Microsatellite instability and the PTEN1 gene mutation in a subset of early onset gliomas carrying germline mutation or promoter methylation of the hMLH1 gene

Abstract Background Tumor molecular screening allows categorization of molecular alterations to select the best therapeutic strategy. AT-rich interactive domain-containing 1A (ARID1A) gene mutations are present in gastric, endometrial, and clear cell ovarian tumors. Inactivation of this gene impairs mismatch repair (MMR) machinery leading to an increased mutation burden that correlates with microsatellite instability (MSI), associated with tumor-infiltrating lymphocytes and programmed death ligand 1 (PD-L1) expression. This is the first case report in lung adenocarcinoma of ARID1A gene alterations leading to sporadic MSI, through somatic mutL homolog 1 (MLH1) promoter methylation, with an MLH1 gene mutation as the second somatic hit. Case presentation A 50-year-old never-smoker Bulgarian woman, with no comorbidities and no family history of cancer, was diagnosed with metastatic lung adenocarcinoma. PD-L1 immunohistochemistry (IHC) of tissue biopsies on right groin adenopathies resulted in 30% positivity. Liquid biopsy test reported actionable alterations in ARID1A gene, rearranged during transfection (RET) gene fusions, epidermal growth factor receptor (EGFR) gene R776H mutation, breast cancer (BRCA) genes 1/2, and cyclin-dependent kinase inhibitor 2A (CDKN2A) gene mutations. The patient was treated with immunotherapy, and showed a treatment response lasting for 19 months until a new metastasis appeared at the right deltoid muscle. Genomic analysis of a sample of this metastasis confirmed PD-L1 positivity of greater than 50% with CD8+ T cells expression and showed MSI with a deleterious c.298C>T (p.R100*) MLH1 gene mutation. Multiplex ligation-dependent probe amplification (MLPA) of this sample unveiled MLH1 gene promoter methylation. The MLH1 gene mutation and the MLH1 gene methylation were not present at the germline setting. Conclusions In this particular case, we show that ARID1A gene mutations with sporadic MSI due to somatic MLH1 gene promoter methylation and MLH1 gene mutation could change the prognosis and define the response to immunotherapy in a patient with lung adenocarcinoma. Comprehensive solid and liquid biopsy tests are useful to find out resistance mechanisms to immune checkpoint inhibitors. Our data encourages the development of new therapies against ARID1A mutations and epigenomic methylation when involved in MSI neoplasms.

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Early Onset Primary Hyperparathyroidism Associated with a Novel Germline Mutation inCDKN1B

Case Reports in Endocrinology ◽

10.1155/2015/510985 ◽

2015 ◽

Vol 2015 ◽

pp. 1-4 ◽

Cited By ~ 8

Author(s):

Marianne S. Elston ◽

Goswin Y. Meyer-Rochow ◽

Michael Dray ◽

Michael Swarbrick ◽

John V. Conaglen

Keyword(s):

Primary Hyperparathyroidism ◽

Missense Mutation ◽

Gene Mutation ◽

Germline Mutation ◽

Early Onset ◽

Middle Age ◽

Age Of Onset ◽

Germline Mutations ◽

Germline Gene ◽

Exon 1

Individuals presenting with primary hyperparathyroidism (PHPT) at a young age commonly have an underlying germline gene mutation in one of the following genes:MEN1, CASR, orCDC73. A small number of families with primary hyperparathyroidism have been identified with germline mutations inCDKN1Band those patients with primary hyperparathyroidism have almost exclusively been women who present in middle age suggesting that the age of onset of PHPT in MEN4 may be later than that of MEN1. We present a case of apparently sporadic PHPT presenting in adolescence with single gland disease associated with a novelCDKN1Bgermline mutation (heterozygote for a missense mutation in exon 1 of theCDKN1Bgene (c.378G>C) (p.E126D)). The implication from this case is thatCDKN1Bgermline mutations may be associated with PHPT at an earlier age than previously thought.

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Abstract #805292: Early Onset Primary Hyperparathyroidism with CD73 Gene Mutation

Endocrine Practice ◽

10.1016/s1530-891x(20)39617-8 ◽

2020 ◽

Vol 26 ◽

pp. 59-60

Author(s):

Ana Del Carmen Rivadeneira

Keyword(s):

Primary Hyperparathyroidism ◽

Gene Mutation ◽

Early Onset

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Charcot-Marie-Tooth polyneuropathy type 2A related to a mitofusin 2 gene mutation presenting as severe early-onset axonal polyneuropathy

Aktuelle Neurologie ◽

10.1055/s-2006-953303 ◽

2006 ◽

Vol 33 (S 1) ◽

Author(s):

C. Neusch ◽

J. Senderek ◽

M. Bähr ◽

C. Schneider-Gold

Keyword(s):

Gene Mutation ◽

Early Onset ◽

Mitofusin 2 ◽

Charcot Marie Tooth ◽

Axonal Polyneuropathy

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Correction to: Perampanel treatment in early-onset epileptic encephalopathy with infantile movement disorders associated with a de novo GRIN1 gene mutation: a 3-year follow-up

Neurological Sciences ◽

10.1007/s10072-021-05084-7 ◽

2021 ◽

Author(s):

Daniela Dicanio ◽

Antonio Gennaro Nicotera ◽

F. Cucinotta ◽

G. Di Rosa

Keyword(s):

Gene Mutation ◽

Movement Disorders ◽

Early Onset ◽

De Novo ◽

Epileptic Encephalopathy

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Perampanel treatment in Early-onset Epileptic Encephalopathy with infantile movement disorders associated with a de novo GRIN1 gene mutation: a 3-year follow-up

Neurological Sciences ◽

10.1007/s10072-020-04935-z ◽

2021 ◽

Author(s):

Daniela Dicanio ◽

Antonio Gennaro Nicotera ◽

F. Cucinotta ◽

G. Di Rosa

Keyword(s):

Gene Mutation ◽

Movement Disorders ◽

Early Onset ◽

De Novo ◽

Epileptic Encephalopathy

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Novel SPTBN2 gene mutation and first intragenic deletion in early onset spinocerebellar ataxia type 5

Annals of Clinical and Translational Neurology ◽

10.1002/acn3.51345 ◽

2021 ◽

Vol 8 (4) ◽

pp. 956-963

Author(s):

Romina Romaniello ◽

Andrea Citterio ◽

Elena Panzeri ◽

Filippo Arrigoni ◽

Marta De Rinaldis ◽

...

Keyword(s):

Gene Mutation ◽

Spinocerebellar Ataxia ◽

Early Onset ◽

Spinocerebellar Ataxia Type ◽

Intragenic Deletion

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Clinical, Molecular and Genetic Characteristics of Early Onset Gastric Cancer: Analysis of a Large Multicenter Study

Cancers ◽

10.3390/cancers13133132 ◽

2021 ◽

Vol 13 (13) ◽

pp. 3132

Author(s):

Anna Pocurull ◽

Cristina Herrera-Pariente ◽

Sabela Carballal ◽

Joan Llach ◽

Ariadna Sánchez ◽

...

Keyword(s):

Gastric Cancer ◽

Germline Mutation ◽

Early Onset ◽

Personal Information ◽

Familial Aggregation ◽

High Morbidity ◽

Advanced Stage ◽

Genetic Characteristics ◽

Clinical Criteria ◽

Large Multicenter Study

Gastric adenocarcinoma (GC) is a common tumor with high morbidity and mortality. Only 7% of patients with GC are diagnosed before age 50 (early onset gastric cancer (EOGC)), and their characteristics have been poorly described. We aimed to describe clinical, molecular, and genetic characteristics of EOGC. A total of 309 patients with EOGC were retrospectively studied in four Spanish centers. Personal information, family history, and tumor information were registered. Germinal genetic analysis was performed in patients who met current criteria of a hereditary syndrome at the time of diagnosis. The median age at diagnosis was 44 years. The majority (73.3%) of tumors were diffuse, and 78.3% were diagnosed in an advanced stage. Familial aggregation of GC was present in 18/117 (15.4%) cases, and 5/117 (4.3%) met criteria for familial GC. MMR-IHC was performed in 126/309 (40.7%) tumors: 4/126 (3.1%) had loss of expression in MLH1/PMS2, without an associated germline mutation. Sixteen germline genetic analyses were performed, detecting a pathogenic variant in four (25%) cases: one in BRCA2, one in TP53, and two in CDH1. Most EOGC are diffuse and diagnosed in an advanced stage. In these patients, DNA MMR system deficiency is uncommon. Although familial aggregation was observed in only 15% of cases, a germline mutation was found in 25% of patients tested with clinical criteria. This demonstrates that EOGC has a marked genetic heterogeneity, reinforcing the importance of an accurate genetic counseling and enhancing the emerging use of multigene panels.

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