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Sarcoma Comprehensive Panel

Diseases Targeted:

Sarcoma
Soft Tissue Sarcoma
Osteosarcoma

Overview:

The Sarcoma Comprehensive Panel examines 26 genes associated with an increased risk for sarcoma. This test includes both well-established sarcoma susceptibility genes, as well as candidate genes with limited evidence of an association with sarcoma. Genes associated with both soft tissue sarcoma and osteosarcoma are included.

Who is this test for?

Patients with a personal or family history suggestive of a hereditary sarcoma syndrome. Red flags for hereditary sarcoma could include onset of cancer prior to the age of 55 years, more than one primary cancer in a single person, and multiple affected people within a family with a history of hematologic, pancreatic, gastric, thyroid, brain, breast, renal, or colon cancer, among others. After consideration of a patient’s clinical and family history, this testing may be appropriate for some pediatric patients. (If there are specific genes that you do NOT want included, please indicate this on the test requisition form.) This test is designed to detect individuals with a germline pathogenic variant, and is not validated to detect mosaicism below the level of 20%. It should not be ordered on tumor tissue.

What are the potential benefits for my patient?

Patients identified with hereditary syndrome can benefit from increased surveillance and preventative steps to better manage their risk for cancer. Also, your patient’s family members can be tested to help define their risk. If a pathogenic variant is identified in your patient, close relatives (children, siblings, parents) could have as high as a 50% risk to also be at increased risk. Because preventative action and surveillance should begin in childhood for some genes included in this panel, testing of minors may be appropriate.

Order Options

Sequencing (included)
Del/Dup (included)

 

Genes

APC, BLM, CDKN1C, DICER1, EPCAM, FH, HRAS, KIT, MLH1, MSH2, MSH6, NBN, NF1, PDGFRA, PMS2, PRKAR1A, PTCH1, RB1, RECQL4, SDHA, SDHB, SDHC, SDHD, SUFU, TP53, WRN ( 26 genes)

Coverage:

99% at 50x

Specimen Requirements:

Blood (two 4ml EDTA tubes, lavender top) or Extracted DNA (3ug in EB buffer) or Buccal Swab or Saliva (kits available upon request)

Test Limitations:

Test results and variant interpretation are based on the proper identification of the submitted specimen and use of correct human reference sequences at the queried loci. In very rare instances, errors may result due to mix-up or co-mingling of specimens. Positive results do not imply that there are no other contributions, genetic or otherwise, to the patient's phenotype, and negative results do not rule out a genetic cause for the indication for testing. Result interpretation is based on the collected information and Alamut annotation available at the time of reporting. This assay is not designed or validated for the detection of mosaicism. DNA alterations in regulatory regions or deep intronic regions (greater than 20bp from an exon) will not be detected by this test. There are technical limitations on the ability of DNA sequencing to detect small insertions and deletions. Our laboratory uses a sensitive detection algorithm, however these types of alterations are not detected as reliably as single nucleotide variants. Rarely, due to systematic chemical, computational, or human error, DNA variants may be missed. Although next generation sequencing technologies and our bioinformatics analysis significantly reduce the confounding contribution of pseudogene sequences or other highly-homologous sequences, sometimes these may still interfere with the technical ability of the assay to identify pathogenic variant alleles in both sequencing and deletion/duplication analyses. Deletion/duplication analysis can identify alterations of genomic regions which are a single exon in size. When novel DNA duplications are identified, it is not possible to discern the genomic location or orientation of the duplicated segment, hence the effect of the duplication cannot be predicted. Where deletions are detected, it is not always possible to determine whether the predicted product will remain in-frame or not. Unless otherwise indicated, in regions that have been sequenced by Sanger, deletion/duplication analysis has not been performed.

Patients with Bone Marrow Transplants:
DNA extracted from cultured fibroblasts should be submitted instead of blood/saliva/buccal samples from individuals who have undergone allogeneic bone marrow transplant and from patients with hematologic malignancy.

Gene Specifics:

Gene Notes
MSH2 Inversion of MSH2 exons 1-7 ("Boland" inversion) is assessed for Lynch Syndrome, Colorectal, Endometrial, and Prostate Cancer Panel testing (for both Focus and Comprehensive Panels) as well as Comprehensive Gastric Cancer Panel testing. Unless otherwise specified, this testing is not performed for other cancer panels, but is available upon request.

CPT Codes:

CPT Code 81445, 81479

NOTE: The CPT codes listed on the website are in accordance with Current Procedural Terminology, a publication of the American Medical Association. CPT codes are provided here for the convenience of our clients. Clients who bill for services should make the final decision on which codes to use.

Gene Descriptions:

Gene Reason Reference
APC Heterozygous pathogenic variants in APC are associated with both classic and attenuated familial adenomatous polyposis (FAP), Gardner syndrome, Turcot syndrome, and Hereditary Desmoid disease, which increase the risk for soft tissue tumors, including desmoid sarcomas. PubMed: 20301519, 22701333; OMIM: 175100
BLM Biallelic pathogenic variants in the BLM gene cause Bloom's syndrome. Individuals with Bloom's syndrome are at a greatly increased risk for many types of cancer, including sarcomas. Cancer often occurs at younger than typical ages. Patients with Bloom's syndrome are hypersensitive to some forms of cancer treatment. Additionally, carriers of heterozygous pathogenic BLM variants may be at a small increased risk for breast cancer, as well as others (low/moderate penetrance). However, additional studies are needed to confirm an association. PubMed: 20301572, 19432957, 23404160, 24733792, 26358404; OMIM: 210900
CDKN1C Autosomal dominant, maternally inherited, pathogenic variants in the CDKN1C gene are one cause of Beckwith-Wiedemann syndrome, which is associated with an increased risk for embryonal tumors, including Wilms tumor, hepatoblastoma, neuroblastoma, and rhabdomyosarcoma, as well as other clinical conditions. PubMed: 20301568; OMIM: 600856
FH Heterozygous germline pathogenic variants in FH are associated with Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC). While some cases of leiomyosarcoma have been reported in individuals with HLRCC, evidence for an association has been contradictory. Additional research is needed. PubMed: 20301430, 20301679; OMIM: 136850
MSH6 While heterozygous pathogenic variants in MSH6 are associated with Hereditary Non-Polyposis Colorectal Cancer (HNPCC), also known as Lynch Syndrome, biallelic pathogenic variants have been associated with constitutional mismatch repair deficiency syndrome (CMMRD). While various kinds of sarcomas have been reported in individuals with Lynch Syndrome, additional research is needed to further define this risk. PubMed: 20301390, 22692065; OMIM: 120436
HRAS Heterozygous pathogenic variants in HRAS cause Costello syndrome. Individuals with Costello syndrome have a 15% lifetime risk for developing a malignant tumor, with rhabdomyosarcomas occuring most frequently. PubMed: 20301680; OMIM: 190020
KIT Heterozygous germline mutations in the KIT gene have been associated with familial gastrointestinal stromal tumor syndrome. PubMed: 9697690, 23083126, 25209843, 24745671, 25504284, 27777718; OMIM: 164920
EPCAM Autosomal dominant pathogenic variants in EPCAM cause Lynch syndrome. While Lynch syndrome has been associated with an increased risk for sarcoma in some studies, additional research is needed to determine whether Lynch syndrome caused by variants in EPCAM influences susceptability. PubMed: 20301390, 23462293
MLH1 While heterozygous pathogenic variants in MLH1 are associated with Hereditary Non-Polyposis Colorectal Cancer (HNPCC), also known as Lynch Syndrome, biallelic pathogenic variants have been associated with constitutional mismatch repair deficiency syndrome (CMMRD). While various kinds of sarcomas have been reported in individuals with Lynch Syndrome, additional research is needed to further define this risk. PubMed: 20301390, 22692065; OMIM: 120436
MSH2 While heterozygous pathogenic variants in MSH2 are associated with Hereditary Non-Polyposis Colorectal Cancer (HNPCC), also known as Lynch Syndrome, biallelic pathogenic variants have been associated with constitutional mismatch repair deficiency syndrome (CMMRD). While various kinds of sarcomas have been reported in individuals with Lynch Syndrome, additional research is needed to further define this risk. PubMed: 20301390, 22692065; OMIM: 120436
NBN Biallelic pathogenic variants in NBN have been associated with Nijmegen Breakage syndrome (NBS). Individuals with NBS generally have progressive intellectual disability, growth retardation and immunodeficiency, and are at an increased risk for a variety of cancers, including rhabdomyosarcoma, lymphoma, glioma, and medulloblastoma. Heterozygous pathogenic variants in NBN (also known as NBS1) have been associated with a number of malignancies including melanoma, non-Hodkins lymphoma, medulloblastoma, and colorectal, prostate, and breast cancers . Other studies have shown possible associations with aplastic anemia and acute lymphoblastic leukemia. PubMed: 14973119, 15185344, 16474176, 16770759, 18079974, 19908051, 21514219,15338273,11325820, 20301355; OMIM: 609135, 251260
NF1 Autosomal dominant pathogenic variants in NF1 cause Neurofibromatosis Type 1, which is associated with several types of benign tumors and cancer, including neurofibromas, optic glioma, gastrointestinal stromal tumors, plexiform neurofibromas, and malignant peripheral nerve sheath tumors, and breast cancer. PubMed: 17636453, 20301288, 9639526, 27787920; OMIM: 613113
PDGFRA Heterozygous germline pathogenic variants are a rare cause of Familial Gastrointestinal Stromal Tumor Syndrome. PubMed: 27437068
PMS2 While heterozygous pathogenic variants in PMS2 are associated with Hereditary Non-Polyposis Colorectal Cancer (HNPCC), also known as Lynch Syndrome, biallelic pathogenic variants have been associated with constitutional mismatch repair deficiency syndrome (CMMRD). While various kinds of sarcomas have been reported in individuals with Lynch Syndrome, additional research is needed to further define this risk. PubMed: 20301390, 22692065; OMIM: 120436
PRKAR1A Heterozygous pathogenic variants in PRKAR1A are associated with Carney Complex, which should not be confused with "Carney Triad (PubMed: 25859840)." Unlike individuals with "Carney Triad individuals with Carney Complex do not appear to be at an increased risk for sarcomas. PubMed: 20301463; OMIM: 188830
PTCH1 Autosomal dominant pathogenic variants in PTCH1 are associated with Nevoid Basal Cell Carcinoma syndrome (NBCSS). Some evidence suggests an increased risk for various types of sarcomas in individuals with NBCSS, although additional research is needed to confirm this association. PubMed: 19032739, 24517952, 20301330; OMIM: 601309
RB1 Heterozygous and biallelic pathogenic variants in RB1 are association with an increased risk for retinoblastoma, melanoma, and osteo- and soft tissue sarcomas. Individuals with biallelic variants are more severely affected than those who are heterozygous. PubMed: 20301625
SDHA Autosomal dominant pathogenic variants in SDHA are one genetic cause of Hereditary Paragangliomas-Pheochromocytoma Syndromes (HPPS), and are responsible for approximately .6-3% of cases PubMed: 20301715, 26273102
SDHB Autosomal dominant pathogenic variants in SDHB are one genetic cause of Hereditary Paraganglioma-Pheochromocytoma syndrome (HPPS) and are responsible for approximately 22-38% of cases. They are also associated with Carney-Stratakis syndrome, which is characterized by the presence of paragangliomas and gastrointestinal stromal tumors. SDHB-related HPPS has the highest risk for malignancy in comparison to the different genetic causes of the condition. PubMed: 20301715, 26273102; OMIM: 606864
SDHC Heterozygous pathogenic variants in the SDHC gene are responsible for between 4 and 8% of cases of Hereditary Parganglioma-Pheochromocytoma syndrome (HPPS), which increases the risk for Gastrointestinal Stromal tumors. PubMed: 20301715; OMIM: 602413
SDHD Autosomal dominant pathogenic variants in the SDHC gene are the most common cause of Hereditary Parganglioma-Pheochromocytoma syndrome (HPPS), which is associated with an increased risk for gastrointestinal stromal tumors. Of note, tumor development occurs much more frequently when the pathogenic variant is inherited from the father (paternal origin). PubMed: 20301715; OMIM: 602690
TP53 Heterozygous pathogenic variants in the TP53 gene are associated with Li-Fraumeni syndrome, a condition that increases risk for many types of cancer. PubMed: 20301488, 26014290, 2614290; OMIM: 151623, 191170
WRN Biallelic pathogenic variants in the gene WRN are associated with Werner syndrome, which is characterized by features of premature aging that includes an increased risk for many types of cancer. At this time, heterozygous carriers of a pathogenic variant in WRN have not been shown to have an increased risk of cancer. PubMed: 20301687, 8722214, 10811130, 20301687; OMIM: 277700
RECQL4 Biallelic pathogenic variants in RECQL4 have been associated with Rothmund-Thomson syndrome (RTS), Baller-Gerold syndrome (BGS), and RAPADILINO syndrome. Individuals with these conditions are at an increased risk for various cancers, including osteosarcoma, basal cell carcinoma, squamous cell carcinoma, and lymphoma. PubMed: 20301383, 20301415; OMIM: 603780
DICER1 Autosomal dominant mutations in DICER1 have been associated with DICER1 syndrome, a familial tumor susceptibility syndrome which includes susceptibility to many different kinds of tumors. PubMed: 24761742; OMIM: 606241
SUFU Autosomal dominant pathogenic variants in SUFU have been associated with Nevoid basal cell Carcinoma syndrome (NBCCS; also called Gorlin syndrome). While a few cases of rhabdomyosarcoma have been reported in individuals with NBCCS, additional research is needed to confirm this association given the small number of reported cases. PubMed: 6855699, 16294371, 20301330; OMIM: 607035
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