Molecular Features of the Serrated Pathway to Colorectal Cancer: Current Knowledge and Future Directions

Satorres, Carla; García-Campos, María; Bustamante-Balén, Marco

doi:10.5009/gnl19402

Cited by 15 publications

(14 citation statements)

References 76 publications

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“…An observation about the control group showed that all BRAF -mutated SSLs without dysplasia were MSS. It is interesting to know if the evolving lesions in this group will suffer further mutations or if these lesions are going to evolve towards a BRAF -mutated MSS carcinoma, entity that has, usually, as precursor, a TSA [ 42 ].…”

Section: ⧉ Discussionmentioning

confidence: 99%

MLH1, BRAF and p53 – searching for significant markers to predict evolution towards adenocarcinoma in colonic sessile serrated lesions

Răduţă

Dincă²,

Micu³

et al. 2022

Rom J Morphol Embryol

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Background and Aim : Colonic serrated lesions are premalignant lesions, using an alternative malignization pathway, including multiple genetic and epigenetic alterations, as: mismatch repair deficiency due to MutL homolog 1 ( MLH1 ) promoter methylation, tumor protein p53 ( TP53 ) mutations, activating mutations of v-Raf murine sarcoma viral oncogene homolog B ( BRAF ) and Kirsten rat sarcoma viral oncogene homolog ( KRAS ). Our study aims to evaluate MLH1, BRAF and p53 immunohistochemical (IHC) status in sessile serrated lesions (SSLs), with and without dysplasia. Materials and Methods : This is a retrospective case-control study including 20 SSLs with dysplasia and 20 SSLs without dysplasia (matching sex and age). IHC expression of MLH1, BRAF and p53 was evaluated as the percent of nuclear loss of MLH1, cytoplasmic positivity of BRAF and nuclear positivity of p53. Data concerning age, sex, localization of the lesion, dysplasia and IHC results were statistically processed using Microsoft Excel. Results : We had very polymorphous patterns of IHC expression for BRAF, MLH1 and p53, especially in the dysplastic group. Thus, two patients were BRAF+/MLH1-/p53+, three were BRAF+/MLH1-/p53-, one was BRAF+/MLH1+/p53- and six were BRAF+/MLH1+/p53+. Dysplastic lesions without BRAF mutation exhibited the following phenotype: one case BRAF-/MLH1-/p53+, four BRAF-/MLH1-/p53- and three BRAF-/MLH1+/p53+. In the control group (SSLs without dysplasia), there was a more homogenous distribution of cases: eight cases BRAF+/MLH1+/p53-, seven BRAF-/MLH1+/p53-, one BRAF-/MLH1-/p53+, two BRAF-/MLH1-/p53- and two BRAF-/MLH1+/p53+. Conclusions : There are more routes on the serrated pathway, with different mutations and time of acquisition of each genetic or epigenetic lesion with the same morphological result. These lesions should be stratified according to their risk to poor outcome and their need to further surveillance.

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Section: ⧉ Discussionmentioning

confidence: 99%

MLH1, BRAF and p53 – searching for significant markers to predict evolution towards adenocarcinoma in colonic sessile serrated lesions

Răduţă

Dincă²,

Micu³

et al. 2022

Rom J Morphol Embryol

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“…2021, 22, 6767 2 of 15 tumor cells [8]. Indeed, microsatellite sequences are tracts of tandemly repeated DNA motifs ranging from one to six nucleotides in length, which are susceptible to accumulate mutations [9].…”

Section: Introductionmentioning

confidence: 99%

“…The highest specificity and sensitivity are reached using a panel of two or more polyA mononucleotide (BAT25, BAT26, NR-21, NR-22, NR-24, and NR-27) and three dinucleotide (D2S123, D5S346, and D17S250) markers. At least two of these different markers are needed to classify the tumor as MSIhigh, whereas tumors with only one affected marker are considered MSI-low [9]. IHC is used to detect the expression of the four MMR proteins (MLH1, MSH2, MSH6, and PMS2), whose loss is highly concordant (>90%) with DNA-based assays.…”

Section: Introductionmentioning

confidence: 99%

From Genetics to Histomolecular Characterization: An Insight into Colorectal Carcinogenesis in Lynch Syndrome

Signorile

Disciglio

Carlo

et al. 2021

IJMS

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Lynch syndrome is a hereditary cancer-predisposing syndrome caused by germline defects in DNA mismatch repair (MMR) genes such as MLH1, MSH2, MSH6, and PMS2. Carriers of pathogenic mutations in these genes have an increased lifetime risk of developing colorectal cancer (CRC) and other malignancies. Despite intensive surveillance, Lynch patients typically develop CRC after 10 years of follow-up, regardless of the screening interval. Recently, three different molecular models of colorectal carcinogenesis were identified in Lynch patients based on when MMR deficiency is acquired. In the first pathway, adenoma formation occurs in an MMR-proficient background, and carcinogenesis is characterized by APC and/or KRAS mutation and IGF2, NEUROG1, CDK2A, and/or CRABP1 hypermethylation. In the second pathway, deficiency in the MMR pathway is an early event arising in macroscopically normal gut surface before adenoma formation. In the third pathway, which is associated with mutations in CTNNB1 and/or TP53, the adenoma step is skipped, with fast and invasive tumor growth occurring in an MMR-deficient context. Here, we describe the association between molecular and histological features in these three routes of colorectal carcinogenesis in Lynch patients. The findings summarized in this review may guide the use of individualized surveillance guidelines based on a patient’s carcinogenesis subtype.

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“…Sessile serrated lesions (SSL) may be responsible for up to 35 % of colorectal cancers (CRC) 1 , through the so-called serrated pathway 2 . Because of their morphologic characteristics, they can be more easily missed or incompletely removed 3 , and some data suggest that progression to cancer may be greatly accelerated when dysplasia is already present 4 .…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the optical criteria for sessile serrated lesions of the colon: A prospective study on a colorectal cancer screening population

et al. 2021

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Background and study aims We aimed to describe the presence and combination of Hazewinkelʼs optical diagnosis (OD) criteria for sessile serrated lesions (SSL), determining which lesion characteristics increase the probability of a correct OD, with a focus on diminutive lesions. Patients and methods This was a prospective study describing the presence of Hazewinkelʼs OD criteria for SSL in lesions found in consecutive CRC screening colonoscopies. The presence of each OD criterion and their diagnostic combinations in SSL, related to the lesion’s NBI International Colorectal Endoscopic (NICE) classification category, size, and location, were described. The presence of two or more optical criteria was considered diagnostic of SSL. The OD was compared to pathology as the gold standard. Results Seventy-nine SSLs (5.6 %) were diagnosed. Cloud-like appearance was the most prevalent OD criterion (35, 44.3 %). OD criteria were more frequently identified in NICE type 1, ≥ 10 mm, and proximal lesions. Only 26 SLLs fulfilled the OD criteria (sensitivity 32.9 %, 95 % CI 29.1 %–36.7 %). The sensitivity for diminutive SSL was 14.7 %, (95 % CI 11.9 %–17.6 %). Eighty-five lesions were optically diagnosed as SSL. However, only in 26 SSL was this the definitive diagnosis (positive predictive value 30.6 %, 95 % CI 26.9 %–34.3 %). Size > 5 mm and proximal location increased the probability of a correct diagnosis. The overall accuracy of the optical criteria was 92.0 % (95 % CI, 89.8 %–94.2 %). Conclusions The Hazewinkelʼs optical criteria are not reliable for a positive diagnosis of SSL, particularly for diminutive lesions.

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Molecular Features of the Serrated Pathway to Colorectal Cancer: Current Knowledge and Future Directions

Cited by 15 publications

References 76 publications

MLH1, BRAF and p53 – searching for significant markers to predict evolution towards adenocarcinoma in colonic sessile serrated lesions

MLH1, BRAF and p53 – searching for significant markers to predict evolution towards adenocarcinoma in colonic sessile serrated lesions

From Genetics to Histomolecular Characterization: An Insight into Colorectal Carcinogenesis in Lynch Syndrome

Evaluation of the optical criteria for sessile serrated lesions of the colon: A prospective study on a colorectal cancer screening population

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