Linkage analysis in a large Swedish family supports the presence of a susceptibility locus for adenoma and colorectal cancer on chromosome 9q22.32-31.1

Skoglund, Johanna; Djureinovic, Tatjana; Xl, Zhou; Vandrovcová, Jana; Renkonen, Elise; Iselius, Lennart; Ml, Bisgaard; Peltomäki, Païvi; Lindblom, Annika

doi:10.1136/jmg.2005.033928

Cited by 45 publications

(42 citation statements)

References 16 publications

(16 reference statements)

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“…This gene colocalizes to the same chromosomal region (9q22.2-31.2) identified by the Colon Neoplasia Sibling Study (6) and recently validated in studies from Sweden and United Kingdom as a putative susceptibility locus for colorectal neoplasia (7,8). To determine whether the TGFBR1*6A allele is responsible for the observed linkage at 9q22.2-31.2, we genotyped 53 kindreds from the Colon Neoplasia Sibling Study with colon cancer or advanced colon adenomas for the presence of the TGFBR1*6A or TGFBR1*9A allele.…”

Section: Introductionmentioning

confidence: 54%

Is TGFBR16A* a Susceptibility Allele for Nonsyndromic Familial Colorectal Neoplasia?

Daley¹,

Morgan²,

Lewis³

et al. 2007

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Section: Introductionmentioning

confidence: 54%

Is TGFBR16A* a Susceptibility Allele for Nonsyndromic Familial Colorectal Neoplasia?

Daley¹,

Morgan²,

Lewis³

et al. 2007

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…5 Other workers have proposed additional loci for CRC susceptibility genes on the basis of linkage, most notably on 9q22.2 -31.2. 6,7 To further examine the impact of unknown moderate/ high-penetrance genes on CRC risk, we conducted a further GWLS on an additional 34 HNSCRC families using the same analytical platform employed in our first analysis. We then pooled data from scans.…”

mentioning

confidence: 99%

Deciphering the genetics of hereditary non-syndromic colorectal cancer

Papaemmanuil¹,

Carvajal‐Carmona

Sellick³

et al. 2008

Eur J Hum Genet

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Previously we have localized to chromosome 3q21-q24, a predisposition locus for colorectal cancer (CRC), through a genome-wide linkage screen (GWLS) of 69 families without familial adenomatous polyposis or hereditary non-polyposis CRC. To further investigate Mendelian susceptibility to CRC, we extended our screen to include a further GWLS of an additional 34 CRC families. We also searched for a disease gene at 3q21-q24 by linkage disequilibrium mapping in 620 familial CRC cases and 960 controls by genotyping 1676 tagging SNPs and sequencing 30 candidate genes from the region. Linkage analysis was conducted using the Affymetrix 10K SNP array. Data from both GWLSs were pooled and multipoint linkage statistics computed. The maximum NPL score (3.01; P ¼ 0.0013) across all families was at 3q22, maximal evidence for linkage coming from families segregating rectal CRC. The same genomic position also yielded the highest multipoint heterogeneity LOD (HLOD) score under a dominant model (HLOD ¼ 2.79; P ¼ 0.00034), with an estimated 43% of families linked. In the case-control analysis, the strongest association was obtained at rs698675 (P ¼ 0.0029), but this was not significant after adjusting for multiple testing. Analysis of candidate gene mapping to the region of maximal linkage on 3q22 failed to identify a causal mutation. There was no evidence for linkage to the previously reported 9q CRC locus (NPL ¼ 0. 1 It is therefore likely that a significant proportion of inherited predisposition to CRC is mediated through susceptibility to CRAs. These observations have provided a strong rationale for searching of novel predisposition genes through genome-wide linkage screens (GWLSs) of hereditary non-FAP/HNPCC CRC families (hereditary nonsyndromic colorectal cancer -HNSCRC). Using a high-density SNP array, we have previously performed a GWLS of 69 HNSCRC families in which involvement of known predisposition genes had been excluded and a novel CRC susceptibility locus at 3q21 -q24 was identified. 5 Other workers have proposed additional loci for CRC susceptibility genes on the basis of linkage, most notably on 9q22.2 -31.2. 6,7 To further examine the impact of unknown moderate/ high-penetrance genes on CRC risk, we conducted a further GWLS on an additional 34 HNSCRC families using the same analytical platform employed in our first analysis. We then pooled data from scans. In an effort to predict the most likely location of the putative CRC gene on 3q21 -q24, we undertook linkage disequilibrium (LD) mapping at 1676 tagging SNPs in 620 HNSCRC cases and 961 controls. In addition, we have sought to identify disease-causing variants by direct mutational analysis of candidate genes localizing to the region of maximal linkage on 3q22. Materials and methods Ascertainment and collection of families and casesFor clarity, we refer to our previously reported GWLS of 69 pedigrees as phase 1 8 and the current analysis of 34 pedigrees as phase 2. As before, familial CRC cases were ascertained through the COloRectal tumour Gene Identification (C...

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“…Details on family 24 have been published earlier (Skoglund et al, 2006). Owing to stringent surveillance only one individual alive (Co-166) had developed CRC.…”

Section: Mutation Screening Of Tgfbr1mentioning

confidence: 99%

“…In addition, the TGFBR1*6A variant has been proposed to be directly causally responsible for a proportion of hereditary nonpolyposis colorectal cancer (HNPCC), especially those without MMR deficiency (Bian et al, 2005). Intriguingly, TGFBR1 maps to chromosome 9q22.32-31.1, a from several independent studies suggested CRC susceptibility locus (Wiesner et al, 2003;Kemp et al, 2006;Skoglund et al, 2006).…”

mentioning

confidence: 99%

“…Using a case -control design, we compared TGFBR1*6A and Int7G24A allele frequencies in HNPCC and non-HNPCC familial CRC cases with population-based controls. We also examined whether germ-line TGFBR1 mutations are responsible for the CRC susceptibility locus on chromosome 9 by screening the entire coding region of TGFBR1 in affected members of a large family with adenoma and CRC linked to chromosome 9q22.32-31.1 (Skoglund et al, 2006).…”

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confidence: 99%

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TGFBR1 variants TGFBR1*6A and Int7G24A are not associated with an increased familial colorectal cancer risk

et al. 2009

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Variants of the transforming growth factor-beta receptor type 1 (TGFBR1) gene, TGFBR1*6A and Int7G24A, have been suggested to act as low-penetrance tumour susceptibility alleles with TGFBR1*6A being causally responsible for some cases of familial colorectal cancer (CRC). We performed a case -control study of 262 unrelated familial CRC cases; 83 hereditary non-polyposis colorectal cancer (HNPCC) and 179 non-HNPCC. Patients were genotyped for TGFBR1*6A and Int7G24A and compared with 856 controls. Further, we screened the coding region of TGFBR1 in affected members of a large family with CRC linked to 9q22.32-31.1. TGFBR1*6A allelic frequency was not significantly different in all of the familial cases compared with controls (0.107 and 0.106, respectively; P ¼ 0.915). In a subgroup analysis allele frequencies were, however, different between HNPCC and non-HNPCC familial cases (0.157 and 0.084, respectively; P ¼ 0.013). TGFBR1*6A genotype did not influence age of onset. Int7G24A allele frequencies were similar in cases and controls. No germ-line mutation was identified in the family with CRC linked to this chromosomal region. Our study provides no substantial support for the hypothesis that the polymorphic variants TGFBR1*6A or Int7G24A contribute to familial CRC risk. We cannot, however, exclude the possibility that TGFBR1 variants have a modifying effect on inherited risk per se.

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Linkage analysis in a large Swedish family supports the presence of a susceptibility locus for adenoma and colorectal cancer on chromosome 9q22.32-31.1

Abstract: Our result supports the presence of a susceptibility locus predisposing to adenoma and colorectal cancer in this chromosomal region.

Cited by 45 publications

References 16 publications

Is TGFBR16A* a Susceptibility Allele for Nonsyndromic Familial Colorectal Neoplasia?

Is TGFBR16A* a Susceptibility Allele for Nonsyndromic Familial Colorectal Neoplasia?

Deciphering the genetics of hereditary non-syndromic colorectal cancer

TGFBR1 variants TGFBR1*6A and Int7G24A are not associated with an increased familial colorectal cancer risk

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Linkage analysis in a large Swedish family supports the presence of a susceptibility locus for adenoma and colorectal cancer on chromosome 9q22.32-31.1

Abstract: Our result supports the presence of a susceptibility locus predisposing to adenoma and colorectal cancer in this chromosomal region.

Cited by 45 publications

References 16 publications

Is TGFBR1*6A a Susceptibility Allele for Nonsyndromic Familial Colorectal Neoplasia?

Is TGFBR1*6A a Susceptibility Allele for Nonsyndromic Familial Colorectal Neoplasia?

Deciphering the genetics of hereditary non-syndromic colorectal cancer

TGFBR1 variants TGFBR1*6A and Int7G24A are not associated with an increased familial colorectal cancer risk

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Product

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Is TGFBR16A* a Susceptibility Allele for Nonsyndromic Familial Colorectal Neoplasia?

Is TGFBR16A* a Susceptibility Allele for Nonsyndromic Familial Colorectal Neoplasia?