How does genetic risk information for Lynch syndrome translate to risk management behaviours?

Steel, Emma; Robbins, Andrew M.; Jenkins, Mark A.; Flander, Louisa; Gaff, Clara; Keogh, Louise

doi:10.1186/s13053-016-0061-6

Cited by 10 publications

(11 citation statements)

References 43 publications

(38 reference statements)

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“…All P/LPVs identified in our study are heterozygous variants. This is in accordance with the mode of inheritance for these genes regarding their association with pancreatic cancer susceptibility [ 29 ].…”

Section: Discussionsupporting

confidence: 85%

Clinical Significance of Germline Cancer Predisposing Variants in Unselected Patients with Pancreatic Adenocarcinoma

Fountzilas

Eliades²,

Koliou

et al. 2021

Cancers

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Our aim was to determine the prevalence, prognostic and predictive role of germline pathogenic/likely pathogenic variants (P/LPVs) in cancer predisposing genes in patients with pancreatic ductal adenocarcinoma (PDAC). Germline testing of 62 cancer susceptibility genes was performed on unselected patients diagnosed from 02/2003 to 01/2020 with PDAC, treated at Hellenic Cooperative Oncology Group (HeCOG)-affiliated Centers. The main endpoints were prevalence of P/LPVs and overall survival (OS). P/LPVs in PDAC-associated and homologous recombination repair (HRR) genes were identified in 22 (4.0%) and 42 (7.7%) of 549 patients, respectively. P/LPVs were identified in 16 genes, including ATM (11, 2.0%) and BRCA2 (6, 1.1%), while 19 patients (3.5%) were heterozygotes for MUTYH P/LPVs and 9 (1.6%) carried the low-risk allele, CHEK2 p.(Ile157Thr). Patients carrying P/LPVs had improved OS compared to non-carriers (22.6 vs. 13.9 months, p = 0.006). In multivariate analysis, there was a trend for improved OS in P/LPV carriers (p = 0.063). The interaction term between platinum exposure and mutational status of HRR genes was not significant (p-value = 0.35). A significant proportion of patients with PDAC carries clinically relevant germline P/LPVs, irrespectively of age, family history or disease stage. The predictive role of these P/LPVs has yet to be defined. ClinicalTrials.gov Identifier: NCT03982446.

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Section: Discussionsupporting

confidence: 85%

Clinical Significance of Germline Cancer Predisposing Variants in Unselected Patients with Pancreatic Adenocarcinoma

Fountzilas

Eliades²,

Koliou

et al. 2021

Cancers

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“…Finally, we observed that BRAF was the most common gene mutated among samples, in agreement with previous studies, where BRAF mutations were very frequent in SSA (75%) and in mixed polyps (86%) [ 42 ]. Accordingly, Horpaopan et al [ 43 ] detected that 50% of serrated polyps presented BRAF p.V600E mutation in a 41-years old female patient.…”

Section: Discussionmentioning

confidence: 99%

Germline and Somatic Whole-Exome Sequencing Identifies New Candidate Genes Involved in Familial Predisposition to Serrated Polyposis Syndrome

Lima

Arnau‐Collell

Díaz‐Gay

et al. 2021

Cancers

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The serrated polyposis syndrome (SPS) is the most common and yet underdiagnosed colorectal polyposis syndrome. It is characterized by multiple and/or large colonic serrated polyps and a higher associated risk for colorectal cancer (CRC). The main objective of this study was to identify new candidate genes involved in the germline predisposition to SPS/CRC. Thirty-nine SPS patients from 16 families (≥2 patients per family) were recruited without alterations in well-known hereditary CRC genes, and germline and somatic whole-exome sequencing were performed. Germline rare variants with plausible pathogenicity, located in genes involved in cancer development, senescence and epigenetic regulation were selected. Somatic mutational profiling and signature analysis was pursued in one sample per family, when possible. After data filtering, ANXA10, ASXL1, CFTR, DOT1L, HIC1, INO80, KLF3, MCM3AP, MCM8, PDLIM2, POLD1, TP53BP1, WNK2 and WRN were highlighted as the more promising candidate genes for SPS germline predisposition with potentially pathogenic variants shared within families. Somatic analysis characterized mutational profiles in advanced serrated polyps/tumors, revealing a high proportion of hypermutated samples, with a prevalence of clock-like mutational signatures in most samples and the presence of DNA mismatch repair-defective signatures in some cases. In conclusion, we identified new candidate genes to be involved in familial SPS. Further functional studies and replication in additional cohorts are required to confirm the selected candidates.

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“…The combination of both genetic and environmental factors contributes to CRC formation. It is estimated that > 35% of CRC development is due to genetic predisposition, wherein nearly 1% of all CRCs are attributed to familial adenomatous polyposis (FAP) ( 87 , 88 ). FAP is an autosomal dominant inherited disorder that describes the development of numerous colorectal adenomatous polyps.…”

Section: Literature Reviewmentioning

confidence: 99%

The Mechanism of Bacteroides fragilis Toxin Contributes to Colon Cancer Formation

Cheng

Kantilal

Davamani

2020

MJMS

105

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The Bacteroides fragilis ( B. fragilis ) produce biofilm for colonisation in the intestinal tract can cause a series of inflammatory reactions due to B. fragilis toxin (BFT) which can lead to chronic intestinal inflammation and tissue injury and play a crucial role leading to colorectal cancer (CRC). The enterotoxigenic B. fragilis (ETBF) forms biofilm and produce toxin and play a role in CRC, whereas the non-toxigenic B. fragilis (NTBF) does not produce toxin. The ETBF triggers the expression of cyclooxygenase (COX)-2 that releases PGE2 for inducing inflammation and control cell proliferation. From chronic intestinal inflammation to cancer development, it involves signal transducers and activators of transcription (STAT)3 activation. STAT3 activates by the interaction between epithelial cells and BFT. Thus, regulatory T-cell (Tregs) will activates and reduce interleukin (IL)-2 amount. As the level of IL-2 drops, T-helper (T h 17) cells are generated leading to increase in IL-17 levels. IL-17 is implicated in early intestinal inflammation and promotes cancer cell survival and proliferation and consequently triggers IL-6 production that activate STAT3 pathway. Additionally, BFT degrades E-cadherin, hence alteration of signalling pathways can upregulate spermine oxidase leading to cell morphology and promote carcinogenesis and irreversible DNA damage. Patient with familial adenomatous polyposis (FAP) disease displays a high level of tumour load in the colon. This disease is caused by germline mutation of the adenomatous polyposis coli ( APC ) gene that increases bacterial adherence to the mucosa layer. Mutated- APC gene genotype with ETBF increases the chances of CRC development. Therefore, the colonisation of the ETBF in the intestinal tract depicts tumour aetiology can result in risk of hostility and effect on human health.

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How does genetic risk information for Lynch syndrome translate to risk management behaviours?

Cited by 10 publications

References 43 publications

Clinical Significance of Germline Cancer Predisposing Variants in Unselected Patients with Pancreatic Adenocarcinoma

Clinical Significance of Germline Cancer Predisposing Variants in Unselected Patients with Pancreatic Adenocarcinoma

Germline and Somatic Whole-Exome Sequencing Identifies New Candidate Genes Involved in Familial Predisposition to Serrated Polyposis Syndrome

The Mechanism of Bacteroides fragilis Toxin Contributes to Colon Cancer Formation

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