Distinct Mutational Profile of Lynch Syndrome Colorectal Cancers Diagnosed under Regular Colonoscopy Surveillance.
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SUBMITTER: Ahadova A
PROVIDER: S-EPMC8198627 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background/aimsThe risk of recurrence of colorectal adenoma among obese individuals without metabolic abnormalities or in those with metabolically healthy obesity is largely unexplored. Therefore, we longitudinally investigated the risk of adenoma occurrence in individuals undergoing surveillance colonoscopy according to metabolic status and obesity.MethodsThis retrospective cohort study included 16,872 Korean adults who underwent their first screening colonoscopy between 2003 and 2012 and who then underwent follow-up colonoscopy until 2017. Participants were categorized into a metabolically healthy nonobese group (reference group), a metabolically healthy obese group, a metabolically abnormal nonobese group, and a metabolically abnormal obese group. Hazard ratios (HRs) for adenoma recurrence compared to the reference group were calculated in each group.ResultsDuring a median follow-up duration of 47.3 months (interquartile range, 35.6 to 58.9 months), 3,673 (21.8%) and 292 (1.73%) participants developed adenoma and advanced adenoma, respectively. When age, sex, smoking, alcohol consumption, family history of colorectal cancer, and baseline adenoma risk were adjusted, the risk of adenoma recurrence was increased in metabolically healthy obese individuals (HR, 1.33; 95% confidence interval [CI], 1.12 to 1.57) and metabolically abnormal obese individuals (HR, 1.18; 95% CI, 1.08 to 1.30) but not in metabolically abnormal nonobese individuals (HR, 1.03; 95% CI, 0.94 to 1.13).ConclusionsIn this study, metabolically healthy obese individuals and metabolically abnormal obese individuals exhibited increased risks of occurrence of colorectal adenoma diagnosed by surveillance colonoscopy. This finding implies that obesity itself, even without metabolic abnormalities, is associated with an increased risk of adenoma recurrence.
| S-EPMC8129661 | biostudies-literature
Project description:Patients with Lynch syndrome often present with multiple synchronous or metachronous colorectal cancers (CRCs). The presence of multiple CRCs with distinct genetic profiles and driver mutations could complicate treatment as each cancer may respond differently to therapy. Studies of sporadic CRCs suggested that synchronous tumors have distinct etiologies, but could not rule out differences in genetic background. The presence of multiple cancers in a patient with a predisposing mutation provides an opportunity to profile synchronous cancers in the same genetic background. Here, we describe the case of a patient with Lynch syndrome that presented with six synchronous CRCs. Microsatellite instability (MSI) and genomic profiling indicated that each lesion had a unique pattern of instability and a distinct profile of affected genes. These findings support the idea that in Lynch syndrome, synchronous CRCs can develop in parallel with distinct mutation profiles and that these differences may inform treatment decisions.
| S-EPMC4880766 | biostudies-literature
Project description:BackgroundLynch syndrome (LS) is a hereditary condition that increases the risk for endometrial and other cancers. The identification of endometrial cancer (EC) patients with LS has the potential to influence life-saving interventions. We aimed to study the prevalence of LS among EC patients in our population.MethodsUniversal screening for LS was applied for a consecutive series EC. Tumor testing using microsatellite instability (MSI), immunohistochemistry (IHC) for mismatch-repair (MMR) protein expression and MLH1-methylation analysis, when required, was used to select LS-suspicious cases. Sequencing of corresponding MMR genes was performed.ResultsOne hundred and seventy-three EC (average age, 63 years) were screened. Sixty-one patients (35%) had abnormal IHC or MSI results. After MLH1 methylation analysis, 27 cases were considered suspicious of LS. From these, 22 were contacted and referred for genetic counseling. Nineteen pursued genetic testing and eight were diagnosed of LS. Mutations were more frequent in younger patients (<50 yrs). Three cases had either intact IHC or MSS and reinforce the need of implement the EC screening with both techniques.ConclusionThe prevalence of LS among EC patients was 4.6% (8/173); with a predictive frequency of 6.6% in the Spanish population. Universal screening of EC for LS is recommended.
| S-EPMC3820559 | biostudies-literature
Project description:Some individuals are diagnosed with colorectal cancer (CRC) despite recent colonoscopy. We examined individuals under colonoscopic surveillance for colonic adenomas to assess possible reasons for diagnosing cancer after a recent colonoscopy with complete removal of any identified polyps.Primary data were pooled from eight large (>800 patients) North American studies in which participants with adenoma(s) had a baseline colonoscopy (with intent to remove all visualised lesions) and were followed with subsequent colonoscopy. We used an algorithm based on the time from previous colonoscopy and the presence, size and histology of adenomas detected at prior exam to assign interval cancers as likely being new, missed, incompletely resected (while previously an adenoma) or due to failed biopsy detection.9167 participants (mean age 62) were included in the analyses, with a median follow-up of 47.2 months. Invasive cancer was diagnosed in 58 patients (0.6%) during follow-up (1.71 per 1000 person-years follow-up). Most cancers (78%) were early stage (I or II); however, 9 (16%) resulted in death from CRC. We classified 30 cancers (52%) as probable missed lesions, 11 (19%) as possibly related to incomplete resection of an earlier, non-invasive lesion and 14 (24%) as probable new lesions. The cancer diagnosis may have been delayed in three cases (5%) because of failed biopsy detection.Despite recent colonoscopy with intent to remove all neoplasia, CRC will occasionally be diagnosed. These cancers primarily seem to represent lesions that were missed or incompletely removed at the prior colonoscopy and might be avoided by increased emphasis on identifying and completely removing all neoplastic lesions at colonoscopy.
| S-EPMC4383397 | biostudies-literature
Project description:Background and aimsPostcolonoscopy colorectal cancers (PCCRCs) are defined as those detected ≤10 years after an index colonoscopy negative for cancer, but modifiable risk factors are not well established in large, community-based populations.MethodsWe evaluated risk factors from the index colonoscopy for PCCRCs diagnosed 1 to 10 years after an index colonoscopy using a case-control design. Odds ratios (OR) and 95% confidence intervals (CI) were adjusted for potential confounders.ResultsA proximal polyp ≥10 mm (OR, 8.18; 95% CI, 4.59-14.60), distal polyp ≥10 mm (OR, 3.30; 95% CI, 1.65-6.58), adenoma with (OR, 3.23; 95% CI, 1.83-5.68) and without advanced histology (OR, 1.87; 95% CI, 1.37-2.55), and an incomplete colonoscopy (OR, 5.52; 95% CI, 2.98-10.21) were associated with PCCRC. Risk factors for early versus late cancers (12-36 months vs >36 months to 10 years after examination) included incomplete polyp excision in the colonic segment of the subsequent cancer (OR, 4.76; 95% CI, 2.35-9.65); failure to examine the segment (OR, 2.42; 95% CI, 1.27-4.60); and a polyp ≥10 mm in the segment (OR, 2.38; 95% CI, 1.53-3.70). A total of 559 of 1206 patients with PCCRC (46.4%) had 1 or more risk factors that were significant for PCCRC (incomplete examination, large polyp, or any adenoma).ConclusionsIn a large community-based study with comprehensive capture of PCCRCs, almost half of PCCRCs had potentially modifiable factors related to polyp surveillance or removal and examination completeness. These represent potential high-yield targets to further increase the effectiveness of colorectal cancer screening.
| S-EPMC7486003 | biostudies-literature
Project description:BRAFV600E mutation in microsatellite-unstable (MSI) colorectal carcinomas (CRCs) virtually excludes Lynch syndrome (LS). In microsatellite-stable (MSS) CRCs it predicts poor prognosis. We propose a universal CRC LS screening algorithm using concurrent reflex immunohistochemistry (IHC) for BRAFV600E and mismatch-repair (MMR) proteins. We compared BRAFV600E IHC with multiplex polymerase chain reaction (PCR) and matrix-assisted laser desorption/ionization-time of flight mass spectrometry in 216 consecutive CRCs from 2011. Discordant cases were resolved with real-time PCR. BRAFV600E IHC was performed on 51 CRCs from the Australasian Colorectal Cancer Family Registry (ACCFR), which were fully characterized for BRAF mutation by allele-specific PCR, MMR status (MMR IHC and MSI), MLH1 promoter methylation, and germline MLH1 mutation. We then assessed MMR and BRAFV600E IHC on 1403 consecutive CRCs. By matrix-assisted laser desorption/ionization-time of flight mass spectrometry 15 cases did not yield a BRAF result, whereas 38/201 (19%) were positive. By IHC 45/216 (20%) were positive. Of the 7 discordant cases, real-time PCR confirmed the IHC result in 6. In the 51 CRCs from the ACCFR, IHC was concordant with allele-specific PCR in 50 cases. BRAFV600E and MSI IHC on 1403 CRCs demonstrated the following phenotypes: BRAF/MSS (1029 cases, 73%), BRAF/MSS (98, 7%), BRAF/MSI (183, 13%), and BRAF/MSI (93, 7%). All 11/1403 cancers associated with proven LS were BRAF/MSI. We conclude that BRAF IHC is highly concordant with 2 commonly used PCR-based BRAFV600E assays; it performed well in identifying MLH1 mutation carriers from the ACCFR and identified all cases of proven LS among the 1403 CRCs. Reflex BRAFV600E and MMR IHC are simple cheap tests that facilitate universal LS screening and identify the poor prognosis of the BRAFV600E-mutant MSS CRC phenotype.
| S-EPMC3773060 | biostudies-literature
Project description:Background. Surveillance colonoscopy 1-year after colorectal cancer (CRC) surgery effectively reduces CRC mortality, yet less than half of survivors undergo this procedure. Text message reminders can improve CRC screening and other health behaviors, but use of this strategy to address barriers to CRC surveillance has not been reported. Objectives. The goal of this qualitative study was to assess CRC survivor perspectives on barriers to colonoscopy to inform the design of a theory-based, short message service (SMS) intervention to increase surveillance colonoscopy utilization. Method. CRC survivors in Western Washington participated in one of two focus groups to explore perceived barriers to completing surveillance colonoscopy and preferences for SMS communication. Content analysis using codes representative of the health belief model and prospect theory constructs were applied to qualitative data. Results. Thirteen CRC survivors reported individual-, interpersonal-, and system-level barriers to surveillance colonoscopy completion. Participants were receptive to receiving SMS reminders to mitigate these barriers. They suggested that reminders offer supportive, loss-framed messaging; include educational content; and be personalized to communication preferences. Finally, they recommended that reminders begin no earlier than 9 months following CRC surgery and not include response prompts. Conclusions. Our study demonstrates that CRC survivors perceive SMS reminders as an acceptable, valuable tool for CRC surveillance. Furthermore, there may be value in integrating theoretical frameworks to design, implement, and evaluate SMS interventions to address barriers to CRC surveillance. As physicians play a key role in CRC surveillance, provider- and system-level interventions that could additively improve the impact of SMS interventions are also worth exploring.
| S-EPMC7398620 | biostudies-literature
Project description:BACKGROUND & AIMS:Recommendations for surveillance after curative surgery for colorectal cancer (CRC) include a 1-year post-resection abdominal-pelvic computed tomography (CT) scan and optical colonoscopy (OC). CT colonography (CTC), when used in CRC screening, effectively identifies colorectal polyps ?10 mm and cancers. We performed a prospective study to determine whether CTC, concurrent with CT, could substitute for OC in CRC surveillance. METHODS:Our study enrolled 231 patients with resected stage 0-III CRC, identified at 5 tertiary care academic centers. Approximately 1 year after surgery, participants underwent outpatient CTC plus CT, followed by same-day OC. CTC results were revealed after endoscopic visualization of sequential colonic segments, which were re-examined for discordant findings. The primary outcome was performance of CTC in the detection of colorectal adenomas and cancers using endoscopy as the reference standard. RESULTS:Of the 231 participants, 116 (50.2%) had polyps of any size or histology identified by OC, and 15.6% had conventional adenomas and/or serrated polyps ?6 mm. No intra-luminal cancers were detected. CTC detected patients with polyps of ?6 mm with 44.0% sensitivity (95% CI, 30.2-57.8) and 93.4% specificity (95% CI, 89.7-97.0). CTC detected polyps ?10 mm with 76.9% sensitivity (95% CI, 54.0-99.8) and 89.0% specificity (95% CI, 84.8-93.1). Similar values were found when only adenomatous polyps were considered. The negative predictive value of CTC for adenomas ?6 mm was 90.7% (95% CI, 86.7-94.5) and for adenomas ?10 mm the negative predictive value was 98.6% (95% CI, 97.0-100). CONCLUSIONS:In a CRC surveillance population 1 year following resection, CTC was inferior to OC for detecting patients with polyps ?6 mm. Clinical Trials.gov Registration Number: NCT02143115.
| S-EPMC5847443 | biostudies-literature
Project description:BackgroundMajor advances have been achieved in the characterization of early breast cancer (eBC) genomic profiles. Metastatic breast cancer (mBC) is associated with poor outcomes, yet limited information is available on the genomic profile of this disease. This study aims to decipher mutational profiles of mBC using next-generation sequencing.Methods and findingsWhole-exome sequencing was performed on 216 tumor-blood pairs from mBC patients who underwent a biopsy in the context of the SAFIR01, SAFIR02, SHIVA, or Molecular Screening for Cancer Treatment Optimization (MOSCATO) prospective trials. Mutational profiles from 772 primary breast tumors from The Cancer Genome Atlas (TCGA) were used as a reference for comparing primary and mBC mutational profiles. Twelve genes (TP53, PIK3CA, GATA3, ESR1, MAP3K1, CDH1, AKT1, MAP2K4, RB1, PTEN, CBFB, and CDKN2A) were identified as significantly mutated in mBC (false discovery rate [FDR] < 0.1). Eight genes (ESR1, FSIP2, FRAS1, OSBPL3, EDC4, PALB2, IGFN1, and AGRN) were more frequently mutated in mBC as compared to eBC (FDR < 0.01). ESR1 was identified both as a driver and as a metastatic gene (n = 22, odds ratio = 29, 95% CI [9-155], p = 1.2e-12) and also presented with focal amplification (n = 9) for a total of 31 mBCs with either ESR1 mutation or amplification, including 27 hormone receptor positive (HR+) and HER2 negative (HER2-) mBCs (19%). HR+/HER2- mBC presented a high prevalence of mutations on genes located on the mechanistic target of rapamycin (mTOR) pathway (TSC1 and TSC2) as compared to HR+/HER2- eBC (respectively 6% and 0.7%, p = 0.0004). Other actionable genes were more frequently mutated in HR+ mBC, including ERBB4 (n = 8), NOTCH3 (n = 7), and ALK (n = 7). Analysis of mutational signatures revealed a significant increase in APOBEC-mediated mutagenesis in HR+/HER2- metastatic tumors as compared to primary TCGA samples (p < 2e-16). The main limitations of this study include the absence of bone metastases and the size of the cohort, which might not have allowed the identification of rare mutations and their effect on survival.ConclusionsThis work reports the results of the analysis of the first large-scale study on mutation profiles of mBC. This study revealed genomic alterations and mutational signatures involved in the resistance to therapies, including actionable mutations.
| S-EPMC5189935 | biostudies-literature
Project description:Lynch-like syndrome (LLS) is an increasingly common clinical challenge with an underlying molecular basis mostly unknown. To shed light onto it, we focused on a very young LLS early-onset colorectal cancer (CRC) cohort (diagnosis ≤ 40 y.o.), performing germline and tumor whole-exome sequencing (WES) of 15 patients, and additionally analyzing their corresponding tumor mutational burden (TMB) and mutational signatures. We identified four cases (27%) with double somatic putative variants in mismatch repair (MMR) core genes, as well as three additional cases (20%) with double MSH3 somatic alterations in tumors with unexplained MSH2/MSH6 loss of expression, and two cases (13%) with POLD1 potential biallelic alterations. Average TMB was significantly higher for LLS cases with double somatic alterations. Lastly, nine predicted deleterious variants in genes involved in the DNA repair functions and/or previously associated with CRC were found in nine probands, four of which also showed MMR biallelic somatic inactivation. In conclusion, we contribute new insights into LLS CRC, postulating MSH3 and POLD1 double somatic alterations as an underlying cause of a microsatellite instability (MSI) phenotype, proposing intrinsic biological differences between LLS with and without somatic alterations, and suggesting new predisposing candidate genes in this scenario.
| S-EPMC7999079 | biostudies-literature