Linkage analysis revealed risk loci on 6p21 and 18p11.2-q11.2 in familial colon and rectal cancer, respectively

Holst, Susanna von; Jiao, Xiang; Li, Wen; Kontham, Vinaykumar; Thutkawkorapin, Jessada; Ringdahl, Jenny; Bryant, Patrick; Lindblom, Annika

doi:10.1038/s41431-019-0388-3

Cited by 4 publications

(3 citation statements)

References 49 publications

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“…The current state of research indicates very few germline variants for the PTK7 gene that have been associated with the development of any disease. A recent genome-wide linkage analysis of Swedish CRC families identified a candidate risk variant in the PTK7 gene (A785V) [43]. Additionally, germline variants in PTK7 have been associated with neural tube defects [44].…”

Section: Discussionmentioning

confidence: 99%

Whole-Exome Sequencing Identifies a Novel Germline Variant in PTK7 Gene in Familial Colorectal Cancer

Miao

Skopelitou

Srivastava

et al. 2022

IJMS

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Colorectal cancer (CRC) is the third most frequently diagnosed malignancy worldwide. Only 5% of all CRC cases are due to germline mutations in known predisposition genes, and the remaining genetic burden still has to be discovered. In this study, we performed whole-exome sequencing on six members of a Polish family diagnosed with CRC and identified a novel germline variant in the protein tyrosine kinase 7 (inactive) gene (PTK7, ENST00000230419, V354M). Targeted screening of the variant in 1705 familial CRC cases and 1674 healthy elderly individuals identified the variant in an additional familial CRC case. Introduction of this variant in HT-29 cells resulted in increased cell proliferation, migration, and invasion; it also caused down-regulation of CREB, p21 and p53 mRNA and protein levels, and increased AKT phosphorylation. These changes indicated inhibition of apoptosis pathways and activation of AKT signaling. Our study confirmed the oncogenic function of PTK7 and supported its role in genetic predisposition of familial CRC.

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Section: Discussionmentioning

confidence: 99%

Whole-Exome Sequencing Identifies a Novel Germline Variant in PTK7 Gene in Familial Colorectal Cancer

Miao

Skopelitou

Srivastava

et al. 2022

IJMS

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“…It is likely that there are at least two genetic risk variants at this locus, similar to what we have seen in previous studies. 24,35 The RBPMS2 gene has been implicated in gastrointestinal stromal tumors. 36 Interestingly, the gene PIF1 has been implicated in the pathway of multiple sessile serrated adenomas.…”

Section: Discussionmentioning

confidence: 99%

Colorectal cancer risk susceptibility loci in a Swedish population

Liu

Mahdessian

Helgadottir

et al. 2021

Molecular Carcinogenesis

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To search for colorectal cancer (CRC) risk loci, Swedish samples were used for a genome-wide haplotype analysis. A logistic regression model was employed in 2663 CRC cases and 1642 controls in the discovery analysis. Three analyses were done, on all, familial-, and nonfamilial CRC samples and only results with odds ratio (OR) > 1 were analyzed. single nucleotide polymorphism (SNP) analysis did not generate any statistically significant results. Haplotype analysis suggested novel loci, on chromosome 2q36.1 (OR = 1.71, p value = 5.6924 × 10 −8 ) in all CRC samples, chromosome 1q43 (OR = 4.04 p value = 3.24 × 10 −8 ) in familial CRC samples, and two hits in nonfamilial CRC samples, chromosomes 2q36.1 (OR = 1.71 p value = 5.69 × 10 −8 ) and 3p24.3 (OR = 1.62 p value = 6.21 × 10 −9 ). Moreover, one locus on chromosome 20q13.33 was suggested in analyses of all samples, and five more novel loci were suggested on chromosomes 10q25. 3, 15q,22.31, 17p11.2, 1p34.2, and 3q24. The haplotypes from the analysis of all samples were replicated in a second study of CRC cases and controls from the same part of Sweden. In summary, using haplotype analysis in Swedish CRC samples, the best hits were novel loci and the locus on chromosomes 2q36.1 and 20q13.33 suggested in the analysis of all samples were confirmed in a second cohort. The ORs were often higher than ORs from published genome-wide association study (GWAS). The study suggested it was possible that a risk locus could involve more than one gene, and that haplotypes could give information on the gene or genes possibly involved in the risk at specific locus.

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“…3,4 However, most of the CRC with a typical high-risk pedigree do not show segregated mutations in known genes and traditional linkage analysis has failed to demonstrate causative genes. 5,6 As a consequence, cancer and other diseases were considered to be complex diseases and a different strategy using genome-wide association studies (GWAS) have been used to define the genetic risk factors involved. Large GWAS have identified more than 100 loci associated with an increased risk of CRC.…”

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confidence: 99%

Identification of known and novel familial cancer genes in Swedish colorectal cancer families

Helgadottir

Thutkawkorapin

Rohlin

et al. 2021

Intl Journal of Cancer

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Identifying new candidate colorectal cancer (CRC) genes and mutations are important for clinical cancer prevention as well as in cancer care. Genetic counseling is already implemented for known high-risk variants; however, the majority of CRC are of unknown causes. In our study, 110 CRC patients in 55 Swedish families with a strong history of CRC but unknown genetic causes were analyzed with the aim of identifying novel candidate CRC predisposing genes. Exome sequencing was used to identify rare and high-impact variants enriched in the families. No clear pathogenic variants were found in known CRC predisposing genes; however, potential pathogenic variants in novel CRC predisposing genes were identified. Over 3000 variants with minor allele frequency (MAF) <0.01 and Combined Annotation Dependent Depletion (CADD) > 20 were seen aggregating in the CRC families. Of those, 27 variants with MAF < 0.001 and CADD>25 were considered high-risk mutations. Interestingly, more than half of the high-risk variants were detected in three families, suggesting cumulating contribution of several variants to CRC. In summary, our study shows that despite a strong history of CRC within families, identifying pathogenic variants is challenging. In a small number of families, few rare mutations were shared by affected family members. This could indicate that in the absence of known CRC predisposing genes, a cumulating contribution of mutations leads to CRC observed in these families.

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Linkage analysis revealed risk loci on 6p21 and 18p11.2-q11.2 in familial colon and rectal cancer, respectively

Cited by 4 publications

References 49 publications

Whole-Exome Sequencing Identifies a Novel Germline Variant in PTK7 Gene in Familial Colorectal Cancer

Whole-Exome Sequencing Identifies a Novel Germline Variant in PTK7 Gene in Familial Colorectal Cancer

Colorectal cancer risk susceptibility loci in a Swedish population

Identification of known and novel familial cancer genes in Swedish colorectal cancer families

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