Ovarian and endometrial endometrioid adenocarcinomas have distinct profiles of microsatellite instability, <scp>PTEN</scp> expression, and <scp>ARID</scp>1A expression

Huang, Hsien Neng; Lin, Ming-Nan; Tseng, Li Hui; Chiang, Ying‐Cheng; Lin, Liang In; Lin, Yu Feng; Huang, Hung Chang; Kuo, Kuan-Ting

doi:10.1111/his.12543

Cited by 37 publications

(29 citation statements)

References 36 publications

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“…22–25 Previous literature indicates that ~41–71% of endometrial cancers and 14–32% of colorectal cancers have a mutation in any exon of PIK3CA . 26–29 A modestly higher frequency of PIK3CA mutations has been reported in MSI colorectal cancers compared to MSS cancers, without differentiation by etiology of MSI.…”

Section: Discussionmentioning

confidence: 99%

“…We used a selection of Lynch syndrome, MLH1 hypermethylated, and MSS cases for comparison with a large number of double somatic MMR cases. Unlike many prior reports, 22, 24, 42 our analysis was not restricted to certain exons or codons. Even with the relatively small number of cases in this study, we observed multiple significant differences between groups.…”

Section: Discussionmentioning

confidence: 99%

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Frequent PIK3CA Mutations in Colorectal and Endometrial Tumors With 2 or More Somatic Mutations in Mismatch Repair Genes

et al. 2016

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Background & Aims Double somatic mutations in mismatch repair (MMR) genes have recently been described in colorectal and endometrial cancers with microsatellite instability (MSI) not attributable to MLH1 hypermethylation or germline mutation. We sought to define the molecular phenotype of this newly recognized tumor subtype. Methods From two prospective Lynch syndrome screening studies, we identified patients with colorectal and endometrial tumors harboring ≥2 somatic MMR mutations, but normal germline MMR testing (“double somatic”). We determined the frequencies of tumor PIK3CA, BRAF, KRAS, NRAS, and PTEN mutations by targeted next-generation sequencing and used logistic-regression models to compare them to: Lynch syndrome, MLH1 hypermethylated, and microsatellite stable (MSS) tumors. We validated our findings using independent datasets from The Cancer Genome Atlas (TCGA). Results Among colorectal cancer cases, we found that 14/21 (67%) of double somatic cases had PIK3CA mutations vs. 4/18 (22%) Lynch syndrome, 2/10 (20%) MLH1 hypermethylated, and 12/78 (15%) MSS tumors; p<0.0001. PIK3CA mutations were detected in 100% of 13 double somatic endometrial cancers (p=0.04). BRAF mutations were absent in double somatic and Lynch syndrome colorectal tumors. We found highly similar results in a validation cohort from TCGA (113 colorectal, 178 endometrial cancer), with 100% of double somatic cases harboring a PIK3CA mutation (p<0.0001). Conclusions PIK3CA mutations are present in double somatic mutated colorectal and endometrial cancers at substantially higher frequencies than other MSI subgroups. PIK3CA mutation status may better define an emerging molecular entity in colorectal and endometrial cancers, with the potential to inform screening and therapeutic decision making.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Frequent PIK3CA Mutations in Colorectal and Endometrial Tumors With 2 or More Somatic Mutations in Mismatch Repair Genes

et al. 2016

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“…Endometrioidni karcinomi niskog gradusa pokazuju odstupanja u Wnt (engl. Wingless type) signalnom putu koja obuhvaćaju somatske mutacije gena CTNNB1 koji kodira β-catenin, PTEN i PIK3CA 30 . Mucinozni karcinomi u više od 50 % pokazuju KRAS mutaciju 31,32 .…”

Section: Tip 1 Tumoriunclassified

Recent concepts of ovarian cancer

2016

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Sažetak. Karcinom jajnika je vodeći uzrok smrti među zloćudnim novotvorinama ženskog spolnog sustava. Usprkos pokušajima razvoja programa probira s ciljem ranog otkrivanja bolesti, kao i novim terapijskim pristupima, mortalitet nije značajno smanjen. Jedan od razloga ovog neuspjeha bio je slabo razumijevanje patogeneze karcinoma jajnika koji je smatran jedinstvenom bolešću. Nove spoznaje pokazuju da je karcinom jajnika vrlo heterogena bolest, koja se na temelju kliničkopatoloških karakteristika te molekularnih i genetičkih promjena može podijeliti u dvije skupine: tip 1 i tip 2 tumori. Ovaj novi model patogeneze karcinoma jajnika danas ima važan klinički i terapijski značaj.Ključne riječi: karcinom jajnika; morfologija; patogeneza; terapija Abstract. Ovarian cancer is the most lethal gynecologic malignancy. Efforts to develop screening methods and new therapeutic approaches to reduce mortality have been unsuccessful. One of the main reasons for this is our lack of knowledge of the origin and pathogenesis of ovarian cancer. This led to the postulate that it is a single disease. Recent studies have shown that ovarian cancer is a heterogeneous disease composed of diverse types of tumors that can be classified based on clinicopathologic and molecular genetic features into two broad groups designated type 1 and type 2. This new model of pathogenesis of ovarian cancer has significant clinical and therapeutic implication.

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“…A close relationship has been identified between MSI and ARID1A alteration in some neoplasms . SWI/SNF family members such as ARID1A, INI1, BRG1, BRM, BAF155, and BAF170 are involved in the regulation of vital cellular processes, such as proliferation and differentiation, in a wide variety of neoplasms .…”

Section: Introductionmentioning

confidence: 99%

Solid‐type poorly differentiated adenocarcinoma of the stomach: Deficiency of mismatch repair and SWI/SNF complex

et al. 2020

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ARID1A, one of the subunits in SWI/SNF chromatin remodeling complex, is frequently mutated in gastric cancers with microsatellite instability (MSI). The most frequent MSI in solid‐type poorly differentiated adenocarcinoma (PDA) has been reported, but the SWI/SNF complex status in solid‐type PDA is still largely unknown. We retrospectively analyzed 54 cases of solid‐type PDA for the expressions of mismatch repair (MMR) proteins (MLH1, PMS2, MSH2, and MSH6), SWI/SNF complex subunits (ARID1A, INI1, BRG1, BRM, BAF155, and BAF170) and EBER, and mutations in KRAS and BRAF. We analyzed 40 cases of another histological type of gastric cancer as a control group. The solid‐type PDAs showed coexisting glandular components (76%), MMR deficiency (39%), and complete/partial loss of ARID1A (31%/7%), INI1 (4%/4%), BRG1 (48%/30%), BRM (33%/33%), BAF155 (13%/41%), and BAF170 (6%/2%), EBER positivity (4%), KRAS mutation (2%), and BRAF mutation (2%). Compared to the control group, MMR deficiency and losses of ARID1A, BRG1, BRM, and BAF155 were significantly frequent in solid‐type PDAs. Mismatch repair deficiency was associated with the losses of ARID1A, BRG1, and BAF155 in solid‐type PDAs. In the MMR‐deficient group, solid components showed significantly more frequent losses of ARID1A, BRG1, BRM, and BAF155 compared to glandular components (P = .0268, P = .0181, P = .0224, and P = .0071, respectively). In the MMR‐proficient group, solid components showed significantly more frequent loss of BRG1 compared to glandular components (P = .012). In conclusion, solid‐type PDAs showed frequent losses of MMR proteins and the SWI/SNF complex. We suggest that loss of the SWI/SNF complex could induce a morphological shift from differentiated‐type adenocarcinoma to solid‐type PDA.

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Ovarian and endometrial endometrioid adenocarcinomas have distinct profiles of microsatellite instability, PTEN expression, and ARID1A expression

Abstract: The different frequencies of molecular genetic alterations between endometrial endometrioid adenocarcinomas and ovarian endometrioid adenocarcinomas imply that distinct processes may be involved in their tumorigenesis or tumour progression.

Cited by 37 publications

References 36 publications

Frequent PIK3CA Mutations in Colorectal and Endometrial Tumors With 2 or More Somatic Mutations in Mismatch Repair Genes

Frequent PIK3CA Mutations in Colorectal and Endometrial Tumors With 2 or More Somatic Mutations in Mismatch Repair Genes

Recent concepts of ovarian cancer

Solid‐type poorly differentiated adenocarcinoma of the stomach: Deficiency of mismatch repair and SWI/SNF complex

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