Pole-Mutation – Definition
The POLE gene encodes the catalytic subunit of DNA polymerase epsilon. The enzyme is involved in DNA repair and chromosomal DNA replication. Mutations in this gene have been associated with colorectal cancer 12 (CRC12), endometrial cancer and other carcinomas. In some cases POLE mutation causes the FILS syndrome or IMAGE syndrome.
Synonyms:
POLE1
Gen:
POLE (polymerase (DNA directed), epsilon, catalytic subunit)
Gene products
POLE
Function:
DNA repair and chromosomal DNA replication
Heredity
autosomal dominant
Prevalence:
unknown
Genotype-phenotype
unknown
Penetrance:
unknown
Pole-Mutation – Diagnosestellung
The diagnosis is established in patients with a heterozygous germline pathogenic variant identified in the POLE gene on molecular genetic testing. In case of a familial clustering of POLE mutation-associated tumors, a genetic assessment and testing for POLE mutations are recommended. Families in which a germline POLE mutation is found should receive counselling regarding cancer risk management options and risks to family members.
Differential Diagnoses
Some disorders/gene mutations to consider in the differential diagnosis:
- HNPCC/Lynch syndrome
- Adenomatous polyposis (APC/MUTYH)
Clinical Presentation
Patients with POLE mutation frequently develop a variety of tumors:
POLE-related susceptibility to Colorectal Carcinoma 12 (OMIM 615083)
Individuals with germline heterozygous POLE pathogenic variants are at increased risk for CRC. The disorder called Colorectal cancer-12 is characterized by a predisposition to the development of colorectal adenomas and carcinomas. These individuals may present with few to numerous polyps. Onset is usually before age 40 years.
Polymerase proofreading-associated polyposis (PPAP)
PPAP is caused by germline variations in the POLE and POLD1 genes which lead to multiple adenomatous polyps and synchronous colon cancers.
Endometrial and ovarian cancer
- 7-12% of endometrial cancers are assumed to be found in POLE mutation carriers.
- Study results implicated that POLE1 mutation might be actively involved in the pathogenesis of ovarian endometrioid carcinoma, but might not be actively involved in other subtypes of ovarian carcinoma.
Non-small cell lung cancer (NSCLC)
POLE mutation represents an uncommon phenotype in non-small cell lung carcinoma.
Several additional types of following cancers have been reported in families of individuals with a POLE pathogenic variant; however further studies are needed:
- Malignant solid tumor
- Urothelial carcinoma
- Basal cell carcinoma
- Malignant salivary gland neoplasm
- Squamous cell carcinoma of the penis
- Bladder carcinoma
- Head and Neck Carcinoma
- Gastric Carcinoma
- Non-Hodgkin Lymphoma
- Non-Clear Cell Renal Cell Carcinoma
- Endometrial Serous Adenocarcinoma
- Diffuse Large B-cell Lymphoma
- Lymphoma
- Mature T-Cell And NK-Cell Non-Hodgkin Lymphoma
- Carcinosarcoma of Uterine Corpus
- Adnexal Carcinoma
- B-Cell Non-Hodgkin Lymphoma
- Mantle Cell Lymphoma
Some studies have shown that the POLE mutation is also responsible for FILS syndrome. This manifests itself in facial dysmorphism, immunodeficiency, livedo, and short stature.
In addition, in isolated cases, POLE mutation causes IMAGE syndrome, which is characterized by intrauterine growth delay, metaphysical dysplasia with shortened limbs, congenital adrenal hypoplasia and genital abnormalities.
Special features of the treatment
Treatment should be carried out by a professional, multidisciplinary team.
Studies show that the presence of the POLE mutation appears to result in a better prognosis and could therefore directly influence treatment decisions. Immunotherapies are currently being researched for POLE mutation-associated cancers and appear to be very successful.
The screening tests listed below are particularly important to detect tumors early and treat them successfully.
Diagnose Pole-Mutation. Wie geht es weiter?
Nach der Diagnose ist es ratsam, die Weiterbehandlung von betroffenen Patient:innen durch eine:n Spezialist:in für dieses Krebsprädispositionssyndrom durchführen zu lassen. Im folgenden Abschnitt schildern wir Ihnen, ob Untersuchungen zur Krebsfrüherkennung oder andere Maßnahmen erforderlich sind und wie diese erfolgen sollten. Zudem finden Sie am Ende dieser Seite noch ein paar weiterführende Informationen wie z.B. die Links von Selbsthilfegruppen.
Diagnose Pole-Mutation. Wie geht es weiter?
Nach der Diagnose ist es ratsam, die Weiterbehandlung von betroffenen Patient:innen durch eine:n Spezialist:in für dieses Krebsprädispositionssyndrom durchführen zu lassen. Im folgenden Abschnitt schildern wir Ihnen, ob Untersuchungen zur Krebsfrüherkennung oder andere Maßnahmen erforderlich sind und wie diese erfolgen sollten. Zudem finden Sie am Ende dieser Seite noch ein paar weiterführende Informationen wie z.B. die Links von Selbsthilfegruppen.
Recommendations for early detection in your patients
Further research is still needed regarding the various manifestations of POLE mutation carriers to establish standardized monitoring recommendations. However, the following early detection recommendations are provided under HNPCC guidelines:
- Colonoscopy every 1–2 years: initially at the age of 15, and if the findings are unremarkable, then annually from the age of 20.
- Annual ultrasound examination of the abdominal cavity.
- Annual physical examination.
- Upper endoscopy every 3 years, starting at the age of 20 to 25. If adenomas are detected, at least annual follow-up examinations are recommended.
- For women: Endometrial cancer screening (transvaginal ultrasound and endometrial biopsy) from the age of 35-40 for POLD1 carriers.
Since the disease profile has only recently become known and is therefore not yet conclusively researched, these are provisional recommendations that may change in the coming years.
Pole-Mutation – weitere Informationen
Further information
Unfortunately, we are not yet aware of any self-help groups for patients with the POLE mutation. As soon as we have new information, we will add it here.
