Original Article
Genetic Analysis of an Inherited Predisposition to Colon Cancer in a Family with a Variable Number of Adenomatous Polyps
N Engl J Med 1990; 322:904-908March 29, 1990
- Abstract
- Abstract
We studied a large kindred with a history of colorectal cancer of early onset. Proctosigmoidoscopic examination of 51 family members identified only 2 with familial polyposis coli, which strongly predisposes those who have it to colorectal cancer and which is defined as the presence of more than 100 polyps in the colon. However, eight family members had 2 to 40 colonic polyps. We suspected that in this family, colorectal cancer was the result of a mutation in the gene on chromosome 5 that is responsible for familial polyposis coli.
To test our hypothesis, we obtained genotypic information on 81 family members with respect to seven polymorphic DNA markers previously shown to be linked to the locus for familial polyposis coli. Multilocus analysis of the data demonstrated genetic linkage (lod score, 5.58) between these markers and the locus responsible for the defined syndrome of colonic polyps or colorectal cancer in this kindred. These findings constitute evidence that the genetic defect in this family is a mutation in the gene that causes familial polyposis coli.
We conclude that mutations at the genetic locus for familial polyposis coli may be the cause of other, more subtle syndromes involving an inherited susceptibility to coIonic adenomatous polyps and colorectal cancer. (N Engl J Med 1990; 322:904–8.)
Media in This Article
Figure 1
Portion of Kindred Evaluated for Linkage Analysis.Figure 2
Genetic Map of the Region of Chromosome 5 Containing the Gene for Familial Adenomatous Polyposis Coli (APC) and Gardner's Syndrome (GS).Article Activity
- Article
COLON carcinoma is the second leading cause of death due to cancer in the United States. Because genetic factors are thought to contribute substantially to the pathogenesis of about 10 percent of cases of colorectal cancer, it is important to understand these genetic components in as much detail as possible. A specific genetic condition, familial adenomatous polyposis coli, occurs in approximately 1 in 8000 persons. If it remains untreated, there is a high probability that adenocarcinoma will develop in the patient at a relatively young age. According to present evidence, the neoplasm arises from a preexisting adenomatous polyp.1 , 2
A diagnosis of adenomatous polyposis coli has been defined by the presence of more than 100 visible adenomatous polyps in the colon by the end of the second or third decade of life; typically, more than 1000 polyps are found.3 Many patients also have numerous polyps of the fundic glands and adenomatous polyps of the duodenum and small bowel. Recently, the gene responsible for adenomatous polyposis coli (the APC gene) was mapped to a region on the long arm of chromosome 5 by means of polymorphic DNA markers.4 , 5
We have characterized a large kindred susceptible to colon cancer, in which the great majority of affected members did not meet the criteria for the diagnosis of familial polyposis, although many had smaller numbers of polyps. We performed genetic linkage studies with DNA markers in the region of the APC locus, with the presumption that an inherited defect at or near this locus was responsible for the clinical phenotype in the kindred we studied.
Methods
Clinical Description of Subjects
A phenotypically distinctive family (Fig. 1Figure 1
Portion of Kindred Evaluated for Linkage Analysis.) was originally identified at the University of Utah Medical Center by Dr. Eldon Gardner on the basis of the occurrence of colon cancer with an early onset and an apparent autosomal dominant pattern of segregation for this trait. We obtained DNA from the peripheral-blood leukocytes of 81 family members from two branches of the pedigree. Informed consent was obtained from all participants. Fifty-one members had been examined clinically over a period of 10 years at the Gastrointestinal Laboratory at the University of Utah or at St. Mark's Hospital by two of the authors. Our initial approach to clinical screening was to examine each patient with a 60-cm flexible proctosigmoidoscope (Olympus CF P10S), followed by full colonoscopy with a fiberoptic endoscope (Olympus CF 1T10L) if distal polyps were present. However, as the familial risk of colon cancer in the kindred became better appreciated, full colonoscopy was used to screen some adult family members. These diagnostic procedures were all performed before or without knowledge of the genotypic characterization and genetic analysis described below. For the genetic study, the results of the examinations of the upper gastrointestinal tract were recorded if available, although systematic examinations of the stomach and duodenum were not a requirement of the study. Pathological reports of the gross and microscopical findings were reviewed at the University of Utah Medical Center by one of the authors, who also reviewed histologic slides obtained for the few participants who were not examined at either medical center. Clinical information concerning dead members of early generations of the kindred was obtained from medical records or death certificates. Ophthalmologic examinations of selected family members, with specific attention to the possibility of hyperplasia in retinal pigment epithelium, were performed in the Department of Ophthalmology at the University of Utah Medical Center.DNA Markers
The seven polymorphic DNA markers used to test for linkage to the APC locus in the kindred have been described in previous mapping studies: pC11p11, which originally localized the gene to chromosome 5q,4 , 5 and six additional markers that constitute a high-resolution linkage map of the region containing the APC defect or defects.6 Four of the markers were haplotyped during the analysis of the subjects because each of these markers revealed two separate site polymorphisms. Two of these polymorphisms were new: an MspI polymorphism for the probe cYN5.48, and a PstI two-allele polymorphism for the probe pMC5.61. The genotypes of the 81 subjects were determined by standard Southern-blot hybridization procedures on nylon membranes.5
Linkage Analysis
The analysis of linkage was carried out with the LINKAGE software package.7 The limited number of subjects from this kindred who were available for study did not warrant formal segregation analysis to infer the mode of inheritance. Rather, the consistent observation of affected members over five generations led us to assume that the mode was autosomal dominant. Furthermore, because adequate information regarding the distribution of adenomatous polyps according to the subjects' ages could not be derived from this phenotypically distinct kindred, separate analyses were performed in which we either assumed a low level of penetrance (0.5) or reclassified all unaffected subjects as of unknown status. The gene frequency of the postulated allele was varied over the range 0.01 to 0.0001. Calculations to estimate the risk or probability of inheritance of a mutant allele at the APC locus were generated by programs within LINKAGE; probabilities above 0.95 were considered to indicate the presence of a defective gene at the APC locus on chromosome 5q, whereas probabilities below 0.05 were considered to indicate two normal homologues of the putative gene. For the purposes of calculating the risk, the gene was assumed to be equidistant from the two flanking marker loci, YN5.64 and YN5.48, in the same interval as the APC gene. The clinical and genotypic data base used for this analysis was contained on a computer disk in LINKAGE format (available from the authors on request).
Results
The two branches of the kindred chosen for study contained 115 members from seven generations. Colon cancer was found in 15 members, 12 of whom died of the disease. Most of these subjects were relatively young at diagnosis, ranging in age from 35 to 77 years; the mean was 54 years, approximately the midpoint between the mean ages at the onset of colorectal cancer related to adenomatous polyposis coli (40 years3) and sporadic cases of colorectal cancer (67 years8). Colon cancer has been documented in four successive generations in this kindred, in a pattern consistent with autosomal dominant inheritance of a gene for susceptibility to colon cancer. Our examination of medical records indicated that several of the members with colon cancer also had a small number of adenomatous polyps; moreover, endoscopic examinations revealed that some asymptomatic members of the kindred had colonic adenomatous polyps. From our assessment of the clinical findings a syndrome was identified that was characterized by a relatively small number of inherited adenomatous colonic polyps —generally fewer than 30 — appearing by the age of 40 and by a susceptibility to early-onset colon cancer.
A wide variation in phenotype was observed among the family members. For example, one member, Subject VI-4 in Figure 1, died of colon cancer when 48, although examination had revealed no visible colonic polyps. Two others, Subjects V-11 and V-24, from different branches of the kindred, had features typical of adenomatous polyposis coli. Analysis of tissue removed by colectomy when these patients were 53 revealed hundreds of polyps in both of them. No other family member met the established criteria for adenomatous polyposis coli; however, five members had multiple gastric polyps and one had a mandibular osteoma (Subject VII-18), a finding usually associated with Gardner's syndrome, a clinically distinct variant of adenomatous polyposis coli. Ophthalmologic examinations of two affected members, Subjects VI-10 and VI-12, showed no evidence of the hypertrophy of retinal pigment epithelium that is occasionally observed in adenomatous polyposis coli and in Gardner's syndrome.
Before linkage analysis could be initiated, disease criteria had to be established for the family. Because members who had a few colonic polyps might not be distinguished from members in whom the presence of adenomatous polyps were an apparently random occurrence, the diagnostic criteria were defined prospectively to minimize the inclusion of members with sporadic adenomas. Family members were considered affected if they met at least one of the following three criteria: the occurrence of colon cancer at any age, the presence of five or more adenomatous polyps, and the presence of two to four colonic adenomatous polyps with either multiple gastric polyps of the fundic glands9 or microadenomas in histologic sections of the colon.3 Findings of either multiple gastric polyps or microadenomas would be unusual in the general population. The clinical findings are summarized in Table 1Table 1
Clinical Phenotypes of the 12 Affected Members of the Kindred for Whom DNA Samples Were Available. for all living affected members of the kindred.Under these restrictive criteria, 12 of the 81 kindred members available for study were classified as affected. Eight of the 12 had fewer than 20 colonic adenomatous polyps, and 6 of these 8 were 35 years of age or older. Forty-one other members who were thought to be at risk of inheriting the mutant allele were also screened for colonic polyps, and none of them met our diagnostic criteria for the disease. These 41 subjects, along with all their living spouses, were initially designated as unaffected for purposes of linkage analysis (Fig. 1). Subjects in the pedigree for whom the results of genotyping with DNA markers but no clinical data were available were classified as of unknown status. We analyzed linkage twice, once using a low level of penetrance (0.5) for all age groups (Table 2Table 2
Pairwise Lod Scores for the Disease Gene and 11 Marker Systems.*) and once reclassifying all unaffected subjects as of unknown status. The pairwise lod scores from both analyses were similar, although the scores calculated from the data on affected subjects alone were slightly lower. Under either assumption of penetrance, DNA marker cYN5.64, when typed for both enzyme systems, yielded a lod score of more than 3; this result remained invariant over a broad range of gene frequencies. It should be noted that a lod score of 3 has greater importance in testing for a single locus than in screening a whole genome against many markers. Moreover, in this family we observed recombinants between the putative gene for the disease and markers known to be on either side of the APC locus on chromosome 5q, placing the hypothesized genetic defect in the kindred in the same region as the APC gene — between the loci defined by cYN5.120 and pMC5.61 (Fig. 2Figure 2Genetic Map of the Region of Chromosome 5 Containing the Gene for Familial Adenomatous Polyposis Coli (APC) and Gardner's Syndrome (GS).). Multilocus analysis, using the nearest flanking markers (cYN5.64 and cYN5.48), extended the support for linkage, with a lod score of 5.58 — an odds ratio of 380,000:1 in favor of linkage of the disease gene to the APC region — when unaffected subjects were included and a penetrance of 0.5 was assumed. When the status of unaffected members was reclassified as unknown —a conservative assumption that would make the inference independent of the level of penetrance — the lod score remained high, at 4.55.Since the results of linkage analysis demonstrated that the defined phenotype of the kindred was a consequence of the inheritance of a defective allele at or near the APC locus, we used the genotypes at the flanking marker loci YN5.64 and YN5.48 as a basis on which to calculate the probability of carrying the mutant APC allele in each of the family members, specifically those at risk who were originally classified as unaffected. Table 3Table 3
Probability of Being a Carrier of Disease Allele among 19 Members Originally Designated as Unaffected. lists the risks calculated for the subjects in this category, both members who were likely to be carriers of the disease allele (P>0.95) and those who apparently were not (P<0.05). Twenty subjects were not included in Table 3 because they were not informative for the two flanking markers and their probabilities were intermediate. In this group, no adenomatous polyps were detected among members for whom information on the phenotype was available.The most striking finding was that all four subjects in whom the probability of carriage of the genetic lesion at the APC locus was greater than 0.95 did in fact have evidence of early colonic polyps, even though they had not met the previously defined diagnostic criteria. Subjects VII-7 and VII-17, both 26 years old, each had only a single adenomatous polyp. The other two subjects also had small numbers of polyps; one (Subject VII-13) had two polyps at age 17, and the other (Subject VI-16) had three polyps by age 34. In contrast, 15 of the 16 subjects predicted to be normal on the basis of analysis of marker genotypes, whose risk probability was less than 0.05, had no visible polypoid lesions when screened by endoscopy. The only subject (V-14) among the noncarriers in whom a single polyp was identified was found to have this feature at an age (49 years) when polyps are more common in the general population. Because 5 of the 12 adults in the low-risk category in Table 3, as well as the 4 subjects in the high-risk group, had been screened initially with full colonoscopy, any bias incurred by our protocol for screening would only be toward underascertainment of polyps among subjects at low risk.
Discussion
The clinical features among the members of kindred 353 who had the syndrome of inherited polyps varied widely, from members with colon cancer but no colonic polyps, to members with only a few polyps, to members with hundreds. Our linkage studies show that the genetic defect responsible for the predisposition to polyps and cancers of the colon in this kindred is located on the long arm of chromosome 5 at or very near the site of the mutation responsible for familial adenomatous polyposis coli. However, the mutation found in this study seems to differ from the mutant alleles responsible for adenomatous polyposis as it has previously been understood, in that subjects who inherited the responsible allele generally had a very moderate number of polyps. A diversity of APC alleles is a reasonable supposition, because new mutations are relatively frequent in familial adenomatous polyposis coli3 and because both the typical form of this disease and Gardner's syndrome are known to result from mutations at this same locus.6 Furthermore, the number of polyps developing in persons inheriting the defective allele can range from 1 or a few to more than 100. The wide variation in expression might be explained by the influence of other genes or by environmental differences. The findings also suggest the possibility that the APC gene is involved in other, as yet untested families prone to colon cancer in which typical polyposis is absent. Recently, in a few families classified as having colon cancer unrelated to polyposis, some members were found to have a small number (2 to 70) of adenomatous polyps.10 , 11
Furthermore, the apparently familial nature of common colorectal cancer, together with recent work suggesting that colon cancer in general may often be due to a genetic predisposition to the development of small numbers of polyps,12 leads us to speculate that this hypothesized genetic predisposition may ultimately be due in part to alleles at the APC locus that have even lower phenotypic expressivity than the mutation in the kindred described here. Such alleles may perhaps predispose a person to the development of an average of 2 to 5 polyps rather than the 30 to 40 that are characteristic of the kindred. This speculative hypothesis can be tested by linkage analysis using the highly informative set of DNA markers available for the APC locus.
On the other hand, the inherited mutation in some families susceptible to colon cancer could lie at loci other than APC — for example, at loci involved in tumor progression, such as the p53 locus on chromosome 17, or at loci on chromosome 18q.13 , 14 One published study reported linkage to the Kidd locus on chromosome 18 in a group of families with colorectal cancer unrelated to polyposis; however, the exclusion of two families with neoplasms that were not colon cancers from the analysis was not supported by formal tests for genetic heterogeneity.15
It is unlikely, however, that all cases of colon cancer are associated with an inherited predisposition. A common genetic causation can be maintained by somatic mutation of the same gene that is inherited in mutant form in the families of kindred 353 and in families with adenomatous polyposis coli. Such a phenomenon has been observed in cases of inherited and sporadic forms of retinoblastoma.16
Knowledge of the genotype for markers linked to the APC locus can often permit the inference of gene-carrier status among members of the kindred. This is important because members found to lack the disease allele will not need frequent clinical surveillance and will be freed from anxiety about the risk to their offspring. Members who do carry the disease genotype can be monitored more aggressively.
The wide range of phenotypic presentation associated with inheritance of the mutant APC allele may, however, have complex implications for caring for patients and counseling the members of the kindred. It is possible, for example, that members who inherit the mutant allele but have only one or a few polyps might be at relatively low risk for the development of colon cancer, as compared with other family members who have many polyps. Polypectomy might be an adequate intervention; colectomy could be postponed or might even be unnecessary if polyps are few. However, it should be noted that carcinoma was found in Subject VI-4, who had no polyps. Definitive therapeutic recommendations will require a more precise description of the prognosis in family members, as a function of their age and number of polyps.
Furthermore (and with relevance to other families), if the subjects with only a few adenomatous polyps had been examined outside the context of a large family study, these patients and their family members might not have been recognized as gene carriers with a predisposition to polyp formation and an increased risk of colon cancer. Without the statistical power provided by a large kindred, it is often difficult to determine in individual patients whether their several polyps are due to an inherited genetic lesion or to somatic mutation. It is therefore important that the APC gene be identified, cloned, and sequenced; we will then have a basis for the direct determination of molecular lesions in the APC genes of such patients.
Drs. Lalouel and White are Investigators at the Howard Hughes Medical Institute.
*Deceased (emeritus professor of biology, Utah State University, Logan, Utah).
We are indebted to Dr. Mano Swartz for performing the ophthalmologic examinations of the patients in the kindred, to Barbara Ogden, Tena Sears, and Dora Stauffer for technical assistance, to Rick Lifton for critically reading the manuscript, to Ruth Foltz for editing the manuscript, and to Diane Christopherson for compiling the pedigree information.
Source Information
From the Howard Hughes Medical Institute and the Department of Human Genetics (M.L., Y.N., S.W., J.-M.L., R.W.), the Gastroenterology Division, Department of Medicine (R.B.), and the Department of Pathology (W.S.), University of Utah School of Medicine, Salt Lake City; and St. Mark's Hospital (J.P.H.), Salt Lake City. Address reprint requests to Dr. Leppert at the Howard Hughes Medical Institute, 603 Wintrobe Bldg., University of Utah Health Sciences Center, Salt Lake City, UT 84132.
- References
References
1
Muto
CrossRef | Web of Science | Medline2
Burt
Web of Science | Medline3
Bussey HJR. Familial polyposis coli: family studies, histopathology, differential diagnosis, and results of treatment. Baltimore: Johns Hopkins University Press, 1975.
4
Bodmer
CrossRef | Web of Science | Medline5
Leppert
CrossRef | Web of Science | Medline6
Nakamura
Web of Science | Medline7
Lathrop
Web of Science | Medline8
Cancer in Utah (1967–1977). Report no. 3. Salt Lake City: Utah Cancer Registry, 1979.
9
Iida
Web of Science | Medline10
Lynch
CrossRef | Web of Science | Medline11
Lanspa
Web of Science12
Cannon-Albright
Full Text | Web of Science | Medline13
Baker
CrossRef | Web of Science | Medline14
Vogelstein
Full Text | Web of Science | Medline15
Lynch
CrossRef | Web of Science | Medline16
Cavenee
CrossRef | Web of Science | Medline
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1
A. Roessner, D. Kuester, T. Guenther. (2011) Kolorektale Polyposen. Der Pathologe 32:4, 303-313
CrossRef2
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Mark M. Pomerantz, Matthew L. Freedman. (2011) The Genetics of Cancer Risk. The Cancer Journal 17:6, 416-422
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CrossRef5
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CrossRef6
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CrossRef7
Neal R. Swerdlow, Martin Weber, Ying Qu, Gregory A. Light, David L. Braff. (2008) Realistic expectations of prepulse inhibition in translational models for schizophrenia research. Psychopharmacology 199:3, 331-388
CrossRef8
Deborah W. Neklason, Jeffery Stevens, Kenneth M. Boucher, Richard A. Kerber, Nori Matsunami, Jahn Barlow, Geraldine Mineau, Mark F. Leppert, Randall W. Burt. (2008) American Founder Mutation for Attenuated Familial Adenomatous Polyposis. Clinical Gastroenterology and Hepatology 6:1, 46-52
CrossRef9
Jeremy R. Jass. (2007) Gastrointestinal Polyposes: Clinical, Pathological and Molecular Features. Gastroenterology Clinics of North America 36:4, 927-946
CrossRef10
EUI JIN LEE, CHEOL KEUN PARK, JONG-WON KIM, DONG KYUNG CHANG, KYOUNG-MEE KIM. (2007) Deletion mutation of BRAF in a serrated adenoma from a patient with familial adenomatous polyposis. APMIS 115:8, 982-986
CrossRef11
A. Plawski, D. Nowakowska, M. Podralska, D. Lipinski, J. Steffen, R. Slomski. (2007) The AAPC case, with an early onset of colorectal cancer. International Journal of Colorectal Disease 22:4, 449-451
CrossRef12
Ritsuko Yanaru-Fujisawa, Takayuki Matsumoto, Yoji Kukita, Shotaro Nakamura, Takashi Yao, Kenshi Hayashi, Mitsuo Iida. (2007) Impact of Phospholipase A2 Group IIa Gene Polymorphism on Phenotypic Features of Patients with Familial Adenomatous Polyposis. Diseases of the Colon & Rectum 50:2, 223-231
CrossRef13
Rosa Valanzano, Ferdinando Ficari, Maria Cristina Curia, Gitana Aceto, Serena Veschi, Alessandro Cama, Pasquale Battista, Francesco Tonelli. (2007) Balance between endoscopic and genetic information in the choice of ileorectal anastomosis for familial adenomatous polyposis. Journal of Surgical Oncology 95:1, 28-33
CrossRef14
A Jablensky. (2006) Subtyping schizophrenia: implications for genetic research. Molecular Psychiatry 11:9, 815-836
CrossRef15
Marie Luise Bisgaard, Steffen Bülow. (2006) Familial adenomatous polyposis (FAP): Genotype correlation to FAP phenotype with osteomas and sebaceous cysts. American Journal of Medical Genetics Part A 140A:3, 200-204
CrossRef16
Patrick M. Lynch. (2005) Cancer screening guidelines and prevention factors for high-risk patients with a family history of colorectal cancer. Current Colorectal Cancer Reports 1:2, 110-116
CrossRef17
C. Richard Boland. (2005) Evolution of the Nomenclature for the Hereditary Colorectal Cancer Syndromes. Familial Cancer 4:3, 211-218
CrossRef18
Christodoulos S Flordellis. (2005) The emergence of a new paradigm of pharmacogenomics. Pharmacogenomics 6:5, 515-526
CrossRef19
N. Penel, C. Berthon, A. Kara, L. Vanseymortier, A. Adenis. (2005) Association sarcome des tissus mous et polypose adénomateuse familiale : à propos d'un cas. La Revue de Médecine Interne 26:7, 596-597
CrossRef20
Wolfgang M. Brueckl, Wolfgang G. Ballhausen, Thomas Förtsch, Klaus Günther, Wolfgang Fiedler, Bernhard Gentner, Roland Croner, Frank Boxberger, Thomas Kirchner, Eckhart G. Hahn, Werner Hohenberger, Axel Wein. (2005) Genetic Testing for Germline Mutations of the APC Gene in Patients With Apparently Sporadic Desmoid Tumors but a Family History of Colorectal Carcinoma. Diseases of the Colon & Rectum 48:6, 1275-1281
CrossRef21
Anders Merg, Henry T. Lynch, Jane F. Lynch, James R. Howe. (2005) Hereditary colon cancer—Part I. Current Problems in Surgery 42:4, 195-256
CrossRef22
Mitchell S. Cappell. (2005) The pathophysiology, clinical presentation, and diagnosis of colon cancer and adenomatous polyps. Medical Clinics of North America 89:1, 1-42
CrossRef23
Elena Sancho, Eduard Batlle, Hans Clevers. (2004) SIGNALING PATHWAYS IN INTESTINAL DEVELOPMENT AND CANCER. Annual Review of Cell and Developmental Biology 20:1, 695-723
CrossRef24
Henry T. Lynch, Trudy G. Shaw, Jane F. Lynch. (2004) Inherited predisposition to cancer: A historical overview. American Journal of Medical Genetics 129C:1, 5-22
CrossRef25
Randall W. Burt, Mark F. Leppert, Martha L. Slattery, Wade S. Samowitz, Lisa N. Spirio, Richard A. Kerber, Scott K. Kuwada, Deborah W. Neklason, James A. DiSario, Elaine Lyon, J.Preston Hughes, William Y. Chey, Raymond L. White. (2004) Genetic testing and phenotype in a large kindred with attenuated familial adenomatous polyposis. Gastroenterology 127:2, 444-451
CrossRef26
Randall W Burt. (2003) Gastric fundic gland polyps. Gastroenterology 125:5, 1462-1469
CrossRef27
David H Robbins, Steven H Itzkowitz. (2002) The molecular and genetic basis of colon cancer. Medical Clinics of North America 86:6, 1467-1495
CrossRef28
Mitchell S Cappell, David Friedel. (2002) The role of sigmoidoscopy and colonoscopy in the diagnosis and management of lower gastrointestinal disorders: endoscopic findings, therapy, and complications. Medical Clinics of North America 86:6, 1253-1288
CrossRef29
Toshinari Minamoto, Ze'ev Ronai. (2001) Gene mutation as a target for early detection in cancer diagnosis. Critical Reviews in Oncology/Hematology 40:3, 195-213
CrossRef30
Robert Freedman, C.E. Adams, Lawrence E. Adler, Paula C. Bickford, Judith Gault, Josette G. Harris, Herbert T. Nagamoto, Ann Olincy, Randal G. Ross, Karen E. Stevens, Merilyne Waldo, Sherry Leonard. (2001) Inhibitory neurophysiological deficit as a phenotype for genetic investigation of schizophrenia. American Journal of Medical Genetics 97:1, 58-64
CrossRef31
Rakefet Shtoyerman-Chen, Eitan Friedman, Arie Figer, Miri Carmel, Yael Patael, Peter Rath, Herma H. Fidder, Simon Bar-Meir, Livia Theodor. (2001) The I1307K APC Polymorphism: Prevalence in Non-Ashkenazi Jews and Evidence for a Founder Effect. Genetic Testing 5:2, 141-146
CrossRef32
Annika Lindblom. (2001) Different mechanisms in the tumorigenesis of proximal and distal colon cancers. Current Opinion in Oncology 13:1, 63-69
CrossRef33
Lauri A Aaltonen. (2000) Hereditary intestinal cancer. Seminars in Cancer Biology 10:4, 289-298
CrossRef34
Thomas J. McGarrity, Francesca M. Ruggiero, William Y. Chey, Rajesh Bajaj, J. Edward Kelly, Gordon L. Kauffman. (2000) Giant fundic polyp complicating attenuated familial adenomatous polyposis. The American Journal of Gastroenterology 95:7, 1824-1828
CrossRef35
Geeta Lal, Steven Gallinger. (2000) Familial adenomatous polyposis. Seminars in Surgical Oncology 18:4, 314-323
CrossRef36
Gloria M. Petersen, Jill D. Brensinger, Karen A. Johnson, Francis M. Giardiello. (1999) Genetic testing and counseling for hereditary forms of colorectal cancer. Cancer 86:S11, 2540-2550
CrossRef37
Gloria M. Petersen, Jill D. Brensinger, Karen A. Johnson, Francis M. Giardiello. (1999) Genetic testing and counseling for hereditary forms of colorectal cancer. Cancer 86:S8, 1720-1730
CrossRef38
Robert T. Pilarski, Arthur R. Brothman, Peter Benn, Sally Shulman Rosengren. (1999) Attenuated familial adenomatous polyposis in a man with an interstitial deletion of chromosome arm 5q. American Journal of Medical Genetics 86:4, 321-324
CrossRef39
Wolfgang T. Hofgartner, Micah Thorp, Mark W. Ramus, Guy Delorefice, William Y. Chey, Charlotte K. Ryan, Garry W. Takahashi, John R. Lobitz. (1999) Gastric adenocarcinoma associated with fundic gland polyps in a patient with attenuated familial adenomatous polyposis. The American Journal of Gastroenterology 94:8, 2275-2281
CrossRef40
Robert K. Montgomery, Andrew E. Mulberg, Richard J. Grand. (1999) Development of the human gastrointestinal tract: Twenty years of progress. Gastroenterology 116:3, 702-731
CrossRef41
Claudio Soravia, Terri Berk, Lisa Madlensky, Angela Mitri, Hong Cheng, Steven Gallinger, Zane Cohen, Bharati Bapat. (1998) Genotype-Phenotype Correlations in Attenuated Adenomatous Polyposis Coli. The American Journal of Human Genetics 62:6, 1290-1301
CrossRef42
Oliver Müller, Inko Nimmrich, Ulrich Finke, Waltraut Friedl, Ingrid Hoffmann. (1998) A β-catenin mutation in a sporadic colorectal tumor of the RER phenotype and absence of β-catenin germline mutations in FAP patients. Genes, Chromosomes and Cancer 22:1, 37-41
CrossRef43
Morton S. Kahlenberg, Daniel L. Stoler, Nicholas J. Petrelli, Miguel Rodriguez-Bigas, Thomas K. Weber, Garth R. Anderson. (1998) Absence of frequent involvement of modifier of MinAPC in sporadic colorectal cancer. Annals of Surgical Oncology 5:2, 181-185
CrossRef44
Joanne Young, Lisa A. Simms, Jabbar Tarish, Ron Buttenshaw, Ngaire Knight, Gregory J. Anderson, Andrew Bell, Barbara Leggett. (1998) A family with attenuated familial adenomatous polyposis due to a mutation in the alternatively spliced region of APC exon 9. Human Mutation 11:6, 450-455
CrossRef45
JEFFREY T. HOLT. (1997) Breast Cancer Genes: Therapeutic Strategies. Annals of the New York Academy of Sciences 833:1 Cancer, 34-41
CrossRef46
Alex R Shoemaker, Karen A Gould, Cindy Luongo, Amy R Moser, William F Dove. (1997) Studies of neoplasia in the Min mouse1C57BL/6J Min/+ mice are available worldwide from The Jackson Laboratory, Bar Harbor, ME 04609, USA.1. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer 1332:2, F25-F48
CrossRef47
Kan Yang, Winfried Edelmann, Kunhua Fan, Kirkland Lau, Venkateswara R. Kolli, Riccardo Fodde, P. Meera Khan, Raju Kucherlapati, Martin Lipkin. (1997) A mouse model of human familial adenomatous polyposis. The Journal of Experimental Zoology 277:3, 245-254
CrossRef48
Tyler Jacks. (1996) TUMOR SUPPRESSOR GENE MUTATIONS IN MICE. Annual Review of Genetics 30:1, 603-636
CrossRef49
Robert P. Erickson. (1996) Mouse models of human genetic disease: Which mouse is more like a man?. BioEssays 18:12, 993-998
CrossRef50
Bart O. Williams, Tyler Jacks. (1996) Mechanisms of carcinogenesis and the mutant mouse. Current Opinion in Genetics & Development 6:1, 65-70
CrossRef51
John D. Potter. (1996) Nutrition and colorectal cancer. Cancer Causes and Control 7:1, 127-146
CrossRef52
Kim M. Summers. (1996) Relationship between genotype and phenotype in monogenic diseases: Relevance to polygenic diseases. Human Mutation 7:4, 283-293
CrossRef53
Jose A. Bufill. (1995) Colorectal cancer genetics. Closing the gap between genotype and phenotype. Cancer 76:12, 2389-2392
CrossRef54
Henry T. Lynch, Thomas Smyrk, Thomas McGinn, Stephen Lanspa, Jennifer Cavalieri, Jane Lynch, Susan Slominski-Castor, Matthew C. Cayouette, Ira Priluck, Michael C. Luce. (1995) Attenuated familial adenomatous polyposis (AFAP) a phenotypically and genotypically distinctive variant of FAP. Cancer 76:12, 2427-2433
CrossRef55
Franco Bazzoli, Stefania Fossi, Sandra Sottili, Paolo Pozzato, Rocco M. Zagari, Maria C. Morelli, Francesco Taroni, Enrico Roda. (1995) The risk of adenomatous polyps in asymptomatic first-degree relatives of persons with colon cancer. Gastroenterology 109:3, 783-788
CrossRef56
Sonia Pellizzer. (1995) Congenital hypertrophy of the retinal pigment epithelium associated with familial adenomatous polyposis. Clinical and Experimental Optometry 78:4, 135-137
CrossRef57
(1995) Gastrointestinal Polyposis and Nonpolyposis Syndromes. New England Journal of Medicine 332:22, 1518-1520
Full Text58
Melina MacPhee, Kenneth P Chepenik, Rebecca A Liddell, Kelly K Nelson, Linda D Siracusa, Arthur M Buchberg. (1995) The secretory phospholipase A2 gene is a candidate for the Mom1 locus, a major modifier of ApcMin-induced intestinal neoplasia. Cell 81:6, 957-966
CrossRef59
Wade S Samowitz, Randall L Burt. (1995) The nonspecificity of histological findings reported for flat adenomas. Human Pathology 26:5, 571-573
CrossRef60
Arthur H. Bertelsen, Gary A. Beaudry, Timothy J. Stoller, Paul P. Trotta, Michael I. Sherman. (1995) Tumor Suppressor Genes: Prospects for Cancer Therapies. Bio/Technology 13:2, 127-131
CrossRef61
Randall W. Burt, M.D, James A. DiSario, M.D, Lisa Cannon-Albright, Ph.D. (1995) GENETICS OF COLON CANCER: Impact of Inheritance on Colon Cancer Risk 1. Annual Review of Medicine 46:1, 371-379
CrossRef62
Alessandro Cama, Raffaele Palmirotta, Maria Cristina Curia, Diana L. Esposito, Annalisa Ranieri, Ferdinando Ficari, Rosa Valanzano, Pasquale Battista, Andrea Modesti, Francesco Tonelli, Renato Mariani-Costantini. (1995) Multiplex PCR analysis and genotype-phenotype correlations of frequentAPC mutations. Human Mutation 5:2, 144-152
CrossRef63
Rustgi, Anil K.. (1994) Hereditary Gastrointestinal Polyposis and Nonpolyposis Syndromes. New England Journal of Medicine 331:25, 1694-1702
Full Text64
D.E. Joshua, J. Gibson, R.D. Brown. (1994) Mechanisms of the escape phase of myeloma. Blood Reviews 8:1, 13-20
CrossRef65
Bharati V. Bapat, John A. Parker, Theresa Berk, Zane Cohen, Robin S. McLeod, Peter N. Ray, Hartley S. Stern. (1994) Combined use of molecular and biomarkers for presymptomatic carrier risk assessment in familial adenomatous polyposis:. Diseases of the Colon & Rectum 37:2, 165-171
CrossRef66
Liu, Edison T., . (1993) From the Molecule to Public Health. New England Journal of Medicine 329:27, 2028-2029
Full Text67
Lisa Spirio, Sylviane Olschwang, Joanna Groden, Margaret Robertson, Wade Samowitz, Geoff Joslyn, Lawrence Gelbert, Andrew Thliveris, Mary Carlson, Brith Otterud, Henry Lynch, Patrice Watson, Patrick Lynch, Pierre Laurent-Puig, Randall Burt, J.P. Hughes, Gilles Thomas, Mark Leppert, Ray White. (1993) Alleles of the APC gene: An attenuated form of familial polyposis. Cell 75:5, 951-957
CrossRef68
DAVID J. KOOREY, GEOFFREY W. McCAUGHAN. (1993) Tumour suppressor genes and colorectal neoplasia. Journal of Gastroenterology and Hepatology 8:2, 174-184
CrossRef69
Joseph P. Miletich, Stephen M. Prescott, Ray White, Philip W. Majerus, Edwin G. Bovill. (1993) Inherited predisposition to thrombosis. Cell 72:4, 477-480
CrossRef70
Mary Lee Fitzsimmons. (1992) Hereditary colorectal cancers. Seminars in Oncology Nursing 8:4, 252-257
CrossRef71
Peter Greenwald. (1992) Colon cancer overview. Cancer 70:S3, 1206-1215
CrossRef72
Stanley R. Hamilton. (1992) Molecular genetics of colorectal carcinoma. Cancer 70:S3, 1216-1221
CrossRef73
Carli M. J. Tops, Hans F. A. Vasen, Gerard van Berge Henegouwen, Peter P. Simoons, Heleen M. van de Klift, Inge S. J. van Leeuwen, Cor Breukel, Riccardo Fodde, Frieda C. A. den Hartog Jager, Fokko M. Nagengast, Gerrit Griffioen, P. Meera Khan. (1992) Genetic evidence that Turcot syndrome is not allelic to familial adenomatous polyposis. American Journal of Medical Genetics 43:5, 888-893
CrossRef74
M. G. Dunlop. (1992) Screening for large bowel neoplasms in individuals with a family history of colorectal cancer. British Journal of Surgery 79:6, 488-494
CrossRef75
Henry T. Lynch, Thomas C. Smyrk, Patrice Watson, Stephen J. Lanspa, Patrick M. Lynch, Joseph X. Jenkins, Jon Rouse, Jennifer Cavalieri, Linda Howard, Jane Lynch. (1992) Hereditary flat adenoma syndrome. Diseases of the Colon & Rectum 35:5, 411-421
CrossRef76
R. S. HOULSTON, A. COLLINS, J. SLACK, N. E. MORTON. (1992) Dominant genes for colorectal cancer are not rare. Annals of Human Genetics 56:2, 99-103
CrossRef77
E. R. Maher, B. Morson, R. Beach, S. V. Hodgson. (1992) Phenotypic variation in hereditary nonpolyposis colon cancer syndrome association with infiltrative fibromatosis (desmoid tumor). Cancer 69:8, 2049-2051
CrossRef78
Alan P. Meagher, Malcolm Stuart. (1992) Colonoscopy in patients with a family history of colorectal cancer. Diseases of the Colon & Rectum 35:4, 315-321
CrossRef79
Stanley R. Hamilton. (1992) Molecular genetic alterations as potential prognostic indicators in colorectal carcinoma. Cancer 69:S6, 1589-1591
CrossRef80
Ray White. (1992) Inherited cancer genes. Current Opinion in Genetics & Development 2:1, 53-57
CrossRef81
(1991) Molecular secrets of colorectal cancer. The Lancet 338:8779, 1363-1364
CrossRef82
Sarah V. Williams, Tania A. Jones, Sally Cottrell, Günther Zehetner, Liliana Varesco, Tristan Ward, Huw Thomas, Paul A. Lawson, Ellen Solomon, Walter F. Bodmer, Anna-Marie Frischauf, Denise Sheer. (1991) Fine Mapping of Probes in the Adenomatous Polyposis Coli Region of Chromosome 5 by In Situ Hybridization. Genes, Chromosomes and Cancer 3:5, 382-389
CrossRef83
Joanna Groden, Andrew Thliveris, Wade Samowitz, Mary Carlson, Lawrence Gelbert, Hans Albertsen, Geoff Joslyn, Jeff Stevens, Lisa Spirio, Margaret Robertson, Leslie Sargeant, Karen Krapcho, Erika Wolff, Randall Burt, J.P. Hughes, Janet Warrington, John McPherson, John Wasmuth, Denis Le Paslier, Hadi Abderrahim, Daniel Cohen, Mark Leppert, Ray White. (1991) Identification and characterization of the familial adenomatous polyposis coli gene. Cell 66:3, 589-600
CrossRef84
Lewis E. Mehl. (1991) A mathematical computer simulation model for the development of colonic polyps and colon cancer. Journal of Surgical Oncology 47:4, 243-252
CrossRef85
Raymond L. White. (1991) Seeking tumor genes with DNA technology. Cancer 67:10, 2436-2438
CrossRef86
Hans Peter Rutz, Nicolas de Tribolet, Jean Marie Calmes, Germain Chapuis. (1991) Long-time survival of a patient with glioblastoma and Turcot's syndrome. Journal of Neurosurgery 74:5, 813-815
CrossRef87
C.Michael Steel. (1990) Genetic abnormalities in cancer. Current Opinion in Biotechnology 1:2, 188-195
CrossRef88
Henry T. Lynch, Thomas C. Smyrk, Stephen J. Lanspa, Patrick M. Lynch, Patrice Watson, Patricia C. Strayhorn, Earlene K. Bronson, Jane F. Lynch, Ira A. Priluck, Henry D. Appelman. (1990) Phenotypic variation in colorectal adenoma/cancer expression in two families. Hereditary flat adenoma syndrome. Cancer 66:5, 909-915
CrossRef89
CHRISTOPHER B. WILLIAMS, LAURENT BEDENNE. (1990) Management of colorectal polyps: Is all the effort worthwhile?. Journal of Gastroenterology and Hepatology 5:S-1, 144-165
CrossRef
