Singapore Familial Adenomatous Polyposis (FAP) Patients with Classical Adenomatous Polyposis but Undetectable APC Mutations Have Accelerated Cancer Progression

Cao, Xiaofeng; Yun, Hong Shik; Eu, Kong Weng; Loi, Carol; Cheah, Peh Yean

doi:10.1111/j.1572-0241.2006.00842.x

Cited by 28 publications

(29 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…It is the most frequent mutation and its frequency varies from population to population. In Slovakia this mutation represents approximately 15% of all identified mutations [18], which is comparable to frequencies reported from Italy [17] and Singapore [20].…”

Section: Discussionsupporting

confidence: 66%

Different phenotype manifestation of familial adenomatous polyposis in families with APC mutation at codon 1309

Stevurková¹,

Adamcikova²,

Holec³

et al. 2009

neo

View full text Add to dashboard Cite

Germline mutation in APC gene induced development of familial adenomatous polyposis (FAP). The risk of developing specific manifestation of FAP is often correlated with the position of the inherited APC mutation. Patients with mutations localized in the largest exon 15 between codons 1286 and 1513 (mutation cluster region, MCR) have generally a worse prognosis with early onset of the disease. We found 6 FAP families with mutation at codon 1309 (3927_3931delAAAGA) in the cohort of 39 FAP Slovak families with rapid cancer progress. In addition, mutation in codon 1309 was detected in three family members, one of them with a very different phenotype. This oldest family member, aged 81, has persisted asymptomatic without clinical manifestations.

show abstract

Section: Discussionsupporting

confidence: 66%

Different phenotype manifestation of familial adenomatous polyposis in families with APC mutation at codon 1309

Stevurková¹,

Adamcikova²,

Holec³

et al. 2009

neo

View full text Add to dashboard Cite

show abstract

“…Individual 7 was the only individual with less than 100 polyps; however, she had six synchronous cancers at time of diagnosis. No APC germline mutations were found in affected members whose lymphocytes were available for screening (Cao et al, 2006b). The mean age at diagnosis of affected members for these APC mutation-negative FAP variant families (47 years) was significantly higher than members of FAP families with APC germline mutations (30.1 years).…”

Section: Characteristics Of the Apc Mutation-negative Fap Variant Familymentioning

confidence: 97%

“…Axin and b-catenin are the two other candidate genes in the Wnt signaling pathway previously implicated in colorectal tumorigenesis (Sparks et al, 1998;Satoh et al, 2000). However, patients from these FAP variant families were found to be also Axin and b-catenin mutation-negative (Cao et al, 2006b), indicating that other disease-causing genes and pathways may be involved.…”

Section: Introductionmentioning

confidence: 93%

“…Subsequently, APC mutation was also found to be an early event in majority of sporadic CRC cases (Miyoshi et al, 1992). Nevertheless, APC germline mutations are not identified in 10-50% of FAP patients across various populations (Sieber et al, 2002;De Rosa et al, 2004;Michils et al, 2005;Cao et al, 2006b;Galiatsatos and Foulkes, 2006).…”

Section: Introductionmentioning

confidence: 97%

“…This enables us to characterize the mutation and phenotypic spectrum of the local families and identify a sub-group of APC mutation-negative FAP variant patients with classical polyposis but accelerated cancer progression (Cao et al, 1999(Cao et al, , 2000(Cao et al, , 2001(Cao et al, , 2006b). Axin and b-catenin are the two other candidate genes in the Wnt signaling pathway previously implicated in colorectal tumorigenesis (Sparks et al, 1998;Satoh et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Genome‐wide scan identifies a copy number variable region at 3q26 that regulates PPM1L in APC mutation‐negative familial colorectal cancer patients

Thean

Loi

et al. 2009

Genes Chromosomes & Cancer

View full text Add to dashboard Cite

Familial adenomatous polyposis (FAP) is an autosomal dominantly inherited form of colorectal cancer (CRC) caused by mutation in the adenomatous polyposis coli (APC) gene. However, APC mutations are not detected in 10-50% of FAP patients. We searched for a new cancer gene by performing genome-wide genotyping on members of an APC mutation-negative FAP variant family and ethnicity-matched healthy controls. No common copy number change was found in all affected members using the unaffected members and healthy controls as baseline. A 111 kb copy number variable (CNV) region at 3q26.1 was shown to have copy number loss in all eight polyps compared to matched lymphocytes of two affected members. A common region of loss in all polyps, which are precursors to CRC, is likely to harbor disease-causing gene in accordance to Knudsen's "two-hit" hypothesis. There is, however, no gene within the deleted region. A 2-Mb scan of the genomic region encompassing the deleted region identified PPM1L, coding for a novel serine-threonine phosphatase in the TGF-beta and BMP signaling pathways. Real-time PCR analyses indicate that the 3'UTR of PPM1L transcript was down-regulated more than two-folds in all six polyps and tumors compared to matched mucosa of the affected member. This down-regulation was not observed in APC mutation-positive FAP patients. Our results suggest that the CNV region at 3q26 harbors an element that regulates the expression of an upstream candidate tumor suppressor, PPM1L, thus providing a novel mechanism for colorectal tumorigenesis in APC mutation-negative familial CRC patients.

show abstract

The orphan nuclear receptor NR0B2 could be a novel susceptibility locus associated with microsatellite‐stable, APC mutation‐negative early‐onset colorectal carcinomas with metabolic manifestation

Lam

Sethi

Tan

et al. 2020

Genes Chromosomes & Cancer

Self Cite

View full text Add to dashboard Cite

Colorectal cancer (CRC) is a high incidence cancer and major cause of cancer mortality. Though disease‐causing tumor suppressors for major syndromes are well characterized, about 10% of CRC is familial but without mutations in known tumor suppressors. We exhaustively screened 100 polyposis families for APC germline mutations and identified 13, which are APC mutation‐negative, microsatellite‐stable (MSS), and with undetectable mutation in known tumor suppressors. Whole exome sequencing in three probands uncovered two with germline frameshift NR0B2 mutations, c.293_301delTTGGGTTGGinsAC and c.227delT. Sanger Sequencing identified a third proband with NR0B2 c.157_166delCATCGCACCT frameshift mutation. All three mutations deleted the C‐terminus activation/repression domain of NR0B2, thus are loss‐of‐function mutations. Real‐time RT‐PCR performed on tumor and matched mucosa of one patient revealed that NR0B2 downstream targets, SMAD3 was derepressed while GLI1 was downregulated in the colonic mucosa compared to healthy controls. Truncated NR0B2 molecule was predicted to have weakened binding with interacting partners SMAD3, GLI1, BCL2, and RXRα, implying perturbation of TGF‐β, Hedgehog, anti‐apoptotic and nuclear hormone receptor signaling pathways. Immunostaining also revealed nuclear retention of the most severely truncated NR0B2 molecule compared to the wildtype. Microsatellite and sequencing analysis did not detect loss of wildtype allele in probands' tumors. The patient who acquired somatic KRAS mutation progressed rapidly whist the other two patients manifested with late‐onset obesity and diabetes. We propose that haploinsufficiency of NR0B2 is associated with a novel CRC syndrome with metabolic phenotypes.

show abstract

Singapore Familial Adenomatous Polyposis (FAP) Patients with Classical Adenomatous Polyposis but Undetectable APC Mutations Have Accelerated Cancer Progression

Cited by 28 publications

References 29 publications

Different phenotype manifestation of familial adenomatous polyposis in families with APC mutation at codon 1309

Different phenotype manifestation of familial adenomatous polyposis in families with APC mutation at codon 1309

Genome‐wide scan identifies a copy number variable region at 3q26 that regulates PPM1L in APC mutation‐negative familial colorectal cancer patients

The orphan nuclear receptor NR0B2 could be a novel susceptibility locus associated with microsatellite‐stable, APC mutation‐negative early‐onset colorectal carcinomas with metabolic manifestation

Contact Info

Product

Resources

About