Genetic testing and phenotype in a large kindred with attenuated familial adenomatous polyposis

Burt, Randall W.; Leppert, M.; Slattery, Martha L.; Samowitz, Wade S.; Spirio, Lisa; Kerber, Richard A.; Kuwada, Scott K.; Neklason, Deborah W.; DiSario, James A.; Lyon, Elaine; Hughes, Jaime; Chey, William Y.; White, R.

doi:10.1053/j.gastro.2004.05.003

Cited by 171 publications

(131 citation statements)

References 29 publications

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“…An attenuated form of FAP is now recognized, called attenuated FAP [11][12][13]. It is characterized by fewer, more proximal colonic adenomas, but nonetheless a 70% to 80% lifetime risk of colon cancer.…”

Section: Inherited Syndromes Of Colon Cancer Familial Adenomatous Polmentioning

confidence: 99%

Inheritance of colorectal cancer

Burt¹

2007

Drug Discovery Today: Disease Mechanisms

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Inheritance is involved in up to one third of colon cancer cases. Highly penetrant inherited syndromes account for approximately 3%, while more common, but less penetrant inherited factors play a role in the remainder. Approaches to recognizing each of these categories and syndromes, using genetic testing for diagnosis where indicated, and accomplishing proper cancer screening and surveillance will be outlined in this review.

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Section: Inherited Syndromes Of Colon Cancer Familial Adenomatous Polmentioning

confidence: 99%

Inheritance of colorectal cancer

Burt¹

2007

Drug Discovery Today: Disease Mechanisms

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“…Among AFAP patients with APC gene mutation, the median age of colon cancer development is 58 years with 75% in the proximal colon (Burt et al, 2004). This AFAP family with APC gene mutation at codon 161 of exon 4 and phenotypically presenting a predominance of rightsided adenomatous polyposis was diagnosed as typical for AFAP.…”

Section: Discussionmentioning

confidence: 93%

Colon Cancer Prevention by Detection of APC Gene Mutation in a Family with Attenuated Familial Adenomatous Polyposis

Poovorawan

Suksawatamnuay²,

Sahakitrungruang³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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Background: Genetic mutation is a significant factor in colon CA pathogenesis. Familial adenomatous polyposis (FAP) is an autosomal dominant hereditary disease characterized by multiple colorectal adenomatous polyps affecting a number of cases in the family. This report focuses on a family with attenuated familial adenomatous polyposis (AFAP) with exon 4 mutation, c.481C>T p.Q161X of the APC gene. Methods: We analyzed 20 members of a family with AFAP. Clinical and endoscopic data were collected for phenotype determination. Genetic analysis was also performed by direct sequencing of the APC gene. Result: Five patients with a phenotype of AFAP were found. Endoscopic polyposis was demonstrated among the second generation with genotype mutation of the disease (age > 50 years) consistent with delayed phenotypic adenomatous polyposis in AFAP. APC gene mutation was identified in exon 4 of the APC gene, with mutation points of c.481C>T p.Q161X. Laparoscopic subtotal colectomy was performed to prevent carcinogenesis. Conclusion: A family with attenuated familial adenomatous polyposis of APC related to exon 4 mutation, c.481C>T p.Q161X, was reported and the phenotypic finding was confirmed by endoscopic examination. Genetic mutation analysis might be advantageous in AFAP for long term colon cancer prevention and management due to subtle or asymptomatic phenotype presentation in early adulthood.

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“…Moreover, the patient had relative sparing of polyps in the proximal colon, a feature in contrast to most mutations at the 5 0 end of exon 9 that typically results in aFAP. 5,8,12 The six synchronous tumors were also predominantly on the left (two transverse, two sigmoid, and two rectal). The exon 8-10 connection reminded us of our previous unpublished finding of a 'skip exon 9' isoform that is present in low abundance in the lymphocytes of all 22 FAP patients and 21 healthy individuals screened with an age range of 14-70 years.…”

Section: Resultsmentioning

confidence: 99%

“…Blood was collected from members 8,19, and 21 of the family with informed consent. Pedigree was retrieved from the Singapore Polyposis Registry.…”

Section: Sample Selectionmentioning

confidence: 99%

“…Nevertheless, there are exceptions where mutation carriers from the same family can present with profuse polyposis, possibly due to other modifiers. [7][8][9] We have previously identified another very lowly expressed isoform that skips exon 9 completely (unpublished data). In this study, we report a novel indel at the 5 0 end of exon 9 that upregulates this 'skip exon 9' isoform and concomitantly downregulates exon 9a, resulting in very severe polyposis and six synchronous advanced cancers in a 37-year-old female proband.…”

Section: Introductionmentioning

confidence: 96%

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A novel indel in exon 9 of APC upregulates a ‘skip exon 9’ isoform and causes very severe familial adenomatous polyposis

et al. 2013

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Germline mutation in the adenomatous polyposis coli (APC) gene causes the majority (80%) of familial adenomatous polyposis (FAP), an autosomal dominantly inherited form of colorectal cancer (CRC). Mutation in 5 0 end of exon 9 of APC usually results in an attenuated form of FAP (aFAP), characterized by later age of onset and fewer polyps. The presence of exon 9a, an in-frame isoform with exon 8 spliced to 3 0 end of exon 9, modulates any deleterious effect of the mutation. A third lowly expressed isoform that completely skips exon 9 is present in both healthy individuals and FAP patients. We report here an interesting case of a proband with an APC mutation in 5 0 end of exon 9 that presented with six synchronous advanced CRCs at age 37. The novel insertion-deletion (indel) at codon 409, c.1226-1229delTTTTinsAAA, caused upregulation of the 'skip exon 9' isoform, r934-1312del, resulting in a premature stop codon at exon 10 and a truncated protein that removed all of the b-catenin (CTNNB1) binding motifs, thus activating the downstream T-cell transcription factor (Tcf) pathway. Exon 9a isoform was concomitantly downregulated. This finding emphasizes the necessity of examining the various isoforms of exon 9 to avoid clinical mismanagement and counseling based on just the mutation site by genomic DNA sequencing alone.

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Genetic testing and phenotype in a large kindred with attenuated familial adenomatous polyposis

Cited by 171 publications

References 29 publications

Inheritance of colorectal cancer

Inheritance of colorectal cancer

Colon Cancer Prevention by Detection of APC Gene Mutation in a Family with Attenuated Familial Adenomatous Polyposis

A novel indel in exon 9 of APC upregulates a ‘skip exon 9’ isoform and causes very severe familial adenomatous polyposis

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