National Cancer Institute®
Last Modified: February 1, 2002
UI - 11743581
AU - Yan H; Dobbie Z; Gruber SB; Markowitz S; Romans K; Giardiello FM;
TI - Kinzler KW; Vogelstein B Small changes in expression affect predisposition to tumorigenesis.
SO - Nat Genet 2002 Jan;30(1):25-6
AD - The Howard Hughes Medical Institute, The Oncology Center, and The Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21231, USA.
We have used quantitative measures of gene expression to show that constitutional 50% decreases in expression of one adenomatous polyposis coli tumor suppressor gene (APC) allele can lead to the development of familial adenomatous polyposis.
UI - 11521793
AU - Olopade OI; Pichert G
TI - Cancer genetics in oncology practice.
SO - Ann Oncol 2001 Jul;12(7):895-908
AD - University of Chicago Pritzker School of Medicine, Illinois, USA. email@example.com
Cancer is a genetic disease caused by the progressive accumulation of mutations in critical genes that control cell growth and differentiation. Completion of the Human Genome Project promises to revolutionize the practice of Medicine, especially Oncology care. The tremendous gains in the knowledge of the structure and function of human genes will surely impact the diagnosis, prognosis and treatment of cancer. Moreover, it will lead to more effective cancer control through the use of genetics to quantify individual cancer risks. This article reviews the current status of genetic testing and counseling for cancer risk assessment and will suggest a framework for integrating such counseling into oncology practice.
UI - 11808944
AU - Matsumoto T; Lida M; Kobori Y; Mizuno M; Nakamura S; Hizawa K; Yao T
TI - Genetic predisposition to clinical manifestations in familial adenomatous polyposis with special reference to duodenal lesions.
SO - Am J Gastroenterol 2002 Jan;97(1):180-5
AD - Department of Endoscopic Diagnostics and Therapeutics, Kyushu University Hospital, Fukuoka, Japan.
OBJECTIVES: In familial adenomatous polyposis (FAP), genetic predisposition for duodenal adenomatosis has not been investigated precisely. The aim of this study was to investigate the correlation between adenomatous polyposis coli (APC) gene mutation and duodenal adenomatosis in FAP. METHODS: APC gene mutation was determined by means of a protein truncation test in 34 patients from 25 families with FAP. The prevalence and grade of duodenal adenomatosis were compared among the proximal mutation group (exons 1-9), the distal mutation group (exons 10-15), and the undetermined groups. The correlation between the course of duodenal adenomatosis and APC gene mutation was retrospectively investigated in 19 patients. RESULTS: The prevalence of duodenal adenomatosis was lower in the proximal mutation group (44%) than in the distal mutation (100%) and undetermined (83%) groups. In patients with positive duodenal adenomatosis, the endoscopic grade did not differ among the groups. The endoscopic grade increased in two of the four patients with the proximal mutation group (50%), in three of 10 patients with the distal mutation group (30%), and in two of five patients (40%) with the undetermined group. CONCLUSIONS: Truncating APC gene mutation proximal to exon 9 may contribute to the less frequent development of duodenal adenomatosis in FAP, but severity and progression of duodenal adenomatosis do not seem to be determined by APC gene mutation alone.
UI - 11771446
AU - Metzger U; Schnider A
TI - Prophylactic surgery in families with familial adenomatous polyposis (FAP) and in colitis.
SO - Swiss Surg 2001;7(6):278-80
AD - Department of Surgery, City-Hospital Triemli, Zurich.
Colorectal cancer is the second most common cause of death from malignant tumors in western countries with approximately 3800 new cases/year in Switzerland. For individuals known to be at high risk for the development of colorectal cancer, screening, chemoprevention and/or prophylactic surgery are the only tools to avoid unnecessary premature death from this disease. With modern molecular and/or genetic testing the risk of developing colorectal cancer can be more precisely estimated on an individualized basis. These individuals need to be enrolled in strong surveillance programs and are clear candidates for prophylactic surgery. The risk of prophylactic surgery (morbidity, mortality, quality of life following surgery) must be clearly weighted against the increasing risk of cancer. These patients should be treated in experienced centers for colorectal surgery in close connection with a genetic testing and counseling team, a molecular laboratory and a psychological support group.
UI - 11754114
AU - Davidson S; Leshanski L; Rennert G; Eidelman S; Amikam D
TI - Maternal mosaicism for a second mutational event--a novel deletion--in a familial adenomatous polyposis family harboring a new germ-line mutation in the alternatively spliced-exon 9 region of APC.
SO - Hum Mutat 2002 Jan;19(1):83-4
AD - Molecular Oncology Laboratory, Rambam Medical Center, Haifa, Israel.
Familial Adenomatous Polyposis (FAP) is an autosomal dominant heritable disorder caused by germ-line mutations in the APC gene. To date, more than 300 germ-line mutations within this gene have been described. Using PCR, SSCP and DNA sequencing, we have identified a new mutation in the alternatively spliced region of exon 9 (1042C-->T), which results in a stop signal. This mutation manifested an aggressive form of FAP with onset of symptoms in one proband at age 17. Our results differ from reported exon 9 mutations in the spliced-out portion of the gene manifesting an attentuated form of FAP (AAPC) [Varesco et al 1994; van der Luijt et al. 1995; Curia et al. 1998; Young et al. 1998]. When analyzing this family, we encountered a mutant FAP gene which had undergone a second mutational event, a deletion. In addition to linkage analysis, both the occurrence of the two exon 9 mutation-carrier siblings, of which one is affected, harboring the same novel deletion in one generation of this family, and its absence in both parents indicates the existence of maternal germ-line mosaicism for cells bearing the latter second mutational event. Our study is only the second report of parental mosaicism in the APC gene. Copyright 2001 Wiley-Liss, Inc.
UI - 11779834
AU - Silverman KA; Koratkar R; Siracusa LD; Buchberg AM
TI - Identification of the modifier of Min 2 (Mom2) locus, a new mutation that influences Apc-induced intestinal neoplasia.
SO - Genome Res 2002 Jan;12(1):88-97
AD - Kimmel Cancer Center, Jefferson Medical College, Philadelphia, Pennsylvania 19107-5541, USA.
Min (Multiple intestinal neoplasia) mice carry a dominant mutation in the adenomatous polyposis coli (Apc) gene and develop multiple adenomas throughout their intestinal tract (Moser et al. 1990; Su et al 1992). Polyp multiplicity in Min mice is greatly influenced by genetic background. A modifier locus, Mom1 (Modifier of Min 1), was identified and localized to distal mouse chromosome 4 (Moser et al. 1992; Dietrich et al. 1993), and accounts for some of the genetic variance in polyp multiplicity. Mom1 is a semidominant modifier of polyp size and multiplicity in Min mice (Gould and Dove 1997), and encodes the secretory type II nonpancreatic phospholipase A2 (Pla2g2a) gene (MacPhee et al. 1995; Cornier et al. 1997, 2000). We now report the identification of a second Modifier of Min 2 (Mom2) locus that is the result of a spontaneous mutation. One resistant Mom2 allele can suppress 88%-95% of polyps detected in Apc(Min)/+ mice, indicating that Mom2 acts in a dominant fashion. Linkage analysis has localized Mom2 to distal mouse chromosome 18. The effects of the Mom2 locus on reducing polyp multiplicity are stronger than the effects of the Mom1 locus, in both the small and large intestines. Some Apc(Min)/+ mice that carried one resistant Mom2 allele were tumor-free at 21 weeks of age, even in the absence of a resistant Mom1 allele. Thus, the resistant Mom2 allele can, in some cases, completely suppress the penetrance of the Apc(Min) mutation.
UI - 11809680
AU - Cheadle JP; Krawczak M; Thomas MW; Hodges AK; Al-Tassan N; Fleming N;
TI - Sampson JR Different combinations of biallelic APC mutation confer different growth advantages in colorectal tumours.
SO - Cancer Res 2002 Jan 15;62(2):363-6
AD - Institute of Medical Genetics, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom.
New facets to Knudsen's "two-hit" hypothesis have been proposed recently in relation to adenomatous polyposis coli (APC): protein inactivation may be selected weakly, and the two hits may be interdependent. We reviewed published data on 165 sporadic and 102 familial adenomatous polyposis-associated colorectal tumors with two characterized mutations. Using a Poisson model, we redefined the mutation cluster region (MCR) to residues 1281-1556 and confirmed that the locations of pairs of APC mutations are interdependent (P < 0.0001). A mathematical model, based on the data for sporadic tumors, implied different growth advantages for different combinations of APC mutations: genotype I/I (I: mutation inside MCR) was 3.9 times more likely to be selected than IO or IL (O: mutation outside MCR, L: allelic loss), which were 27.8 times more likely to be selected than OO or OL.
UI - 10634400
AU - Cetta F; Montalto G; Gori M; Curia MC; Cama A; Olschwang S
TI - Germline mutations of the APC gene in patients with familial adenomatous polyposis-associated thyroid carcinoma: results from a European cooperative study.
SO - J Clin Endocrinol Metab 2000 Jan;85(1):286-92
AD - Interuniversity Center for Research in Hepatobiliary Disease, Institute of Surgical Clinics, University of Siena, Italy.
Papillary thyroid carcinoma (PTC) is one extracolonic manifestation affecting about 1-2% of patients with familial adenomatous polyposis (FAP). Ninety-seven patients with FAP-associated PTC have previously been reported, including 6 pairs of siblings. During a European collaborative study, 15 patients with FAP-associated PTC were collected. All 15 patients were females. The mean age at thyroidectomy was 24.9 yr (range, 19-39 yr). In 13 subjects, APC germline mutations had been detected; they were at codons 140, 593, 778, 976, 993, 1061 (n = 5), 1105 (n = 1), and 1309 (n = 2), respectively. A review of the literature added 11 other patients with FAP-associated PTC and detection of germline APC mutations; they were at codons 313 (n = 2), 698 (n = 3), 848 (n = 2), 1209 (n = 2), 1061 (n = 1), and 1105 (n = 1), respectively. The latter led to formation of the same stop codon (TAA) at 1125-1126 as the mutation at codon 1061. Therefore, 21 of 24 mutations were in exon 15 in the genomic area usually associated with congenital hypertrophy of the retinal pigment epithelium (CHRPE), i.e. codons 463-1387. Typical CHRPE was found in 17 of 18 affected patients who had specific screening. Interestingly, 22 of the 24 patients had their mutation out of the mutation cluster region (codons 1286-1513), which is currently considered the hot spot mutation area, in particular for extracolonic manifestations of FAP. The difference in the incidence of germline mutations before and after codon 1220 between PTC and non-PTC FAP patients was statistically significant (P<0.05) for both patients and kindreds (P = 0.005 and P = 0.049, respectively). Even if most mutations were scattered throughout the entire 5'-portion of exon 15, 8 of 23 patients (6 with mutation at 1061 and 2 with mutation at 1105; i.e. more than one third) had the same truncated protein product. The awareness that patients with PTC usually have APC mutations that cluster in a well defined genomic area, in addition to giving a deeper insight into gene function, could facilitate both earlier diagnosis and better treatment. In particular, intensive screening for thyroid nodules after age 15 yr is recommended when a single patient or an entire kindred have CHRPE and/or mutations in the 5'-portion of exon 15.
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