scholarly journals A Dynamic Family History model Of Hereditary Nonpolyposis Colorectal Cancer and Critical Illness Insurance

2007 ◽  
Vol 2 (2) ◽  
pp. 289-325 ◽  
Author(s):  
L. Lu ◽  
A. S. Macdonald ◽  
H. R. Waters ◽  
F. Yu
Keyword(s):  
Colorectal Cancer ◽  
Critical Illness ◽  
Family History ◽  
Hereditary Nonpolyposis Colorectal Cancer ◽  
Familial Aggregation ◽  
Family History Information ◽  
Dna Mismatch ◽  
Genetic Test Results ◽  
Hereditary Nonpolyposis ◽  
History Of

ABSTRACTHereditary nonpolyposis colorectal cancer (HNPCC) is characterised by the familial aggregation of cancer of the colon and rectum (CRC). It may be caused by any of five mutations in DNA mismatch repair (MMR) genes or by non-genetic factors, such as life style. However, it accounts for only about 2% of CRC, which is a very common cancer. Previous actuarial models, of diseases with only genetic causes, assumed that a family history of the disease shows mutations to be present, but this is not true of HNPCC. This is a significant limitation, since the best information available to an underwriter (especially if the use of genetic test results is banned) is likely to be knowledge of a family history of CRC. We present a Markov model of CRC and HNPCC, which includes the presence of a family history of CRC as a state, and estimate its intensities allowing for MMR genotype. Using this we find the MMR mutation probabilities for an insurance applicant with a family history of CRC. Our model greatly simplifies the intensive computational burden of finding such probabilities by integrating over complex models of hidden family structure. We estimate the costs of critical illness insurance given the applicant's genotype or the presence of a family history. We then consider what the cost of adverse selection might be, if insurers are unable to use genetic tests or family history information. We also consider the effect of using alternative definitions of a family history in underwriting.

Molecular Screening for Hereditary Nonpolyposis Colorectal Cancer: A Prospective, Population-Based Study

2001 ◽  
Vol 19 (19) ◽  
pp. 3944-3950 ◽  
Author(s):  
Antonio Percesepe ◽  
Francesca Borghi ◽  
Mirco Menigatti ◽  
Lorena Losi ◽  
Moira Foroni ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Family History ◽  
Germline Mutation ◽  
Hereditary Nonpolyposis Colorectal Cancer ◽  
Germline Mutations ◽  
Screening Programs ◽  
High Incidence ◽  
Hereditary Nonpolyposis ◽  
Incident Cases ◽  
High Incidence Area

PURPOSE: Germline mutations in mismatch repair genes predispose to hereditary nonpolyposis colorectal cancer (HNPCC). To address effective screening programs, the true incidence of the disease must be known. Previous clinical investigations reported estimates ranging between 0.5% and 13% of all the colorectal cancer (CRC) cases, whereas biomolecular studies in Finland found an incidence of 2% to 2.7% of mutation carriers for the disease. The aim of the present report is to establish the frequency of the disease in a high-incidence area for colon cancer. PATIENTS AND METHODS: Through the data of the local CRC registry, we prospectively collected all cases of CRC from January 1, 1996, through December 31, 1997 (N = 391). Three hundred thirty-six CRC cases (85.9% of the incident cases) were screened for microsatellite instability (MSI) with six to 12 mono- and dinucleotide markers. MSI cases were subjected to MSH2 and MLH1 germline mutation analysis and immunohistochemistry; the methylation of the promoter region was studied for MLH1. RESULTS: Twenty-eight cases (8.3% of the total) showed MSI. MSI cases differed significantly from microsatellite-stable (MSS) cases for their proximal location (P < .01), high mucinous component (P < .01), and poor differentiation (P = .002). Of MSI cases studied (n = 12), only one with a family history compatible with HNPCC had a germline mutation (in MSH2). Five other patients with a family history of HNPCC (two with MSI and three with MSS tumors) did not show germline mutations. CONCLUSION: We conclude that the incidence of molecularly confirmed HNPCC (one [0.3%] of 336) in a high-incidence area for CRC is lower than in previous biomolecular and clinical estimates.

Hereditary Nonpolyposis Colorectal Cancer Syndrome in a Patient With Urothelial Carcinoma of the Upper Urothelial Tract

2003 ◽  
Vol 127 (2) ◽  
pp. e60-e63
Author(s):  
Arndt Hartmann ◽  
John C. Cheville ◽  
Wolfgang Dietmaier ◽  
Ferdinand Hofstädter ◽  
Lawrence J. Burgart ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Urinary Tract ◽  
Urothelial Carcinoma ◽  
Hereditary Nonpolyposis Colorectal Cancer ◽  
Upper Urinary Tract ◽  
Cancer Syndrome ◽  
Tract Cancer ◽  
Hereditary Nonpolyposis ◽  
History Of ◽  
History Of Cancer

Abstract Urothelial carcinoma of the upper urinary tract is relatively uncommon but may develop as a manifestation of the hereditary nonpolyposis colorectal cancer syndrome (HNPCC), which is characterized by mutations in a number of DNA mismatch repair genes and detectable as microsatellite instability or loss of the respective protein by immunostaining. No well-established screening test is available for urothelial carcinomas of the upper urinary tract, and little is known of the clinical impact of screening for HNPCC in patients with upper urinary tract cancer. We describe herein a patient with a urothelial carcinoma of the ureter and a strongly positive history of cancer, who was subsequently found to have HNPCC. Our findings reinforce the importance of obtaining a comprehensive history of cancer in patients with urothelial carcinoma of the renal pelvis and ureter. Subsequent identification of individuals with HNPCC enables the patient and at-risk relatives to benefit from targeted surveillance and management programs.

scholarly journals Muir-Torre Syndrome: The Importance of a Detailed Family History

2019 ◽  
Vol 10 (2) ◽  
pp. 180-185
Author(s):  
Christopher K.H. Burris ◽  
Maria E. Rodriguez ◽  
Meisha L. Raven ◽  
Devasis N. Reddy ◽  
Yaohui G. Xu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Family History ◽  
Hereditary Nonpolyposis Colorectal Cancer ◽  
Autosomal Dominant ◽  
Skin Neoplasms ◽  
Skin Lesions ◽  
Hereditary Nonpolyposis ◽  
Detailed Family History ◽  
Dominant Disease ◽  
Typical Skin

Muir-Torre syndrome, a variant of Lynch syndrome or hereditary nonpolyposis colorectal cancer, is an autosomal dominant disease characterized by skin neoplasms (sebaceous or keratoacanthomas) and visceral malignancies. Due to the rarity of the syndrome there are no firm guidelines on how and when to test patients with its typical skin lesions. We describe a case that highlights the importance of a detailed family history.

scholarly journals Advanced Colon Cancer Before the Age of 20 Years: A Case for Extension of the Current Colonscopy Surveillance Guidelines in Hereditary Nonpolyposis Colorectal Cancer Syndrome

2004 ◽  
Vol 18 (5) ◽  
pp. 319-320 ◽  
Author(s):  
Victor K Wong ◽  
Eric M Yoshida ◽  
Anthony G Ryan ◽  
Stephen GF Ho ◽  
Baljinder Salh
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Hereditary Nonpolyposis Colorectal Cancer ◽  
Pelvic Mass ◽  
Cancer Syndrome ◽  
Advanced Colon Cancer ◽  
Hereditary Nonpolyposis ◽  
History Of ◽  
Current Guidelines ◽  
Colorectal Adenocarcinomas

BACKGROUND:Hereditary nonpolyposis colorectal cancer (HNPCC) currently accounts for between 2% to 6% of all colorectal adenocarcinomas. Controversies exist regarding the current guidelines for colonoscopic screening for colon cancer.CASE REPORT:A case of colon cancer in a young Japanese man with a family history of colon cancer that did not meet the criteria for HNPCC is reported. A malignant pelvic mass discovered shortly before his 20th birthday prompted a colonoscopy. The findings at colonscopy determined that the patient and his family fulfilled the criteria of HNPCC.CONCLUSION:Before finding a pelvic mass metastatic from adenocarcinoma of the ascending colon, this patient was clearly outside of the current guidelines for HNPCC screening. It is suggested that in similar patients, even if they do not fulfill all the criteria for HNPCC, it would be appropriate to consider screening well before the recommended lower age.

scholarly journals Interpretation of Genetic Test Results for Hereditary Nonpolyposis Colorectal Cancer

JAMA ◽  
1999 ◽  
Vol 282 (3) ◽  
pp. 247 ◽  
Author(s):  
Sapna Syngal ◽  
Edward A. Fox ◽  
Christine Li ◽  
Marisa Dovidio ◽  
Charis Eng ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Hereditary Nonpolyposis Colorectal Cancer ◽  
Genetic Test ◽  
Test Results ◽  
Genetic Test Results ◽  
Hereditary Nonpolyposis

An alternative approach to identify women at risk for colorectal cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 1513-1513
Author(s):  
Amanda S. Bruegl ◽  
Bojana Djordjevic ◽  
Shannon Neville Westin ◽  
Pamela T. Soliman ◽  
Amanda C. Brandt ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Family History ◽  
Mismatch Repair ◽  
Dna Mismatch Repair ◽  
Gynecologic Oncology ◽  
Positive Family History ◽  
Dna Mismatch ◽  
Increased Risk ◽  
History Of ◽  
Mlh1 Methylation

1513 Background: Hereditary colorectal cancer (CRC) is preventable; however, identification of individuals at sufficiently high risk to warrant heightened surveillance is difficult. Lynch Syndrome (LS) is an inherited cancer syndrome due to germline mutation in a DNA mismatch repair gene. For women with LS, the lifetime risk of endometrial cancer (EC) is 64% and CRC is 54%. Fifty percent of women with LS will present with EC or ovarian cancer prior to CRC. Therefore, women with LS associated EC represent an ideal group for CRC prevention. The optimal method to identify women with LS associated EC is not known. The purpose of this study was to determine the utility of Amsterdam II and Society of Gynecologic Oncology (SGO) Criteria (modified Bethesda criteria that use EC as the sentinel cancer) in identifying women with LS associated EC. Our ultimate goal is to identify women at increased risk of CRC. Methods: Immunohistochemistry (IHC) for DNA mismatch repair proteins and MLH1 methylation analyses were used to identify LS associated EC among 388 women. EC was designated as LS if there was loss of mismatch repair protein expression. Absence of MLH1 methylation was required to confirm LS in tumors with MLH1 protein loss. Results: Fifty-nine (15.2%) of the EC patients tested had LS. These patients are summarized in the table. Conclusions: Clinical criteria to detect LS identify 17/59 (29%) - 44/59 (74%) of women who present with EC first. EC with MSH2 loss is most likely to occur in younger women and women with positive family history of EC and CRC, features classically associated with LS. In general, the MSH6 mutation is associated with older age at diagnosis and fewer familial CRCs, however, we found a large number of MLH1 (50%) and PMS2 (86%) cases diagnosed at greater than 50 years with no family history of CRC. Our data suggest that classic clinical screening criteria are inadequate to detect patients with LS who present with EC, potentially missing up to 25% of these patients. [Table: see text]

scholarly journals Functional domains of the Saccharomyces cerevisiae Mlh1p and Pms1p DNA mismatch repair proteins and their relevance to human hereditary nonpolyposis colorectal cancer-associated mutations.

1997 ◽  
Vol 17 (8) ◽  
pp. 4465-4473 ◽  
Author(s):  
Q Pang ◽  
T A Prolla ◽  
R M Liskay
Keyword(s):  
Colorectal Cancer ◽  
Saccharomyces Cerevisiae ◽  
Mismatch Repair ◽  
Hereditary Nonpolyposis Colorectal Cancer ◽  
Dna Mismatch Repair ◽  
Functional Domains ◽  
Dna Mismatch ◽  
Amino Terminal ◽  
Enzymatic Function ◽  
Hereditary Nonpolyposis

The MutL protein is an essential component of the Escherichia coli methyl-directed mismatch repair system but has no known enzymatic function. In the yeast Saccharomyces cerevisiae, the MutL equivalent, an Mlh1p and Pms1p heterodimer, interacts with Msh2p bound to mismatch-containing DNA. Little is known of the functional domains of Mlh1p and Pms1p. In this report, we define the Mlh1p and Pms1p domains required for Mlh1p-Pms1p interaction. The Mlh1p-interactive domain of Pms1p is comprised of 260 amino acids near the carboxyl terminus while the Pms1p-interactive domain of Mlh1p resides in the final 212 residues. The two domains are sufficient for Mlh1p-Pms1p interaction, as determined by the two-hybrid assay and by in vitro protein affinity chromatography. Deletions within the domains completely eliminated Mlh1p-Pms1p interaction. Using site-directed mutagenesis, we altered a number of highly conserved residues in the Mlh1p and Pms1p proteins, including some alterations that mimic germline mutations observed for human hereditary nonpolyposis colorectal cancer. Alterations either in the consensus MutL box located in the amino-terminal portion of each protein or in the carboxyl-terminal homology motif of Mlh1p eliminated DNA mismatch repair function but had no effect on Mlh1p-Pms1p interaction. In addition, certain MLH1 and PMS1 mutant alleles caused a dominant negative mutator effect when overexpressed. We discuss the implications of these findings for the structural organization of the Mlh1p and Pms1p proteins and the importance of Mlh1p-Pms1p interaction.

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