MLH1/PMS2 Expression Could Tell Classical NTRK Fusion in Fluorescence In Situ Hybridization Positive Colorectal Carcinomas

To gain insight into the clinicopathologic profile of colorectal carcinomas harboring oncogenic NTRK fusions based on eastern populations as well as make the best testing algorithm for the screen, we use pan-Trk immunohistochemistry (IHC), fluorescence in situ hybridization (FISH) respectively to screen NTRK fusions in a large, unselected cohort of 819 colon cancers; either IHC or FISH positive cases were further detected by next-generation sequencing (NGS). IHC staining was observed in ten (1.22%) cases. FISH positive was observed in 13 (1.59%) cases, and finally, a total of 18 cases were under both a DNA-based and an RNA-based NGS assay. RNA-based NGS was positive in 13 of 18 cases, whereas DNA-based NGS was only positive in three of 18 cases. In total 13 RNA-based NGS NTRK fusion-positive cases, only six cases were pan-TRK IHC positive versus 12 were FISH positive. More important, in 13 RNA-based NGS cases only five cases contain the full length of NTRK tyrosine kinase (TK) domain and form the classical fusion chimeras, other six cases only maintain parts of the TK domain and form the sub-classical fusion chimeras, two cases totally miss the TK domain and form the non-classical fusions. For clinicopathologic characteristics, besides the MMR (mismatch repair) status (p = 0.001), there is no difference between the NTRK fusion-positive and negative cases. Nevertheless, classical fusion cases prefer low differentiation (p = 0.001) and different patterns of growth (p < 0.001). Besides, we found all five classical NTRK fusion cases, and only one sub-classical case was harboring MLH1/PMS2 deficiency. When combining FISH and MMR (Mismatch Repair) status, besides one sub-classical case, all five classical fusions were detected, which means MLH1/PMS2 expression could further narrow the classical fusions in FISH NTRK fusion positive cases. Given the low sensitivity and specificity of the pan-Trk antibody, it would be useless to use IHC to screen NTRK fusion-positive CRCs. Combining FISH and MLH1/PMS2 IHC would be a good testing algorithm for the screen effective NTRK fusions. Finally, if patients are going to undergo TRK-based targeted therapy, only RNA-based NGS for detection of the specific fusion could tell the precise rearrangement information.

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Clinicopathologic Profile of Breast Cancer in Germline ATM and CHEK2 Mutation Carriers

Genes ◽

10.3390/genes12050616 ◽

2021 ◽

Vol 12 (5) ◽

pp. 616

Author(s):

Angela Toss ◽

Elena Tenedini ◽

Claudia Piombino ◽

Marta Venturelli ◽

Isabella Marchi ◽

...

Keyword(s):

Breast Cancer ◽

High Rate ◽

Luminal A ◽

Clinicopathologic Characteristics ◽

Luminal B ◽

Chek2 Mutation ◽

Mutation Carriers ◽

Clinicopathologic Profile ◽

Contralateral Mastectomy

The most common breast cancer (BC) susceptibility genes beyond BRCA1/2 are ATM and CHEK2. For the purpose of exploring the clinicopathologic characteristics of BC developed by ATM or CHEK2 mutation carriers, we reviewed the archive of our Family Cancer Clinic. Since 2018, 1185 multi-gene panel tests have been performed. Nineteen ATM and 17 CHEK2 mutation carriers affected by 46 different BCs were identified. A high rate of bilateral tumors was observed in ATM (26.3%) and CHEK2 mutation carriers (41.2%). While 64.3% of CHEK2 tumors were luminal A-like, 56.2% of ATM tumors were luminal B-like/HER2-negative. Moreover, 21.4% of CHEK2-related invasive tumors showed a lobular histotype. About a quarter of all ATM-related BCs and a third of CHEK2 BCs were in situ carcinomas and more than half of ATM and CHEK2-related BCs were diagnosed at stage I-II. Finally, 63.2% of ATM mutation carriers and 64.7% of CHEK2 mutation carriers presented a positive BC family history. The biological and clinical characteristics of ATM and CHEK2-related tumors may help improve diagnosis, prognostication and targeted therapeutic approaches. Contralateral mastectomy should be considered and discussed with ATM and CHEK2 mutation carriers at the first diagnosis of BC.

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Histopathology and Mismatch Repair Status of 458 Consecutive Colorectal Carcinomas

The American Journal of Surgical Pathology ◽

10.1097/00000478-200311000-00001 ◽

2003 ◽

Vol 27 (11) ◽

pp. 1393-1406 ◽

Cited By ~ 60

Author(s):

Cheryl L. Wright ◽

Ian D. Stewart

Keyword(s):

Mismatch Repair ◽

Colorectal Carcinomas ◽

Mismatch Repair Status

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Colorectal carcinomas and DNA mismatch repair status a statistical analysis of 123 consecutive cases from a tertiary center

10.26226/morressier.5b4709896f4cb30010951eae ◽

2018 ◽

Author(s):

Irina Alexandra Ostahi ◽

Irina Alexandra Cozea

Keyword(s):

Statistical Analysis ◽

Mismatch Repair ◽

Dna Mismatch Repair ◽

Colorectal Carcinomas ◽

Dna Mismatch ◽

Tertiary Center ◽

Mismatch Repair Status

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Mikroszatellita-instabilitás előfordulása, intratumoralis heterogenitása, prognosztikus és prediktív potenciálja primer colorectalis carcinomák és párosított májáttéteik sebészi kezelését követően

Orvosi Hetilap ◽

10.1556/650.2015.30218 ◽

2015 ◽

Vol 156 (36) ◽

pp. 1460-1471 ◽

Cited By ~ 1

Author(s):

Emese Irma Ágoston ◽

Zsolt Baranyai ◽

Kristóf Dede ◽

György Bodoky ◽

Janina Kulka ◽

...

Keyword(s):

Overall Survival ◽

Molecular Markers ◽

Mismatch Repair ◽

Staining Intensity ◽

Response To Therapy ◽

Clinicopathological Parameters ◽

Colorectal Carcinomas ◽

Therapy Regimen ◽

Methylator Phenotype ◽

Mismatch Repair Status

Introduction: Besides clinicopathological parameters, molecular markers can be very important, and further characterize colorectal carcinomas into chromosomally unstable, microsatellite instable and “CqG-island methylator phenotype” groups. Aim: To study the frequency of microsatellite instability using immunohistochemical evaluation of MLH1, MSH2, MSH6 and PMS2 proteins in colorectal carcinoma. Method: 122 colorectal carcinomas as well as in 69 paired liver metastases were evaluated. Additionally, prognostic and predictive potential of mismatch repair status was tested. Results: Microsatellite instable phenotype was identified in 11.5% (14/122) of the tumours. There were no differences regarding staining intensity of tumour regions. Mismatch repair status was discordant in primaries vs. metastases in 20.2%. There was no difference in progression free- and overall survival according to mismatch repair status. The mismatch repair status was not predictive for survival within systemic therapy regimen groups. Conclusions: The subgroups of colorectal carcinomas could be evaluated in a larger and homogenised patient cohort to predict prognosis and response to therapy. Orv. Hetil., 2015, 156(36), 1460–1471.

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