SCIENTIFIC BACKGROUND

BRAF, KIT, NF1, PDGFRA, SDHA, Fusion Genes: NTRK1, NTRK2, NTRK3

Although rare, gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. The most frequent primary localizations are in the stomach area (50-60%) and small intestine (20-30%), less frequently in the colorectum (5-10%) and esophagus (<1%). GISTs represent a morphological and biological continuum from randomly discovered, <10 mm benign micro-GISTs, to large sarcomas. GISTs are divided into three morphological subgroups: about 70% are of the spindle-cell subtype, about 10% are of the epithelioid subtype and another 20% are of the mixed spindle-cell-epithelioid subtype. Immunohistochemistry is essential for a histological diagnosis of GISTs. The antibody against CD117 (KIT receptor) or DOG1 is detectable in about 95% of all GISTs. About 70% to 80% of the cases also express the stem cell-associated antigen CD34.

 

GENOMIC ALTERATIONS

 

Despite the clinicopathological differences, most GISTs share the same genetic profile. This includes KIT and PDGRFA variants, which lead to the constitutive activation of tyrosine kinases. They can be detected in small tumors with a diameter <1 cm, indicating that it is an early pathogenetic event.

 

A hereditary predisposition is very rarely observed. These are either familial GISTs with a corresponding germline variant in KIT, GIST in the context of Carney-Strakatis syndrome or GIST in connection with neurofibromatosis type 1.

 

GISTs that do not have variants in KIT or PDGFRA are classified as succinate dehydrogenase (SDH)-deficient GIST or non-SDH-deficient GIST. The SDH-deficient group accounts for 20% to 40% of the KIT/PDGFRA wild-type GIST and is characterized by a loss of expression of the SDH subunit B (SDHB), mostly due to sporadic and/or germline variants in SDHA, SDHB, SDHC and SDHD (SDHx). In addition to sporadic cases, the SDH-deficient group includes Carney Triad and Carney-Strakatis syndrome. The non-SDH-deficient group includes neurofibromatosis type 1 with variants in NF1 and GIST with variants in BRAF, KRAS and PIK3CA.

 

POSSIBLE THERAPIES

The frequency of KIT variants is about 80% to 90%. Patients with variants in the untreated primary tumor usually respond to treatment with the tyrosine kinase inhibitor (TKI) imatinib. The most frequent variants in KIT are found in exon 11 (60%) and are very heterogeneous in length and type (deletions, insertions, point mutations and combinations). Patients with a KIT exon 11 deletion have a higher risk of relapse than those with an exon 11 insertion or point mutation, PDGFRA variant, or wild type. In 10% to 15% of cases, KIT variants are found in exon 9 where the same six base pair insertion almost always occurs, which leads to duplication of the amino acids alanine 502 and tyrosine 503.

 

Exon 9 variants are predominant in GISTs with small intestine localization, and about half of the cases show a response to imatinib. However, it has been shown that these patients benefit when they are treated from the start with 800 mg of Glivec (imatinib)/day instead of 400 mg Glivec/day or treatment with another TKI. In addition, variants have been described which are detected during treatment with a TKI and lead to resistance. Other KIT variants, in exon 13 (Lys642Glu) and exon 17 (Asn822Lys), are found rarely. For KIT exon 13 and 14 variants, therapy with the second-line TKI sunitinib is possible, while for the exon 17 variant (Asn822Lys), primary resistance can be expected. For secondary KIT exons 17 and 18, sunitinib is also usually ineffective. A response to sorafenib and regorafenib has been shown.

 

The frequency of PDGFRA variants is about 10% to 15%. Here too, patients with variants in the untreated primary tumor usually respond to therapy with the TKI imatinib. However, if the variant Asp842Val is found, it is associated with resistance to imatinib. Treatment with second-line TKI sunitinib or third-line TKI regorafenib is also indicated for these tumors.

 

TARGETED PANEL

BRAF, KIT, NF1, PDGFRA, SDHA, Fusion Genes: NTRK1/2/3, MSI

GENES

BRAF, KIT, NF1, PDGFRA, SDHA, Fusion Genes: NTRK1, NTRK2, NTRK3

How to order

LATEST ARTICLES

Every year on April 25th, DNA Day celebrates the discovery of DNA’s double helix and the advances we’ve made in understanding genetics. D...

Read more

Neurodevelopmental disorders (NDDs) have diverse genetic origins, making diagnosis challenging. A new study analyzing over 1,100 pediatric patients f...

Read more

Colorectal cancer (CRC) remains one of the most prevalent and deadly cancers worldwide, with a significant number of cases presenting at an advanced ...

Read more

Carrier screening is a genetic test designed to identify whether an individual carries a gene with changes (mutations) associated with inherited diso...

Read more

Trisomy 13, also known as Patau syndrome, is a genetic condition in which cells in the body have three copies of chromosome 13 instead of two. The co...

Read more

The human brain develops through a complex series of events, with genes carefully regulating the formation of neurons and glial cells. A recent study...

Read more

Rare diseases affect between 300 and 400 million people worldwide – more than cancer and AIDS combined [1, 2], but despite this, many people face a...

Read more

Rosalind Elsie Franklin was a brilliant and meticulous research scientist whose interdisciplinary work made fundamental contributions to various area...

Read more

February, designated as Cancer Awareness Month, marks a time to reflect on the remarkable progress made in cancer research and to inspire hope for th...

Read more

Introduction Cardiovascular disease (CVD) is a major health issue as it remains a leading cause of death worldwide [1]. CVD is responsible for mor...

Read more