Germline and somatic genetic alterations in two first‐degree relatives with appendiceal low‐grade mucinous carcinoma peritonei

King, Mary Caitlin; Muñoz‐Zuluaga, Carlos; Ledakis, Panayotis; Studeman, Kimberley; Sittig, Michelle; Gushchin, Vadim

doi:10.1002/ccr3.3338

Cited by 3 publications

(15 citation statements)

References 56 publications

(115 reference statements)

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“…Regaining KRAS gene function due to mutations is common in many tumor types [18], particularly those of the gastrointestinal tract [19,20]. In appendiceal tumors, KRAS gene mutations are identified in more than 50% of cases [13], being present in some cases of epithelial tumors: sessile serrated lesions with or without dysplasia [15,16,[21][22][23], low-grade appendiceal mucinous neoplasm (LAMN) [7][8][9][24][25][26][27][28][29][30][31][32][33][34], high-grade appendiceal mucinous neoplasms (HAMN) [27,29], mucinous adenocarcinomas of the appendix [12,35], non-mucinous adenocarcinomas of the appendix [35], and appendiceal goblet cell adenocarcinoma [36,37], but is completely lacking in neuroendocrine tumors of the appendix (Figure 3). Among the single-amino-acid substitution (missense) mutations of the KRAS protein identified in appendix cancers are Gly12Asp/Val/Ser/Arg/Cys and Gly13Asp/Arg/Cys [28,29].…”

Section: Ras-raf-mek-erk Signaling Pathway 211 Ras Gene Familymentioning

confidence: 99%

“…Defects in the FANCA gene are identified in Fanconi anemia, complementation group a, and pituitary stalk interruption syndrome [169]. However, this gene is rarely mutated in appendix cancers, as in a single case of low-grade appendiceal mucinous neoplasm [32].…”

Section: Genes Involved In Dna Metabolism/expressionmentioning

confidence: 99%

“…The KDM6A gene (Xp11.3) encodes the KDM6A-Lysine Demethylase 6A protein (1401 amino acids; 154,177 Da), which catalyzes the demethylation of tri/di-methylated histone H3. Defects in the functioning of the KDM6A gene are present in Kabuki syndromes 1 and 2 [170], and mutations in this gene are reported in a few cases of appendiceal goblet cell adenocarcinomas [32].…”

Section: Genes Involved In Dna Metabolism/expressionmentioning

confidence: 99%

“…When mutated, it is associated with Kabuki syndrome 1 and choanal atresia-athelia-hypothyroidism-delayed puberty-short stature syndrome [171]. However, in appendiceal cancers, mutations in the KTM2D gene are rarely mutated, with two cases of appendiceal goblet cell adenocarcinomas reported so far [32].…”

Section: Genes Involved In Dna Metabolism/expressionmentioning

confidence: 99%

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Landscape of Genetic Mutations in Appendiceal Cancers

Constantin,

Mătanie,

Petrescu

et al. 2023

Cancers

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In appendiceal cancers, the most frequently mutated genes are (i) KRAS, which, when reactivated, restores signal transduction via the RAS–RAF–MEK–ERK signaling pathway and stimulates cell proliferation in the early stages of tumor transformation, and then angiogenesis; (ii) TP53, whose inactivation leads to the inhibition of programmed cell death; (iii) GNAS, which, when reactivated, links the cAMP pathway to the RAS–RAF–MEK–ERK signaling pathway, stimulating cell proliferation and angiogenesis; (iv) SMAD4, exhibiting typical tumor-suppressive activity, blocking the transmission of oncogenic TGFB signals via the SMAD2/SMAD3 heterodimer; and (v) BRAF, which is part of the RAS–RAF–MEK–ERK signaling pathway. Diverse mutations are reported in other genes, which are part of secondary or less critical signaling pathways for tumor progression, but which amplify the phenotypic diversity of appendiceal cancers. In this review, we will present the main genetic mutations involved in appendix tumors and their roles in cell proliferation and survival, and in tumor invasiveness, angiogenesis, and acquired resistance to anti-growth signals.

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Section: Ras-raf-mek-erk Signaling Pathway 211 Ras Gene Familymentioning

confidence: 99%

Section: Genes Involved In Dna Metabolism/expressionmentioning

confidence: 99%

Section: Genes Involved In Dna Metabolism/expressionmentioning

confidence: 99%

Section: Genes Involved In Dna Metabolism/expressionmentioning

confidence: 99%

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Landscape of Genetic Mutations in Appendiceal Cancers

Constantin,

Mătanie,

Petrescu

et al. 2023

Cancers

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“…Understanding cancer susceptibility gene sequence variations associated with appendiceal carcinogenesis has been hampered by limited study sizes and scopes. Overall, published studies screening appendiceal tumors for microsatellite instability, a hallmark of Lynch syndrome, suggest a low prevalence (<4%) of microsatellite instability in the appendix . However, the prevalence of other hereditary cancer syndromes and the spectrum of germline genetic features among patients with appendix cancer are also largely unknown, as previous cohort studies have not been conducted specific to this patient population.…”

Section: Introductionmentioning

confidence: 99%

Inherited Cancer Susceptibility Gene Sequence Variations Among Patients With Appendix Cancer

et al. 2023

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ImportanceGermline sequence variations in APC, BMPR1A, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, PMS2, PTEN, SMAD4, STK11, and TP53 genes are associated with susceptibility to gastrointestinal cancers. As a rare cancer, the evaluation of appendiceal cancer (AC) predisposition has been limited.ObjectiveTo assess the prevalence and spectrum of inherited cancer susceptibility gene sequence variations in patients with AC and the utility of germline genetic testing for this population.Design, Setting, and ParticipantsThis cohort study included patients with AC who underwent germline genetic testing of 14 cancer susceptibility genes performed by a clinical testing laboratory between March 1, 2012, and December 31, 2016. Data were analyzed from March to August 2022. Clinical, individual, and family histories were obtained from clinician-completed test requisition forms. Multigene panel testing was performed by targeted custom capture and sequencing and chromosome rearrangement analysis.Main Outcomes and MeasuresThe main outcomes were germline sequence variation prevalence and spectrum in patients with AC.ResultsAmong the 131 patients with AC in the cohort (90 female [68.7%]), a total of 16 deleterious sequence variations were identified in 15 patients (11.5%). Similarly, when limited to the 74 patients with AC as the first and only primary tumor, a total of 8 patients (10.8%) had at least 1 deleterious sequence variation in a cancer susceptibility gene. Overall, 6 patients (4.6%) had a deleterious sequence variation observed in MUTYH (5 with monoallelic MUTYH and 1 with biallelic MUTYH). All 4 patients with Lynch syndrome (3.1%) had a sequence variation in the MLH1 gene, of whom 3 were aged 50 years or older at AC diagnosis. Five patients (3.8%) had deleterious sequence variations in other cancer predisposition genes (1 with APC [c.3920T&gt;A, p.I1307K], 2 with CHEK2 [c.470T&gt;C, p.I157T], 1 with SMAD4 [c.263 287dup, p.L98IFS*14], and 1 with TP53 [c.524G&gt;A, p.R175H]).Conclusions and RelevanceIn this cohort study, 1 in every 10 patients with AC who underwent testing for hereditary cancer predisposition carried an inherited gene sequence variation associated with cancer susceptibility. Given the high frequency and broad spectrum of germline gene sequence variations, these data suggest that genetic evaluation might be warranted for all patients diagnosed with this rare malignant tumor. A systemic sequencing effort for all patients with AC may also identify cancer vulnerabilities to exploit for therapeutic development in a cancer type for which clinical trials are limited.

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The genetic profile and molecular subtypes of human pseudomyxoma peritonei and appendiceal mucinous neoplasms: a systematic review

Murage

Ahmed

Underwood

et al. 2023

Cancer Metastasis Rev

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Pseudomyxoma peritonei (PMP) is a rare, progressive, slowly growing neoplastic condition which is poorly understood, with a 5-year progression-free survival rate as low as 48%. PMP is most commonly caused by appendiceal mucinous neoplasms (AMN), and understanding their genetic biology and pathogenicity may allow for the development of better novel systemic treatments to target key deleterious mutations and the implicated pathways. The primary aim of this systematic review was to identify the genetic profile of histologically confirmed human PMP or AMN samples. The secondary aim was to identify whether genetic marks could be used to predict patient survival. Ovid EMBASE, Ovid MEDLINE, PubMed, and Web of Science were searched to identify studies investigating the genetic profile of histologically-confirmed human PMP or AMN samples. We review findings of 46 studies totalling 2181 tumour samples. The most frequently identified somatic gene mutations in patients with PMP included KRAS (38–100%), GNAS (17–100%), and TP53 (5–23%); however, there were conflicting results of their effect on survival. Three studies identified molecular subtypes based on gene expression profiles classifying patients into oncogene-enriched, immune-enriched, and mixed molecular subtypes with prognostic value. This review summarises the current literature surrounding genetic aberrations in PMP and AMNs and their potential utility for targeted therapy. Given the recent advances in clinical trials to directly target KRAS and GNAS mutations in other cancers, we propose a rationale to explore these mutations in future pre-clinical studies in PMP with a view for a future clinical trial. Graphical Abstract

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Germline and somatic genetic alterations in two first‐degree relatives with appendiceal low‐grade mucinous carcinoma peritonei

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 3 publications

References 56 publications

Landscape of Genetic Mutations in Appendiceal Cancers

Landscape of Genetic Mutations in Appendiceal Cancers

Inherited Cancer Susceptibility Gene Sequence Variations Among Patients With Appendix Cancer

The genetic profile and molecular subtypes of human pseudomyxoma peritonei and appendiceal mucinous neoplasms: a systematic review

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