Pot1 Tumor Predisposition
Summary
Clinical characteristics.
POT1 tumor predisposition (POT1-TPD) is characterized by an increased lifetime risk for multiple cutaneous melanomas, chronic lymphocytic leukemia (CLL), angiosarcoma (particularly cardiac angiosarcomas), and gliomas. Additional cancers (e.g., colorectal cancer, thyroid cancer, breast angiosarcomas) have been reported in individuals with POT1-TPD but with very limited evidence. The age of onset for first primary cutaneous melanoma ranges from 15 to 80 years. The majority of POT1 associated cancers are diagnosed in adulthood.
Diagnosis/testing.
The diagnosis of POT1-TPD is established in a proband with suggestive findings and a heterozygous germline pathogenic variant in POT1 identified by molecular genetic testing.
Management.
Treatment of manifestations: The treatments for POT1-TPD tumors are those used in standard practice.
Surveillance: Full skin examination by a dermatologist beginning at age 18 years at least every six months with excision of any lesions suspicious for melanoma; consider exams every three months in individuals with multiple atypical nevi, history of melanoma, and/or family history of melanoma. CBC with differential annually beginning at age 18 years to screen for CLL. Annual comprehensive physical examination including examination of lymph nodes. Whole-body MRI annually in families fulfilling Li-Fraumeni syndrome or Li-Fraumeni-like criteria beginning at age 18 years; Consider whole-body MRI every one to two years depending on personal and family history of non-cutaneous, non-brain malignancies. Consider brain MRI every one to two years beginning at age 18 years depending on family history of glioma.
Agents/circumstances to avoid: Tanning bed use and unprotected sun exposure. Avoid radiation in diagnostic procedures.
Evaluation of relatives at risk: Molecular genetic testing for the familial POT1 pathogenic variant should be offered to first-degree relatives to identify those who would benefit from early surveillance and intervention. Although molecular genetic testing for POT1-TPD is generally not recommended for at-risk individuals younger than age 18 years, a history of early cancers in the family may warrant predictive testing prior to age 18.
Genetic counseling.
POT1-TPD is inherited in an autosomal dominant manner. To date, most individuals diagnosed with POT1-TPD have an affected parent; the proportion of POT1-TPD caused by a de novo pathogenic variant is unknown. Each child of an individual with POT1-TPD has a 50% chance of inheriting the POT1 pathogenic variant. It is important to note that clinical manifestations of POT1-TPD cannot be predicted in heterozygous family members because the full phenotypic spectrum and penetrance of POT1-TPD are unknown. The types of POT1-related tumors can vary among different members of the same family and current evidence is limited to disease-focused studies. Once the germline POT1 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk for POT1-TPD and preimplantation genetic testing are possible.
Diagnosis
Suggestive Findings
POT1 tumor predisposition (POT1-TPD) should be suspected in an individual with the following:
- Multiple cutaneous melanomas
- One of the POT1-TPD core cancers and a first- or second-degree relative with a confirmed POT1-TPD core cancer. POT1-TPD core cancers include cutaneous melanoma, chronic lymphocytic leukemia, angiosarcoma, and glioma.
- A POT1 pathogenic variant identified on somatic tumor tissue testing
Establishing the Diagnosis
The diagnosis of POT1-TPD is established in a proband with suggestive findings and a heterozygous germline pathogenic variant in POT1 identified by molecular genetic testing (see Table 1).
Note: Identification of a heterozygous POT1 variant of uncertain significance does not establish or rule out the diagnosis of this disorder. To date, however, most POT1 variants are classified as variants of uncertain significance due to insufficient data according to ACMG classification criteria. Due to limited evidence currently available, decision making should rely on clinical history, family history, segregation of the variant, and in silico analysis within the family.
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing), depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in suggestive findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis has not been considered are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
Single-gene testing. Sequence analysis and deletion/duplication analysis of POT1 is performed.
A hereditary cancer multigene panel that includes POT1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. Of note, given the rarity of POT1 tumor predisposition, some panels for melanoma, brain tumors, and/or hereditary cancer panels may not include this gene. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
Comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in POT1 Tumor Predisposition
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| POT1 | Sequence analysis 3 | All reported sequence variants to date 4, 5 |
| Gene-targeted deletion/duplication analysis 6 | Unknown 7 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Shi et al [2014], Calvete et al [2017]
- 5.
Data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2017]
- 6.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 7.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
Clinical Characteristics
Clinical Description
POT1 tumor predisposition (POT1-TPD) is associated with an increased risk for multiple cutaneous melanomas, chronic lymphocytic leukemia (CLL), angiosarcoma (particularly cardiac angiosarcomas), and gliomas. To date, fewer than than 100 families with a germline POT1 variant have been identified. Disease-associated POT1 variants were initially identified in families with cutaneous melanoma [Robles-Espinoza et al 2014, Shi et al 2014], chronic lymphocytic leukemia [Speedy et al 2016], cardiac and breast angiosarcomas [Calvete et al 2015], and brain tumors [Bainbridge et al 2014]. Initial studies were biased by the cohorts included, which focused on a single disease entity. Additional cancers have been reported in individuals with a germline POT1 variant. However, due to limited data it is unclear if these cancers are associated with POT1 germline variants.
Cutaneous melanoma is the most commonly reported malignancy in individuals with POT1-TPD. The range of onset for first primary cutaneous melanoma is age 15 to 80 years [Robles-Espinoza et al 2014, Shi et al 2014]. Multiple synchronous or metachronous primary cutaneous melanomas are common, with reports ranging from two primary melanomas to eight primary melanomas [Robles-Espinoza et al 2014]. The time between diagnoses of first and second melanoma varied significantly (average ~9 years).
Chronic lymphocytic leukemia (CLL). Disease-associated POT1 variants have been identified in familial CLL. A 3.6-fold increased risk for CLL was reported for individuals with POT1 germline variant p.Gln376Arg [Speedy et al 2016]. This cohort also exhibited a younger average age of diagnosis than in sporadic CLL (59 years vs 70 years). POT1 variants have been identified on somatic testing of CLL (tumor tissue) (see Molecular Genetics, Cancer and Benign Tumors); Germline POT1 molecular testing can distinguish somatic and germline variants.
Angiosarcoma. The germline POT1 variant p.Arg117Cys was identified in three Li-Fraumeni-like (LFL) families with members affected with cardiac angiosarcoma [Calvete et al 2015] and in an individual with a cardiac sarcoma with a negative family history [Calvete et al 2017]. Other germline POT1 variants have been reported in families with LFL in which members had angiosarcoma, and in simplex cases of angiosarcoma or cardiac sarcoma [Kunze et al 2014, Calvete et al 2017]. Germline POT1 variants were found in 27.3% (6/22) of TP53-negative LFL families with members affected with angiosarcoma [Calvete et al 2015, Calvete et al 2017]. Germline POT1 variants were also found in 11.4% (4/35) of individuals with an angiosarcoma or cardiac sarcoma without a family history of sarcomas or a family history suggestive of LFL syndrome [Kunze et al 2014, Calvete et al 2017]. No germline POT1 variants were reported in 34 LFL families without angiosarcoma [Calvete et al 2015, Calvete et al 2017].
Glioma. Two families with more than one individual with glioma were found to have a germline POT1 variant [Bainbridge et al 2014]. One or more individuals in these families presented with oligodendroglioma, suggesting a glioma type-specific susceptibility in these families.
Other cancers reported in individuals with a germline POT1 variant include most notably differentiated thyroid cancer (4 families, 7 individuals) and colorectal cancer (3 individuals) [Chubb et al 2016]. Several other benign and malignant neoplasias have been reported in individuals with a germline POT1 variant; data are too limited to determine if the POT1 variant is causative.
Genotype-Phenotype Correlations
No genotype-phenotype correlations have been confirmed.
The p.Arg117Cys POT1 variant has been reported in three families with LFL in which members had cardiac angiosarcoma, in one family with LFL in which a member had breast angiosarcoma, and in one individual with cardiac sarcoma in the absence of family history [Calvete et al 2015, Calvete et al 2017].
Penetrance
The penetrance of POT1-TPD is currently unknown, fewer than 100 families have been described. Initial studies suggest a very high penetrance but are subject to a selection bias for research cohorts/families. In more than half of reported families only the proband was tested. Many individuals with germline POT1 variants were ascertained based on a strong family history of cancer from tumor-specific consortiums (e.g., The Gliogene Consortium, UK National Study of Colorectal Cancer Genetics, UK Familial Melanoma Study).
Prevalence
The prevalence of POT1-TPD is currently unknown. However, data emerging from studies in individuals with familial melanoma suggest that 2.4% have a germline POT1 variant [Robles-Espinoza et al 2014, Shi et al 2014]. Limited data suggest that a germline POT1 variant was identified in up to 6% of families with familial CLL [Speedy et al 2016].
Differential Diagnosis
Table 2.
Autosomal Dominant Tumor Predisposition Syndromes of Interest in the Differential Diagnosis of POT1 Tumor Predisposition
| Cancer Type | Gene(s) | Associated Disorder / Reference |
|---|---|---|
| Cutaneous melanoma | BAP1 | BAP1 tumor predisposition syndrome |
| BRCA2 | BRCA1- and BRCA2-associated hereditary breast and ovarian cancer | |
| CDK4 | Susceptibility to cutaneous malignant melanoma 3 (OMIM 609048) | |
| CDKN2A | Hereditary melanoma/pancreatic cancer syndrome (OMIM 606719) | |
| MITF | Susceptibility to cutaneous malignant melanoma 8 (OMIM 614456) | |
| PTEN | PTEN hamartoma tumor syndrome (incl Cowden syndrome) | |
| TERT | Susceptibility to cutaneous malignant melanoma 9 (OMIM 615134) | |
| Chronic lymphocytic leukemia | Unknown | Chronic lymphocytic leukemia (OMIM 151400) |
| Angiosarcoma | TP53 | Li-Fraumeni syndrome |
| Glioma | NF1 | Neurofibromatosis 1 |
| NF2 | Neurofibromatosis 2 | |
| TP53 | Li-Fraumeni syndrome | |
| EPCAM MLH1 MSH2 MSH6 PMS2 |
|
- 1.
Biallelic pathogenic variants in MLH1, MSH2, MSH6, or PMS2 are associated with constitutional mismatch repair deficiency (an autosomal recessive variant of Lynch syndrome).
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease in an individual diagnosed with POT1-TPD, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended. The majority of POT1-associated cancers are diagnosed in adulthood. Therefore, screening should begin at age 18 years.
Table 3.
Recommended Evaluations Following Initial Diagnosis in Individuals with POT1 Tumor Predisposition
| System/Concern | Evaluation | Comment |
|---|---|---|
| Cutaneous melanoma | Full skin exam by dermatologist | Beginning at age 18 yrs |
| Chronic lymphocytic leukemia |
| Beginning at age 18 yrs (See Surveillance.) |
| Review of whole-body MRI for enlarged lymph nodes | In persons who undergo MRI for angiosarcoma screening or another reason. | |
| Angiosarcoma (incl cardiac & breast angiosarcoma) | Consider whole-body MRI. | Beginning at age 18 yrs:
|
| Brain tumors (glioma) | Brain MRI w/& w/o contrast | Beginning at age 18 yrs |
LFS = Li-Fraumeni syndrome; LFL = Li-Fraumeni like syndrome
- 1.
See OMIM 151623 for description of Li-Fraumeni like syndrome criteria
Treatment of Manifestations
The treatments for POT1-TPD tumors are those used in standard practice.
Surveillance
There are no published guidelines for surveillance for individuals with POT1-TPD. Decisions regarding individual surveillance protocols should be based on the emerging phenotypic spectrum of POT1-TPD, as well as on the affected individual’s personal and family history. In addition, individuals should be educated regarding general signs and symptoms of malignant diseases and advised to seek medical attention with any concerning findings. Due to the similarity to Li-Fraumeni syndrome (LFS) and Li-Fraumeni-like syndrome, it seems appropriate to employ screening similar to that used in LFS.
Table 4.
Recommended Surveillance for Individuals with POT1 Tumor Predisposition
| System/Concern | Evaluation | Frequency |
|---|---|---|
| Cutaneous melanoma | Dermatologic exam |
|
| Chronic lymphocytic leukemia | CBC w/differential | Annually beginning at age 18 yrs |
| Comprehensive physical exam incl lymph nodes | Annually | |
| Evaluate results of whole-body MRI for enlarged lymph nodes. | When imaging is performed (e.g., in families fulfilling LFL criteria 1) | |
| Angiosarcoma (incl cardiac & breast angiosarcoma) | Whole-body MRI |
|
| Brain tumors (glioma) | Brain MRI 2 | Consider every 1-2 years depending on family history beginning at age 18 yrs. |
LFS = Li-Fraumeni syndrome; LFL = Li-Fraumeni like syndrome
- 1.
See OMIM 151623 for description of Li-Fraumeni like syndrome criteria
- 2.
The initial brain MRI should be done with contrast, and subsequent brain MRIs may be done without contrast if the previous MRI was normal and there is no new abnormality [Kratz et al 2017].
Agents/Circumstances to Avoid
To date, there is no evidence that UV light contributes to the pathogenesis of POT1-TPD-associated melanoma. However, individuals with POT1-TPD should be counseled against tanning bed use, as well as unprotected sun exposure.
It is currently unknown, whether ionizing radiation poses an increased risk to individuals with POT1-TPD, but because of the need for lifelong surveillance, it seems reasonable to avoid radiation in diagnostic procedures and instead recommend MRI or ultrasonography.
Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of first-degree relatives of an affected individual by molecular genetic testing for the POT1 pathogenic variant in the family in order to identify those who would benefit from screening for POT1-associated cancers. Early recognition of cancers associated with POT1 tumor predisposition (POT1-TPD) may allow for timely intervention and improved final outcome.
In general, molecular genetic testing for POT1-TPD is not recommended for at-risk individuals younger than age 18 years. However, predictive testing should be considered if there is a history of early-onset cancer in the family. For unaffected individuals with a POT1 pathogenic variant, screening should begin at age 18 years (see Table 3) or two to five years earlier than the earliest diagnosis in the family. Therefore, a history of early cancers in the family may also warrant testing prior to age 18 years.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Therapies Under Investigation
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.