Table of Contents
1
UI - 21446331
AU - Esplen MJ; Madlensky L; Butler K; McKinnon W; Bapat B; Wong J; Aronson
TI -
M; Gallinger S
Motivations and psychosocial impact of genetic testing for HNPCC.
SO - Am J Med Genet 2001 Sep 15;103(1):9-15
AD - Department of Psychiatry, Faculty of Medicine, University of Toronto,
Toronto, Ontario, Canada. mesplen@mtsinai.on.ca
A type of hereditary colorectal cancer (CRC) known as hereditary
nonpolyposis colorectal cancer (HNPCC) is associated with MLHI and MSH2
gene mutations. This study consists of a pilot, cross-sectional study of
50 individuals who were engaged in the genetic testing process for
HNPCC. The study investigated the motivations and attitudes around
genetic testing and current psychosocial functioning through the use of
standardized measures, as well as obtained information on disclosure
patterns associated with test results. The mean age of the sample was
44.3 years. (SD = 15.0). Twenty-three individuals were identified as
"carriers" (13 had a previous history of CRC), seven were "non-carriers"
and 20 individuals were still awaiting test results. The primary
motivations for participating in genetic testing were similar to
previous reports and included: wanting to know if more screening tests
were needed, obtaining information about the risk for offspring and
increasing certainty around their own risk. The psychosocial scores
demonstrated that a subgroup of individuals exhibited distress, with
greater distress for those individuals awaiting results or testing
positive. There was a high level of satisfaction associated with the
experience of testing. Individuals in this study tended to disclose
their test results to a variety of family and non-family members.
Disclosure was primarily associated with positive experiences however,
some individuals reported regret around disclosure of their results.
These preliminary findings should be further explored in a larger
prospective study design over multiple time points.
2
UI - 21445663
AU - Muller A; Beyser K; Arps H; Bolander S; Becker H; Ruschhoff J
TI -
Genotype and phenotype of a new 2-bp deletion of hMSH2 at codon 233.
SO - Virchows Arch 2001 Aug;439(2):191-5
AD - Department of General Surgery and Human Genetics, University of
Gottingen, Germany. dramueller@aol.com
Germline mutations within mismatch repair genes, such as hMSH2, hMLH1,
and hMSH6, have been shown to be the hallmark of the hereditary
nonpolyposis colorectal cancer (HNPCC) syndrome. The spectrum of tumors
associated with mismatch repair gene defects and the possible
relationship between genotype and phenotype are still unclear.
Therefore, the spectrum of tumors and the possible genotype-phenotype
relationship are still under discussion. Here, we report on a family
with a new germline mutation in the hMSH2 gene with a 2-bp deletion at
codons 232 and 233 leading to a frame shift and a stop at codon 254.
Accordingly, immunohistochemistry revealed loss of hMSH2 expression in
colorectal carcinomas of three affected family members. In this one
family, there was a high penetrance. Interestingly, mutational screening
of the family revealed a high penetrance of the mutation affecting four
of five tested people at risk, with a high mortality rate and a trend
toward lower age of onset in subsequent generations. Finally, a
metachronous breast cancer in one patient turned out to be a tumor
unrelated to microsatellite instability phenocopy, i.e., a sporadic
tumor unrelated to HNPCC that expressed the hMSH2 gene and did not show
any microsatellite instability.
3
UI - 21463150
AU - Percesepe A; Borghi F; Menigatti M; Losi L; Foroni M; Di Gregorio C;
TI -
Rossi G; Pedroni M; Sala E; Vaccina F; Roncucci L; Benatti P; Viel A;
Genuardi M; Marra G; Kristo P; Peltomaki P; Ponz de Leon M
Molecular screening for hereditary nonpolyposis colorectal cancer: a
prospective, population-based study.
SO - J Clin Oncol 2001 Oct 1;19(19):3944-50
AD - Department of Internal Medicine, University of Modena, Modena, Italy.
percesepe.antonio@unimo.it
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.
4
UI - 21266975
AU - Wagner A; Hendriks Y; Meijers-Heijboer EJ; de Leeuw WJ; Morreau H;
TI -
Hofstra R; Tops C; Bik E; Brocker-Vriends AH; van Der Meer C; Lindhout
D; Vasen HF; Breuning MH; Cornelisse CJ; van Krimpen C; Niermeijer MF;
Zwinderman AH; Wijnen J; Fodde R
Atypical HNPCC owing to MSH6 germline mutations: analysis of a large
Dutch pedigree.
SO - J Med Genet 2001 May;38(5):318-22
AD - Department of Clinical Genetics, Erasmus University Rotterdam, The
Netherlands.
Hereditary non-polyposis colorectal cancer (HNPCC) is the most common
genetic susceptibility syndrome for colorectal cancer. HNPCC is most
frequently caused by germline mutations in the DNA mismatch repair (MMR)
genes MSH2 and MLH1. Recently, mutations in another MMR gene, MSH6 (also
known as GTBP), have also been shown to result in HNPCC. Preliminary
data indicate that the phenotype related to MSH6 mutations may differ
from the classical HNPCC caused by defects in MSH2 and MLH1. Here, we
describe an extended Dutch HNPCC family not fulfilling the Amsterdam
criteria II and resulting from a MSH6 mutation. Overall, the penetrance
of colorectal cancer appears to be significantly decreased (p<0.001)
among the MSH6 mutation carriers in this family when compared with MSH2
and MLH1 carriers (32% by the age of 80 v >80%). Endometrial cancer is a
frequent manifestation among female carriers (six out of 13 malignant
tumours). Transitional cell carcinoma of the urinary tract is also
relatively common in both male and female carriers (10% of the
carriers). Moreover, the mean age of onset of both colorectal cancer
(MSH6 v MSH2/MLH1 = 55 years v 44/41 years) and endometrial carcinomas
(MSH6 v MSH2/MLH1 = 55 years v 49/48 years) is delayed. As previously
reported, we confirm that the pattern of microsatellite instability, in
combination with immunohistochemical analysis, can predict the presence
of a MSH6 germline defect. The detailed characterisation of the clinical
phenotype of this kindred contributes to the establishment of
genotype-phenotype correlations in HNPCC owing to mutations in specific
mismatch repair genes.
5
UI - 21330433
AU - Shimizu K
TI -
[Mismatch-repair system and tumorigenesis]
SO - Tanpakushitsu Kakusan Koso 2001 Jun;46(8 Suppl):1130-8
AD - shimke47@md.okayama-u.ac.jp
6
UI - 21322492
AU - Jass JR
TI -
Microsatellite unstable colorectal cancer.
SO - J Clin Pathol 2001 Jul;54(7):573-4
7
UI - 21426337
AU - Cunningham JM; Kim CY; Christensen ER; Tester DJ; Parc Y; Burgart LJ;
TI -
Halling KC; McDonnell SK; Schaid DJ; Walsh Vockley C; Kubly V; Nelson H;
Michels VV; Thibodeau SN
The frequency of hereditary defective mismatch repair in a prospective
series of unselected colorectal carcinomas.
SO - Am J Hum Genet 2001 Oct;69(4):780-90
AD - Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester,
MN 55905, USA.
A comprehensive analysis of somatic and germline mutations related to
DNA mismatch-repair (MMR) genes can clarify the prevalence and mechanism
of inactivation in colorectal carcinoma (CRC). In the present study, 257
unselected patients referred for CRC resection were examined for
evidence of defective DNA MMR. In particular, we sought to determine the
frequency of hereditary defects in DNA MMR in this cohort of patients.
MMR status was assessed by testing of tumors for the presence or absence
of hMLH1, hMSH2, and hMSH6 protein expression and for microsatellite
instability (MSI). Of the 257 patients, 51 (20%) had evidence of
defective MMR, demonstrating high levels of MSI (MSI-H) and an absence
of either hMLH1 (n=48) or hMSH2 (n=3). All three patients lacking hMSH2,
as well as one patient lacking hMLH1, also demonstrated an absence of
hMSH6. DNA sequence analysis of the 51 patients with defective MMR
revealed seven germline mutations-four in hMLH1 (two truncating and two
missense) and three in hMSH2 (all truncating). A detailed family history
was available for 225 of the 257 patients. Of the seven patients with
germline mutations, only three had family histories consistent with
hereditary nonpolyposis colorectal cancer. Of the remaining patients who
had tumors with defective MMR, eight had somatic mutations in hMLH1. In
addition, hypermethylation of the hMLH1 gene promoter was present in 37
(88%) of the 42 hMLH1-negative cases available for study and in all
MSI-H tumors that showed loss of hMLH1 expression but no detectable
hMLH1 mutations. Our results suggest that, although defective DNA MMR
occurs in approximately 20% of unselected patients presenting for CRC
resection, hereditary CRC due to mutations in the MMR pathway account
for only a small proportion of patients. Of the 257 patients, only 5
(1.9%) appear to have unequivocal evidence of hereditary defects in MMR.
The epigenetic (nonhereditary) mechanism of hMLH1 promoter
hypermethylation appears to be responsible for the majority of the
remaining patients whose tumors are characterized by defective DNA MMR.
8
UI - 21467924
AU - Wullenweber HP; Sutter C; Autschbach F; Willeke F; Kienle P; Benner A;
TI -
Bahring J; Kadmon M; Herfarth C; von Knebel Doeberitz M; Gebert J
Evaluation of Bethesda guidelines in relation to microsatellite
instability.
SO - Dis Colon Rectum 2001 Sep;44(9):1281-9
AD - Department of General Surgery, University of Heidelberg, Germany.
PURPOSE: The Bethesda guidelines were developed for selection of
patients whose tumors should be tested for high microsatellite
instability. This study examined the validity of the different Bethesda
criteria in relation to microsatellite instability status to simplify
their use in clinical practice. METHODS: A total of 164 patients with
colorectal or hereditary nonpolyposis colorectal cancer-associated
cancers were registered on the basis of the Amsterdam criteria without
age limitations (11 cases), multiple tumors (2 cases), the accumulation
of colorectal cancer in the family (no first-degree relatives affected
or the index patient's age up to 50 years; 45 cases), an early age at
onset up to 50 years (13 cases), morphologic and histopathologic
manifestations (right-sided colorectal cancer, mucinous undifferentiated
histology; 1 case), and the Bethesda criteria (92 cases). The
microsatellite instability status of tumors was determined using the
International Collaborative Group on Hereditary Non-Polyposis Colorectal
Cancer marker reference panel. RESULTS: When applying all Bethesda
criteria, high microsatellite instability tumors were identified in our
hereditary nonpolyposis colorectal cancer registry with a sensitivity of
87 percent. Twenty-nine percent (27/92) of the Bethesda-positive
patients displayed high microsatellite instability compared with 6
percent of patients (4/72) not meeting these criteria (P < 0.001). Only
Bethesda Criteria 1, 3, and 4 showed a significantly different
distribution of the microsatellite instability status when compared with
those of the remaining patients registered (P < or = 0.001). These three
criteria detected high microsatellite instability tumors in 48 percent
(10/21), 50 percent (18/36), and 31 percent (21/67) of patients,
respectively. When applying these criteria only, a cumulative detection
rate of 77 percent of all (24/31) high microsatellite instability cases
was found, thereby identifying 89 percent of high microsatellite
instability tumors among the Bethesda-positive patients. Patients
matching Criteria 1, 3, and 4 frequently showed hMSH2 or hMLH1 germline
mutations and tumor-specific loss of protein expression. CONCLUSION: In
our hereditary nonpolyposis colorectal cancer registry the complete
Bethesda criteria showed the highest sensitivity to identify patients
with high microsatellite instability tumors. However, for general
medical practice outside academic centers, three criteria are reasonably
accurate for adequate high microsatellite instability tumor selection.
9
UI - 21469633
AU - Nakagawa H; Nuovo GJ; Zervos EE; Martin EW Jr; Salovaara R; Aaltonen LA;
TI -
de la Chapelle A
Age-related hypermethylation of the 5' region of MLH1 in normal colonic
mucosa is associated with microsatellite-unstable colorectal cancer
development.
SO - Cancer Res 2001 Oct 1;61(19):6991-5
AD - Division of Human Cancer Genetics, Comprehensive Cancer Center, The Ohio
State University, Columbus, Ohio 43210, USA.
Hypermethylation of the MLH1 promoter underlies most sporadic colorectal
cancers with microsatellite instability (MSI). To investigate the role
of hypermethylation in the normal colonic mucosa as a possible precursor
lesion, we studied 700 bp upstream of MLH1 covering 51 CpG sites. We
found partially methylated alleles in 15 of 34 (44%) patients <60 years
of age and 20 of 24 (83%) patients > or =80 years of age (P = 0.0026).
Fully methylated alleles were present in 18 of 33 (55%) patients with
MSI+ tumors but in only 18 of 90 (20%) patients with MSI- tumors (P =
0.00019). By in situ analysis, methylation was patchy and located mainly
in the cryptal regions close to the lumen. We conclude that the spread
of methylation in the MLH1 promoter in the normal colonic mucosa is
closely associated with age and the development of sporadic MSI+
colorectal cancers.
10
UI - 21469638
AU - Stella A; Wagner A; Shito K; Lipkin SM; Watson P; Guanti G; Lynch HT;
TI -
Fodde R; Liu B
A nonsense mutation in MLH1 causes exon skipping in three unrelated
HNPCC families.
SO - Cancer Res 2001 Oct 1;61(19):7020-4
AD - University of Pittsburgh Cancer Institute, University of Pittsburgh,
Pittsburgh, Pennsylvania 15213, USA.
Germline mutations in the DNA mismatch repair genes MSH2 and MLH1 are
responsible for the majority of hereditary nonpolyposis colorectal
cancer (HNPCC) families. A common mutation mechanism is to disrupt MLH1
and MSH2 mRNA splicing. The disruption creates aberrant mRNAs lacking
specific coding exons (exon skipping). Here, we report a novel skipping
of MLH1 exon 12 caused by an AAG to TAG nonsense mutation at codon 461
in three HNPCC families of North American origins. The nonsense codon
was found in a conserved haplotype in the three unrelated families and
seems to represent a founder mutation. The skipping created an aberrant
MLH1 mRNA transcript lacking exon 12. The effect of the codon 461
nonsense mutation on exon 12 skipping is evident even though it was
placed in a minigene construct containing entirely different coding
sequences. Notably, the effect of the nonsense mutation on exon skipping
is incomplete. Accordingly, a second aberrant MLH1 transcript
encompassing the nonsense codon is also produced. Whereas the latter
transcript is unstable, presumably because of nonsense-mediated mRNA
decay, neither of the aberrant transcripts seems to affect the stability
of wild-type MLH1 mRNA. This study demonstrates that the germ-line
nonsense mutation at codon 461 of MLH1 disrupts normal MLH1 mRNA
processing, and that exon skipping underlies pathogenesis in these HNPCC
families.
11
UI - 21469647
AU - Sansom OJ; Stark LA; Dunlop MG; Clarke AR
TI -
Suppression of intestinal and mammary neoplasia by lifetime
administration of aspirin in Apc(Min/+) and Apc(Min/+), Msh2(-/-) mice.
SO - Cancer Res 2001 Oct 1;61(19):7060-4
AD - Cardiff School of Biosciences, Cardiff University, Cardiff CF10 3US,
United Kingdom.
Numerous studies have indicated that exposure to nonsteroidal
anti-inflammatory drugs is associated with a lowered risk of colorectal
cancer. However, analyses of the effect of aspirin upon tumorigenesis in
Apc(Min/+) mice have yielded contrasting results. We show that adult
dietary exposure to aspirin does not suppress intestinal tumorigenesis
in Apc(Min/+) mice, but that continual exposure from the point of
conception does. To test whether this regime could suppress the
phenotype of murine models of hereditary nonpolyposis colorectal cancer,
Msh2-deficient mice were exposed to aspirin. This did not modify the
mutator phenotype of Msh2(-/-) mice, but weakly extended survival.
Finally, we analyzed (Apc(Min/+), Msh2(-/-)) mice and found that
lifetime aspirin exposure significantly delayed the onset of both
intestinal and mammary neoplasia. Thus embryonic and perinatal exposure
to aspirin suppresses neoplasia specifically associated with the loss of
Apc function, opening a potential window of opportunity for nonsteroidal
anti-inflammatory drug intervention.
12
UI - 21278632
AU - Caluseriu O; Cordisco EL; Viel A; Majore S; Nascimben R; Pucciarelli S;
TI -
Genuardi M
Four novel MSH2 and MLH1 frameshift mutations and occurrence of a breast
cancer phenocopy in hereditary nonpolyposis colorectal cancer.
SO - Hum Mutat 2001 Jun;17(6):521
AD - Istituto di Genetica Medica, Universita Cattolica del S. Cuore, Rome.
Hereditary nonpolyposis colorectal cancer (HNPCC) is caused by mutations
of genes encoding for proteins of the mismatch repair (MMR) machinery.
The majority of mutations occur in the MLH1 and MSH2 genes, and consist
of splice-site, frameshift and nonsense changes, leading to loss of
protein function. In this study, we screened 7 HNPCC families for
MLH1/MSH2 mutations. Sequence changes were identified in 5 families.
Four alterations were novel 1- or 2-bp deletions or insertions causing a
frameshift and appearance of premature stop codons (MLH1:
c.597-598delGA, c.1520-1521insT; MSH2: c.1444delA, c.119delG). The four
small insertions/ deletions were located within stretches of simple
repeated sequences. By reviewing the HNPCC mutation database, we found
that the majority of 1-2 bp frameshift mutations similarly affects
simple repetitive stretches, pointing to DNA polymerase slippage during
replication as the most likely source of such errors. We also evaluated
microsatellite instability (MSI) in a breast carcinoma (BC) from an MLH1
mutation carrier. While a colon cancer from the same individual showed
MSI, the BC specimen was MSI-negative, indicating that development of
the latter tumor was unrelated to MMR impairment, despite presence of a
constitutional MLH1 mutation. Hum Mutat 17:521, 2001. Copyright 2001
Wiley-Liss, Inc.
13
UI - 21367428
AU - Grandjouan S; Chaussade S
TI -
[From rare to frequent diseases: illustration from digestive tract
oncology]
SO - Ann Med Interne (Paris) 2001 Jun;152(4):243-5
14
UI - 21423764
AU - Paraf F; Gilquin M; Longy M; Gilbert B; Gorry P; Petit B; Labrousse F
TI -
MLH1 and MSH2 protein immunohistochemistry is useful for detection of
hereditary non-polyposis colorectal cancer in young patients.
SO - Histopathology 2001 Sep;39(3):250-8
AD - Service d'Anatomie Pathologique, Centre Hospitalier Regional
Universitaire Dupuytren, Limoges, France. ana.path@chu-limoges.fr
AIMS: Hereditary non-polyposis colorectal cancer is related to germline
mutations of DNA mismatch repair genes MLH1 and MSH2, which result in
microsatellite instability and loss of protein expression of the
corresponding mutated gene in the tumour tissue. METHODS AND RESULTS:
MLH1 and MSH2 protein expression was studied by immunohistochemistry in
paraffin-embedded surgical samples of 100 colorectal adenocarcinomas
occurring before 50 years of age. Absence of tumour cell nuclear
staining with positive internal control (normal mucosa, lymphoid
follicles) was considered negative. Loss of MLH1 or MSH2 expression was
found in 20 cases with microsatellite instability in 15 cases. Twelve of
these patients had a family history of colorectal cancer. Compared with
MLH1- and MSH2-positive cases, MLH1- or MSH2-deficient colorectal
adenocarcinomas were significantly associated on multivariate analysis
with a younger age (38 vs. 43 years, P;0.0224), a larger tumour size (60
+/- 6 vs. 46 +/- 2 mm, P=0.0291), an expanding margin (85% vs. 51%,
P=0.0159), a higher number of tumour-infiltrating lymphocytes assessed
by CD3 immunostaining (202 +/- 48 vs. 33 +/- 4 CD3+ lymphocytes/10
high-power fields, P=0.0039), and a grade 2 Crohn's like lymphoid
reaction (70% vs. 9%, P=0.0037). The two groups were not different for
tumour site, differentiation, pTNM stage, vascular and perineural
invasion, peripheral adenomatous residue, and 5-year survival rates.
CONCLUSIONS: MLH1- or MSH2-deficient colorectal carcinomas of young
patients exhibit pathological and molecular features similar to
hereditary non-polyposis colorectal cancer. This suggests that MLH1 and
MSH2 immunohistochemistry is valuable for detecting hereditary
non-polyposis colorectal cancer in young patients.
15
UI - 21481727
AU - Church J; Lowry A; Simmang C; The Standards Task Force; American Society
TI -
of Colon and Rectal Surgeons
Practice parameters for the identification and testing of patients at
risk for dominantly inherited colorectal cancer--supporting
documentation.
SO - Dis Colon Rectum 2001 Oct;44(10):1404-12
16
UI - 94310427
AU - Nowak R
TI -
Genetic testing set for takeoff.
SO - Science 1994 Jul 22;265(5171):464-7
17
UI - 96200476
AU - Taylor KM; Kelner MJ
TI -
The emerging role of the physician in genetic counselling and testing
for heritable breast, ovarian and colon cancer.
SO - CMAJ 1996 Apr 15;154(8):1155-8
AD - Department of Administrative Studies, York University, North York, Ont.
ktaylor@yorku.ca
As a genetic testing for susceptibility to breast, ovarian and colon
cancer becomes more readily available, physicians are faced with an
increasing demand for information about inherited cancer risk. Because
advances in treatment have not kept pace with advances in predictive
testing, the provision of genetic counselling and testing marks a
departure from the traditional role of the physician. A systematic
framework is needed within which the physician's emerging role in
predictive testing for heritable cancer can be delineated. The
development of such a framework will require collaboration among
professionals in a range of scientific disciplines, as well as the
suspension of traditional assumptions about the physicians role.
18
UI - 99249234
AU - Lerman C; Hughes C; Trock BJ; Myers RE; Main D; Bonney A; Abbaszadegan
TI -
MR; Harty AE; Franklin BA; Lynch JF; Lynch HT
Genetic testing in families with hereditary nonpolyposis colon cancer.
SO - JAMA 1999 May 5;281(17):1618-22
AD - Lombardi Cancer Center, Georgetown University Medical Center,
Washington, DC 20007-4104, USA. Lermanc@gunet.georgetown.edu
CONTEXT: Genetic testing for hereditary nonpolyposis colon cancer
(HNPCC) is available, but the rates of acceptance of testing or barriers
to participation are not known. OBJECTIVE: To investigate rates and
predictors of utilization of genetic testing for HNPCC. DESIGN: Cohort
nonpolyposis colon cancer family registry. PARTICIPANTS: Adult male and
female members (n = 208) of 4 extended HNPCC families contacted for a
baseline telephone interview. INTERVENTIONS: Family education and
individual genetic counseling. MAIN OUTCOME MEASURE: Participant
acceptance of HNPCC test results. RESULTS: Of the 208 family members, 90
(43%) received test results and 118 (57%) declined. Of 139 subjects
(67%) who completed a baseline telephone interview, 84 (60%) received
test results and 55 (40%) declined. Of the 84 subjects who received test
results, 35 (42%) received information indicating that they had
HNPCC-associated mutations and 49 (58%) that they did not. Test
acceptors had higher education levels (odds ratio [OR], 3.74; 95%
confidence interval [CI], 2.49-5.61) and were more likely to have
participated in a previous genetic linkage study (OR, 4.30; 95% CI,
1.84-10.10). The presence of depression symptoms significantly reduced
rates of HNPCC test use (OR, 0.34; 95% CI, 0.17-0.66). Although rates of
test use were identical among men and women, the presence of depression
symptoms resulted in a 4-fold decrease in test use among women (OR,
0.25; 95% CI, 0.08-0.80) and a smaller, nonsignificant reduction among
men (OR, 0.49; 95% CI, 0.19-1.27). CONCLUSIONS: Despite having
significantly elevated risks of developing colon cancer, a relatively
small proportion of HNPCC family members are likely to use genetic
testing. Barriers to test acceptance may include less formal education
and the presence of depression symptoms, especially among women.
Additional research is needed to generalize these findings to different
clinical settings and racially diverse populations.
19
UI - 21063174
AU - Scott RJ; McPhillips M; Meldrum CJ; Fitzgerald PE; Adams K; Spigelman
TI -
AD; du Sart D; Tucker K; Kirk J
Hereditary nonpolyposis colorectal cancer in 95 families: differences
and similarities between mutation-positive and mutation-negative
kindreds.
SO - Am J Hum Genet 2001 Jan;68(1):118-127
AD - Discipline of Medical Genetics, Hunter Area Pathology Service, John
Hunter Hospital, New Lambton, New South Wales, Australia.
rscott@doh.health.nsw.gov.au
Hereditary nonpolyposis colorectal cancer (HNPCC) describes the
condition of a disparate group of families that have in common a
predisposition to colorectal cancer in the absence of a premalignant
phenotype. The genetic basis of this disease has been linked to
mutations in genes associated with DNA mismatch repair. A large
proportion of families harbor changes in one of two genes, hMSH2 and
hMLH1. Approximately 35% of families in which the diagnosis is based on
the Amsterdam criteria do not appear to harbor mutations in
DNA-mismatch-repair genes. In this report we present data from a large
series of families with HNPCC and indicate that there are subtle
differences between families that harbor germline changes in hMSH2 and
families that harbor hMLH1 mutations. Furthermore, there are differences
between the mutation-positive group (hMSH2 and hMLH1 combined) of
families and the mutation-negative group of families. The major findings
identified in this study focus primarily on the extracolonic disease
profile observed between the mutation-positive families and the
mutation-negative families. Breast cancer was not significantly
overrepresented in the hMSH2 mutation-positive group but was
overrepresented in the hMLH1 mutation-positive group and in the
mutation-negative group. Prostate cancer was not overrepresented in the
mutation-positive groups but was overrepresented in the
mutation-negative group. In age at diagnosis of colorectal cancer, there
was no difference between the hMSH2 mutation-positive group and the
hMLH1 mutation-positive group, but there was a significant difference
between these two groups and the mutation-negative group.
20
UI - 21236249
AU - Joint Test and Technology Transfer Committee Working Group, American
TI -
College of Medical Genetics, 9650 Rockville Pike, Bethesda, MD
20814-3998, United States.
Genetic testing for colon cancer: joint statement of the American
College of Medical Genetics and American Society of Human Genetics.
Joint Test and Technology Transfer Committee Working Group.
SO - Genet Med 2000 Nov-Dec;2(6):362-6
21
UI - 21257506
AU - Vasen HF; Morreau H; Nortier JW
TI -
Is breast cancer part of the tumor spectrum of hereditary nonpolyposis
colorectal cancer?
SO - Am J Hum Genet 2001 Jun;68(6):1533-5
22
UI - 21487955
AU - Raedle J; Trojan J; Brieger A; Weber N; Schafer D; Plotz G; Staib-Sebler
TI -
E; Kriener S; Lorenz M; Zeuzem S
Bethesda guidelines: relation to microsatellite instability and MLH1
promoter methylation in patients with colorectal cancer.
SO - Ann Intern Med 2001 Oct 16;135(8 Pt 1):566-76
AD - Second Department of Internal Medicine, Johann Wolfgang
Goethe-University, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main,
Germany. Raedle@em.uni-frankfurt.de
BACKGROUND: Microsatellite instability is a hallmark of mismatch repair
deficiency in hereditary nonpolyposis colorectal cancer and results from
mutations in the mismatch repair genes MLH1 or MSH2 or from gene
inactivation associated with DNA methylation. The Bethesda guidelines
were established to identify patients with colorectal cancer who should
be tested for microsatellite instability. OBJECTIVE: To assess the
Bethesda guidelines for detection of microsatellite instability and to
determine the role of MLH1 promoter methylation in colorectal cancer.
DESIGN: Prospective cohort study. SETTING: Tertiary care referral center
in Frankfurt, Germany. PATIENTS: 125 consecutive patients with
colorectal cancer. MEASUREMENTS: Patients were assessed according to the
Bethesda guidelines, and tumor specimens were analyzed for
microsatellite instability. Patients with microsatellite instability
were tested for MLH1 promoter methylation and MLH1 and MSH2 germline
mutations. RESULTS: Microsatellite instability was detected in 17 of 58
patients who fulfilled and 5 of 67 patients who did not fulfill criteria
of the Bethesda guidelines. In 11 of 17 patients with microsatellite
instability who fulfilled Bethesda guidelines, an MLH1 (n = 3), MSH2 (n
= 7), or combined MLH1 and MSH2 (n = 1) mutation was found. Among the
patients with microsatellite instability who did not fulfill Bethesda
guidelines, no mutations were observed; MLH1 promoter methylation was
observed in 6 of 11 patients with an MLH1 or MSH2 mutation and 5 of 11
patients without an MLH1 or MSH2 mutation. CONCLUSIONS: The Bethesda
guidelines are useful for selecting patients for microsatellite
instability testing. MLH1 and MSH2 testing should be recommended in all
patients with colorectal cancer and microsatellite instability who
fulfill at least one Bethesda criterion. MLH1 promoter methylation may
accompany rather than initiate carcinogenesis in patients with
colorectal cancer who have mismatch repair gene defects.
23
UI - 21487956
AU - Ramsey SD; Clarke L; Etzioni R; Higashi M; Berry K; Urban N
TI -
Cost-effectiveness of microsatellite instability screening as a method
for detecting hereditary nonpolyposis colorectal cancer.
SO - Ann Intern Med 2001 Oct 16;135(8 Pt 1):577-88
AD - Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North
(MP-900), Box 19024, Seattle, WA 98109, USA. sramsey@fhcrc.org
BACKGROUND: The National Cancer Institute has published consensus
guidelines for universal screening for hereditary nonpolyposis
colorectal cancer (HNPCC) in patients with newly diagnosed colorectal
cancer. OBJECTIVE: To determine the cost-effectiveness of screening
compared with standard care in eligible patients with colorectal cancer
and their siblings and children. DESIGN: Cost-effectiveness analysis.
DATA SOURCES: National colorectal cancer registry data, the Creighton
International Hereditary Colorectal Cancer Registry, Medicare claims
records, and published literature. TARGET POPULATION: Patients with
newly diagnosed colorectal cancer and their siblings and children. TIME
HORIZON: Lifetime (varies depending on age at screening). PERSPECTIVE:
Societal. INTERVENTIONS: Initial office-based screening to determine
eligibility (based on personal and family cancer history), followed by
tumor testing for microsatellite instability. Those with microsatellite
instability were offered genetic testing for HNPCC. Siblings and
children of patients with cancer and the HNPCC mutation were offered
genetic testing, and those who were found to carry the mutation received
lifelong colorectal cancer screening. MEASUREMENTS: Life-years gained.
RESULTS OF BASE-CASE ANALYSIS: When only the patients with cancer were
considered, cost-effectiveness of screening was $42 210 per life-year
gained. When patients with cancer and their siblings and children were
considered together, cost-effectiveness increased to $7556 per life-year
gained. RESULTS OF SENSITIVITY ANALYSIS: The model was most sensitive to
the estimated survival gain from screening siblings and children, to the
prevalence of HNPCC mutations among patients with newly diagnosed
cancer, and to the discount rate. In probabilistic analysis, the 90% CI
for the cost-effectiveness of screening patients with cancer plus their
relatives was $4874 to $21 576 per life-year gained. CONCLUSION:
Screening patients with newly diagnosed colorectal cancer for HNPCC is
cost-effective, especially if the benefits to their immediate relatives
are considered.
24
UI - 21488978
AU - Anonymous
TI -
Summaries for patients. Selecting patients with colorectal cancer to
test for genetic abnormalities.
SO - Ann Intern Med 2001 Oct 16;135(8 Pt 1):S-47
25
UI - 21488981
AU - Anonymous
TI -
Summaries for patients. Cost-effectiveness of screening for
microsatellite instability to detect hereditary nonpolyposis colorectal
cancer.
SO - Ann Intern Med 2001 Oct 16;135(8 Pt 1):S-48
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