Exome Resequencing Identifies Potential Tumor-Suppressor Genes that Predispose to Colorectal Cancer

Smith, Chris; Naven, Marc; Harris, Richard; Colley, James; West, Hannah; Li, Ning; Liu, Yuan; Adams, Rachel; Maughan, T; Nichols, Laura; Kaplan, Richard; Wagner, Michael J.; McLeod, Howard L.; Cheadle, Jeremy P.

doi:10.1002/humu.22333

Cited by 48 publications

(46 citation statements)

References 53 publications

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“…For example, ENDOG, mutated in family B (p.R111fs), is a DNase involved in mediating caspase-independent apoptosis 21. DDX31, a RNA-binding protein mutated in family C (p.L367fs), is frequently mutated in medulloblastoma,22 and a germline truncating mutation was observed in a patient with sporadic CRC 23. Family D carries a RGS19 nonsense mutation (p.Q89X), a gene involved in regulating G-protein signalling and autophagy in intestinal cells 24.…”

Section: Resultsmentioning

confidence: 99%

RNF43 germline and somatic mutation in serrated neoplasia pathway and its association with BRAF mutation

Yan

Lai

et al. 2016

Gut

175

176

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Section: Resultsmentioning

confidence: 99%

RNF43 germline and somatic mutation in serrated neoplasia pathway and its association with BRAF mutation

Yan

Lai

et al. 2016

Gut

175

176

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“…In addition, homozygous missense mutations in FANCM (c.5164C>T, p.P1722S) have been found in breast tumors (35), and four different FANCM SNPs have been associated with osteosarcoma risk (36). Also, in colorectal cancer (CRC) patients, an FANCM nonsense mutation (c.5791C>T, p.Arg1931Ter) has been identified (37), but further studies are needed to clarify the potential role of FANCM in CRC susceptibility. However, only one FA patient has been found to carry truncating FANCM mutation and this individual also carries biallelic mutations in the FANCA gene (33,38).…”

Section: Discussionmentioning

confidence: 99%

Exome sequencing identifies FANCM as a susceptibility gene for triple-negative breast cancer

Kiiski

Pelttari

Khan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

160

170

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Inherited predisposition to breast cancer is known to be caused by loss-of-function mutations in BRCA1, BRCA2, PALB2, CHEK2, and other genes involved in DNA repair. However, most families severely affected by breast cancer do not harbor mutations in any of these genes. In Finland, founder mutations have been observed in each of these genes, suggesting that the Finnish population may be an excellent resource for the identification of other such genes. To this end, we carried out exome sequencing of constitutional genomic DNA from 24 breast cancer patients from 11 Finnish breast cancer families. From all rare damaging variants, 22 variants in 21 DNA repair genes were genotyped in 3,166 breast cancer patients, 569 ovarian cancer patients, and 2,090 controls, all from the Helsinki or Tampere regions of Finland. In Fanconi anemia complementation gene M (FANCM), nonsense mutation c.5101C>T (p.Q1701X) was significantly more frequent among breast cancer patients than among controls [odds ratio (OR) = 1.86, 95% CI = 1.26-2.75; P = 0.0018], with particular enrichment among patients with triplenegative breast cancer (TNBC; OR = 3.56, 95% CI = 1.81-6.98, P = 0.0002). In the Helsinki and Tampere regions, respectively, carrier frequencies of FANCM p.Q1701X were 2.9% and 4.0% of breast cancer patients, 5.6% and 6.6% of TNBC patients, 2.2% of ovarian cancer patients (from Helsinki), and 1.4% and 2.5% of controls. These findings identify FANCM as a breast cancer susceptibility gene, mutations in which confer a particularly strong predisposition for TNBC.breast cancer | DNA repair | FANCM | exome sequencing | triple-negative breast cancer B reast cancer is the most common cancer affecting women worldwide. It is also the principal cause of death from cancer among women globally, accounting for 14% of all cancer deaths (1). The etiology of breast cancer is multifactorial, and the risk depends on various factors like age, family history, and reproductive, hormonal, or dietary factors. The majority of breast cancers are sporadic, but approximately 15% of cases show familial aggregation (2, 3). Since the identification of the first breast and ovarian cancer susceptibility genes breast cancer 1 and 2 (BRCA1 and BRCA2, respectively) by linkage analysis and positional cloning, several breast cancer susceptibility genes and alleles with different levels of risk and prevalence in the population have been recognized. BRCA1 and BRCA2 mutation carriers have more than 10-fold increased risk of breast cancer compared with women in

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“…Palles et al [35] analyzed families with this disease, and revealed the role of mutations in POLE and POLD1 genes. Strikingly, these findings received a high number of confirmatory reports [36][37][38][39][40][41][42][43]. Whole exome sequencing and subsequent validation studies on familial melanoma revealed a role of MITF and POT1 mutations; however, their actual impact on the disease incidence remains to be determined [52][53][54][55][56].…”

Section: Other Cancer Typesmentioning

confidence: 76%

Identification of novel hereditary cancer genes by whole exome sequencing

et al. 2015

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Whole exome sequencing (WES) provides a powerful tool for medical genetic research. Several dozens of WES studies involving patients with hereditary cancer syndromes have already been reported. WES led to breakthrough in understanding of the genetic basis of some exceptionally rare syndromes; for example, identification of germ-line SMARCA4 mutations in patients with ovarian hypercalcemic small cell carcinomas indeed explains a noticeable share of familial aggregation of this disease. However, studies on common cancer types turned out to be more difficult. In particular, there is almost a dozen of reports describing WES analysis of breast cancer patients, but none of them yet succeeded to reveal a gene responsible for the significant share of missing heritability. Virtually all components of WES studies require substantial improvement, e.g. technical performance of WES, interpretation of WES results, mode of patient selection, etc. Most of contemporary investigations focus on genes with autosomal dominant mechanism of inheritance; however, recessive and oligogenic models of transmission of cancer susceptibility also need to be considered. It is expected that the list of medically relevant tumor-predisposing genes will be rapidly expanding in the next few years.

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Exome Resequencing Identifies Potential Tumor-Suppressor Genes that Predispose to Colorectal Cancer

Cited by 48 publications

References 53 publications

RNF43 germline and somatic mutation in serrated neoplasia pathway and its association with BRAF mutation

RNF43 germline and somatic mutation in serrated neoplasia pathway and its association with BRAF mutation

Exome sequencing identifies FANCM as a susceptibility gene for triple-negative breast cancer

Identification of novel hereditary cancer genes by whole exome sequencing

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