrelated Swiss HNPCC patients, whose cancers displayed microsatellite instability and loss of MLH1 or MSH2 expression, but in whom no germ line mutation could be detected by conventional screening. The aims of the study were (a) to determine the proportion of large genomic rearrangements among Swiss MLH1/MSH2 mutation carriers and (b) to investigate the frequency and nature of loss of heterozygosity as a second, somatic event, in tumors from MLH1/MSH2 germ line deletion carriers. Large genomic deletions were found to account for 4.3% and 10.7% of MLH1 and MSH2 mutations, respectively. Multiplex ligation-dependent probe amplification analysis of 18 cancer specimens from two independent sets of Swiss and Finnish MLH1/MSH2 deletion carriers revealed that somatic mutations identical to the ones in the germ line occur frequently in colorectal cancers (6 of 11; 55%) and are also present in extracolonic HNPCC-associated tumors. Chromosome-specific marker analysis implies that loss of the wild-type allele predominantly occurs through locus-restricted recombinational events, i.e., gene conversion, rather than mitotic recombination or deletion of the respective gene locus. (Cancer Res 2006; (66)2: 659-64).

Pediatric Adrenal Cortical Carcinoma: Brain Metastases and Relationship to NF-1, Case Reports and Review of the Literature

Adrenal cortical carcinoma (ACC) is a rare childhood neoplasm that seldom manifests brain metastases; hence few papers in the literature focus on neurological manifestations associated with ACC. Although ACC is known to be a signature tumor type in several inherited cancer predisposition syndromes, particularly Li Fraumeni, ACC has not been previously associated with neurofibromatosis, type 1 (NF-1), an inherited disorder with frequent CNS lesions that might prompt concern for metastatic disease by neuroimaging studies. We present two pediatric patients with ACC and unusual CNS findings. The first child developed metastasis to the brain 4 years after resection of his adrenal primary and 2 and 1 years, respectively, after metastases to the liver and lungs. Soon after our experience with this patient, a girl with known NF-1 presented with virilization; adrenalectomy disclosed an ACC and systemic metastases were found within months. Disseminated disease prompted concern that her complex intracranial lesions identified by neuroimaging studies might represent brain metastases, but this proved to be NF1-related hamartomatous lesions. We review the literature on ACCs in pediatric patients regarding brain metastases and previous associations with NF-1.

The TP53 mutational spectrum and frequency of CHEK2*1100delC in Li–Fraumeni-like kindreds

Li-Fraumeni syndrome (LFS) is a dominantly inherited cancer predisposition syndrome characterized by a wide spectrum of neoplasms occurring at young age. Germline mutations in the TP53 tumor suppressor gene have been identified in approximately 71 of LFS patients and 22 of Li-Fraumeni-like (LFL) patients. Mutations within the cell cycle checkpoint gene CHEK2 have also been reported in some patients with LFS, LFL, and phenotypically suggestive of LFS (PS-LFS) not carrying a TP53 mutation. In this study, we show that 7 of the 23 patients with LFS/LFL tested positive for deleterious mutations in p53. Fifteen of the remaining sixteen were not found to carry the CHEK2* 1100delCmutation. These results indicate that CHEK2*1100delC is not a common cause of LFS, LFL, or PS-LFS in North American kindreds not carrying a TP53 mutation. Of note, two patients were found to carry p53* R72P, which is of unknown clinical significance. Lack of segregation of this allele in one of these kindreds provides strong evidence that the R72P allele is not disease-causing. While mutations in p53 account for a proportion of patients with LFS/LFL, future studies are needed to determine if other genes are responsible for LFS/LFL families not carrying germline p53 mutations.

The Hedgehog Signaling Pathway as a Target for Anticancer Drug Discovery

The Hedgehog (Hh) signaling pathway directs the development of multiple tissues during embryonic development, and contributes to tissue homeostasis in adults. Deficient Hh signaling results in defective embryogenesis; conversely, excessive Hh signaling is associated with an inherited cancer predisposition syndrome (Gorlin Syndrome), and a growing list of sporadic human cancers. It is now clear that multiple components of "The Hh Pathway" can be altered in tumors. The Hhs are morphogens that signal through effectors that are largely unprecedented in drug discovery, with many key concepts derived from studies in Drosophila melanogaster. However, studies in tumor cell lines have recently identified targets that can be exploited for the discovery of human Hh antagonists, with additional targets likely to emerge as the human pathway is further defined. Here, we review basic aspects of Hh signal transduction, with an emphasis on molecular targets for drug discovery. The use of first-generation Hh antagonists such as cyclopamine will also be discussed; such agents remain invaluable in ongoing efforts to validate drug discovery assays and survey tumor lines for Hh dependence. The various types and frequencies of Hh signaling defects in different human tumors will also be reviewed, as will the status of medicinal chemistry efforts to discover novel Hh antagonists. In section VI, we review assays from the literature that could be utilized to discover new Hh antagonists for the treatment of cancer.

The Hamartomatous Polyposis Syndromes: A Clinical and Molecular Review

Inherited forms of gastrointestinal cancer have been a major focus of study and advancement over the past decade. Familial adenomatous polyposis and hereditary nonpolyposis colon cancer are the two most common heritable colon cancer syndromes. Inherited polyposis syndromes are characterized by the dominant type of polyp (whether adenomatous or hamartomatous) present and by the polyp's location within the gastrointestinal tract. The hamartomatous polyposis syndromes are characterized by an overgrowth of cells native to the area in which they normally occur. They represent a small but appreciable number of the gastrointestinal inherited cancer predisposition syndromes; it is now known that many of these syndromes carry a substantial risk for developing colon cancer as well as other gastrointestinal and pancreatic cancers. Patients afflicted with these syndromes are also at significant risk for extraintestinal malignancies. Seven inherited hamartomatous polyposis syndromes have been described: familial juvenile polyposis syndrome, Cowden's syndrome, Bannayan-Ruvalcaba-Riley syndrome, Peutz-Jeghers syndrome, basal cell nevus syndrome, neurofibromatosis 1, and multiple endocrine neoplasia syndrome 2B. Hereditary mixed polyposis syndrome is a variant of juvenile polyposis characterized by both hamartomatous and adenomatous polyps. The hamartomatous syndromes occur at approximately 1/10th the frequency of the adenomatous syndromes and account for <1% of colorectal cancer in Northern America. While the diagnosis of these inherited syndromes is primarily clinical, genetic testing is now available for all six syndromes. However, there are a significant number of spontaneous mutations seen in each of the syndromes. The management of these patients necessitates a coordinated multidisciplinary approach. The purpose of this review is to characterize the clinical and pathological features of these syndromes and to review the targets of cancer surveillance. The molecular alterations responsible for the inherited hamartomatous polyposis syndromes will also be discussed.

HMSH2 is the most commonly mutated MMR gene in a cohort of Greek HNPCC patients

Germline mutations in genes encoding proteins involved in DNA mismatch repair are responsible for the autosomal dominantly inherited cancer predisposition syndrome hereditary nonpolyposis colorectal cancer (HNPCC). We describe here analysis of hMLH1 and hMSH2 in nine Greek families referred to our centre for HNPCC. A unique disease-causing mutation has been identified in seven out of nine (78%) families. The types of mutations identified are nonsense (five out of seven) (hMLH1: E557X, R226X; hMSH2: Q158X, R359X and R711X), a 2 bp deletion (hMSH2 1704_1705delAG) and a 2.2 kb Alu-mediated deletion encompassing exon 3 of the hMSH2 gene. The majority of mutations identified in this cohort are found in hMSH2 (77.7%). Furthermore, four of the mutations identified are novel. Finally, a number of novel benign variations were observed in both genes. This is the first report of HNPCC analysis in the Greek population, further underscoring the differences observed in the various geographic populations.

TP53 and CHEK2 *1100delC gene mutation in North American families suggestive Li-Fraumeni syndrome: Memorial Sloan-Kettering experience

9537 Background: Li-Fraumeni syndrome (LFS) is a dominantly inherited cancer predisposition syndrome characterized by a wide spectrum of neoplasms including soft-tissue and bone sarcomas, brain tumors, adrenocortical tumors, breast cancers and leukemia occurring at young age. Germline mutations in the tumor suppressor gene TP53 have been identified in approximately 71% of LFS patients and 22% of Li-Fraumeni like (LFL) patients meeting Eeles's or Birch's criteria. Mutations within the checkpoint gene, CHEK2, encoding a kinase required for cell cycle regulation have also been reported in some patients with LFS/LFL not carrying TP53 mutation. Methods: We conducted a study to explore the possible association between a specific CHEK2*1100delC mutation and LFS/LFL. All patients who were evaluated for LFS/LFL at the Clinical Genetics Service at MSKCC from 1994–2003, who underwent testing for a TP53 mutation, and did not have a deleterious mutation identified were anonymously tested for CHEK2*1100delC. Testing for the CHEK2*1100delC mutation was done by DNA sequencing. Results: A total of 23 patients who underwent TP53 testing were identified. M:F ratio was 6:17. 13% of the patients met LFS criteria, 78% LFL and 9% patients did not meet these criteria. All patients tested had at least one primary malignancy (14 breast, 7 sarcoma, 5 hematological, 4 brain, 3 melanoma and 4 other). Median age at diagnosis of first tumor was 30. 57%, 30% and 9% of patients had a total of 2, 3 and 4 primary malignancies respectively. Overall, TP53 mutations were identified in 7 of 23 patients and variants of unknown clinical significance in 2 patients. TP53 germline mutations were identified in 2 of 3 LFS's and 4 of 18 LFL's patients. 15 of 16 patient who did not have a deleterious TP53 mutation were tested for CHEK2*1100delC. None of these TP53 negative patients were found to harbor CHEK2*1100delC. Conclusions: Our results do not support the causative role of the CHEK2*1100delC mutation in patients with LFS/LFL not carrying a TP53 mutation. No significant financial relationships to disclose.

TP53 and CHEK2 *1100delC gene mutation in North American families suggestive Li-Fraumeni syndrome: Memorial Sloan-Kettering experience

9537 Background: Li-Fraumeni syndrome (LFS) is a dominantly inherited cancer predisposition syndrome characterized by a wide spectrum of neoplasms including soft-tissue and bone sarcomas, brain tum...

Glutathione S-transferase M1 associated with cancer occurrence in Korean HNPCC families carrying the hMLH1/hMSH2 mutation

Hereditary non-polyposis colorectal cancer (HNPCC), an inherited cancer predisposition syndrome, has been associated with germline mutations in DNA mismatch repair (MMR) genes. However, because all mutation carriers of hMLH1/hMSH2 do not account for CRC susceptibility, modifying genes may play a role in the variation of disease expression. In this study, we determined the GSTM1 and GSTT1 genotypes in 104 family members representing 19 Korean HNPCCs carrying hMLH1/hMSH2 mutation, and investigated the influence of GSTM1 and GSTT1 geno-/phenotype status on both age at diagnosis of CRC and cancer occurrence. The overall frequency of the GSTM1 and GSTT1 geno-/phenotype in 55 non-carriers, compared with that in mutation carriers (n=49), was not significantly different, and no significant correlation was found between mean age at diagnosis and the allelomorphs encoding the GSTM1 or GSTT1 enzymes. However, a comparison of the allele frequencies of GSTM1 in affected (n=30) and unaffected (n=19) mutation carriers revealed a significant difference, as the null allele was more prevalent in individuals with cancer (p=0.03; odds ratio, 3.7; 95% confidence interval, 1.1-12.7). Our results suggest that the genotypes of GSTM1 are associated with cancer occurrence in Korean HNPCC family members carrying the hMLH1/hMSH2 mutation. However, a bias due to the small sample size of this study cannot be rule out. Although evidence that GST genotypes are associated with increased cancer risk has often been controversial, the genotyping of GSTM1 could have implications for genetic counseling and the management of MMR gene mutation carriers.

Genetic and cellular defects contributing to benign tumor formation in neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is a common inherited cancer predisposition syndrome. The NF1 gene product, neurofibromin, is hypothesized to function as a tumor suppressor and nearly all NF1 patients develop benign peripheral nerve tumors. These neurofibromas presumably arise from NF1 inactivation in S100(+)Schwann cells, but there is no formal proof for this mechanism. We demonstrate that fibro-blasts isolated from neurofibromas carried at least one normal NF1 allele and expressed both NF1 mRNA and protein, whereas the S100(+)cells typically lacked the NF1 transcript. Our findings further indicate that additional molecular events aside from NF1 inactivation in Schwann cells and/or other neural crest derivatives contribute to neurofibroma formation.

Mouse models in tumor suppression.

Genetic lesions found in tumors are often targeted to the negative growth regulatory tumor suppressor genes. Much of our understanding of tumor suppressor gene function is derived from experimental manipulations in cultured cells. Recently, however, the generation of mice with germ line tumor suppressor gene mutations through gene targeting in embryonic stem cells has provided another dimension by allowing experimental studies of tumor suppressor function in an organismal context. Novel insights into the role of tumor suppressors in development, differentiation, cell cycle control, and tumor suppression have been obtained from the studies on these 'knockout' mice. In addition, such mice may serve as disease models for humans with inherited cancer predisposition syndromes. Perhaps the greatest advantage of many of the mouse tumor suppressor models is that they facilitate study of the roles of tumor suppressor gene loss in tumor initiation and progression in vivo. Moreover, derivation of primary cells from tumor suppressor-deficient mice has provided an important resource for in vitro studies on the role of targeted genes in cell cycle regulation, DNA damage response, regulation of apoptotic pathways, and preservation of genomic stability. In this review, we discuss some of the mechanistic insights provided by tumor suppressor-deficient mice and their utility as models for human cancer syndromes.

Tylosis esophageal cancer locus on chromosome 17q25.1 is commonly deleted in sporadic human esophageal cancer

Background & Aims: Tumor-suppressor genes found in inherited cancer predisposition syndromes are also responsible for sporadic cancers of the same type. Recently, the tylosis oesophageal cancer ( TOC) gene locus has been mapped to 17q25 by linkage analyses of pedigrees with focal nonepidermolytic palmoplantar keratoderma associated with a high risk of esophageal cancer development. The aim of this study was to clarify whether the TOC locus is affected in sporadic esophageal cancers. Methods: We investigated loss of heterozygosity (LOH) on 17q in 58 sporadic esophageal squamous cell carcinomas (ESCs) using 20 microsatellite markers focusing on the TOC locus. Results: LOH on 17q was observed in 37 of 52 (71%) informative cases at one or more loci, 89% (33/37) of which included the TOC locus. The smallest common deleted region was at D17S1839 within the TOC locus. Conclusions: The constructed deletion map revealed that the TOC locus is commonly deleted in sporadic ESCs, suggesting that a tumor-suppressor gene responsible for ESC is contained within this locus. GASTROENTEROLOGY 1998;114:1206-1210

Testing for Inherited Cancer Susceptibility

Testing for inherited cancer predisposition syndromes is becoming ever more widely available. In this transition period, health care professionals from many disciplines will be forced to integrate the rapidly evolving technologies and expanding knowledge base of cancer genetics into their patient care paradigms. They will also find it necessary to consider unfamiliar and complex issues with patients and their families while facing pressures to reduce time per patient visit and referral. See also p 1885. Many thoughtful and qualified lay and professional groups are concerned that the availability of predisposition testing outside the research setting may be premature: critical clinical questions have yet to be answered, clinicians appropriately educated, test characteristics adequately defined, and sufficient social protections put into place. 1-5 The risk of insurance and employment discrimination alone may prevent genetics from realizing its true potential for good. 6 The availability of commercial testing for common cancer susceptibility genes