ColoSeq Polyposis

General Information

Lab Name

ColoSeq Polyposis

Lab Code

CSQP

Epic Name

(not orderable in Epic)

Description

ColoSeq™ Polyposis is a paired polyp-germline panel that aims to discover the genetic cause of polyps in patients with unexplained colon polyposis. While many patients with adenomatous polyposis are found to have germline variants in APC, MUTYH and other genes, some patients with polyposis remain unexplained. Constitutional mosaic APC mutations have been described and current germline testing of peripheral blood and saliva has not been adequate to detect mosaic APC mutations. Uniquely, by testing colon polyps and a germline sample, ColoSeq™ Polyposis tests for constitutional mosaic mutations in APC and other genes to look for a common mutation. In a recent series of 28 patients with unexplained adenomatous polyposis, a total of 18 (64%) were found to have constitutional mosaic APC mutations detected in their colon adenomas, often also present at low allelic fraction in their germline sample (9 of 18 mosaic cases)1. ColoSeq™ Polyposis may also be useful for the evaluation of ganglioneuromas, hamartomatous, Peutz Jeghers polyps, and other rare polyposis syndromes.

ColoSeq™ Polyposis includes both a comprehensive pan-cancer germline analysis of 114 genes associated with hereditary cancer syndromes AND a targeted tumor assessment of select somatic and constitutionally mosaic somatic mutations to aid in the identifying the etiology of colon polyposis. The polyp analysis includes microsatellite instability, detection of loss of heterozygosity and BRAF V600E mutation.

ColoSeq™ Polyposis uses next-generation sequencing to detect most mutations in AIP, AKT1, ALK, AMER1, APC, ATM, ATR, AXIN2, BAP1, BARD1, BMPR1A, BRAF, BRCA1, BRCA2, BRIP1, BUB1B, CDC73, CDH1, CDK4, CDK12, CDKN1B, CDKN2A, CEBPA, CHEK2, CTNNA1, CTNNB1, DICER1, DDX41, EGFR, EIF6, ELANE, ELOC, ERCC6L2, EPCAM, ETV6, EXT1, EXT2, FANCM, FH, FLCN, GATA2, GEN1, GREM1, HOXB13, HSD3B1, KDM3B, KIF1B, KIT, LZTR1, MAX, MBD4, MECOM, MEN1, MET, MITF, MLH1, MLH3, MSH2, MSH3, MSH6, MUTYH, NBN, NF1, NF2, NTHL1, NYNRIN, PALB2, PDGFRA, PHOX2B, PIK3CA, PMS2, POLD1, POLE, POLQ, POT1, PRKAR1A, PTCH1, PTEN, RAD51B, RAD51C, RAD51D, RB1, RECQL, RECQL4, RET, REST, RINT1, RNF43, RPS19, RPS20, RSPO3, RTEL1, RUNX1, SBDS, SDHA, SDHAF2, SDHB, SDHC, SDHD, SMAD4, SMARCA4, SMARCB1, SMARCE1, STK11, SUFU, TINF2, TMEM127, TP53, TRIM28, TRIM37, TSC1, TSC2, VHL, and WT1.

Testing is performed on DNA extracted from two colorectal polyps and a germline sample, using next-generation sequencing to detect somatic and germline variants in genes associated with hereditary colon cancer and polyposis. All exons and flanking intronic sequences are analyzed for all panel genes. Promoters and introns are sequenced for the mismatch repair genes and BRCA1/2. Non-coding variants of uncertain significance are assessed with RNA analysis when certain criteria are met. Select patients may be offered long range sequencing if test results suggest an undetected germline variant in a specific gene. Many patients undergoing paired tumor-germline testing have already undergone a lot of testing, and these assays are intended to provide conclusive results whenever possible.  

For an overview of available germline and paired tumor-germline testing for hereditary cancer syndromes, please see: Hereditary Cancer Test Menu: Germline and Paired Tumor-Germline guideline.

Gene	Function/Pathway	Heterozygote Cancer risk*	Associated syndrome	References (PMID)
AIP	Tumor suppressor	Gastrointestinal, Lymphoma	Familial Isolated Pituitary Adenoma	18381572, 38479600
ALK	MYC signaling	Neuroblastoma	Cowden-like	18724359, 28674118
AKT1	AKT signaling	Breast, Thyroid	Cowden-like	23246288
AMER1	Wnt/β-catenin pathway	Wilms tumor, Colon	Osteopathia striata with cranial sclerosis (XL)	17204608
APC	WNT signaling	Colon	Familial adenomatous polyposis	20301519
ATM	Double stranded break repair	Breast, Pancreatic	Ataxia telangiectasia (recessive)	16832357, 19781682, 22585167
ATR	Double stranded break repair	Oropharyngeal	Seckel syndrome (recessive)	22341969
AXIN2	WNT signaling	Colon	Oligodontia-colorectal cancer syndrome	15042511
BAP1	BRCA1-associated protein complex	Uveal Melanoma, Mesothelioma	BAP1 Tumor predisposition syndrome	21874000, 21874003
BARD1	BRCA1-associated protein complex	Breast, Ovarian	Hereditary breast cancer	21344236
BMPR1A	TGF-beta signaling	Colon	Juvenile polyposis	20301642
BRAF	Serine/Threonine protein kinase	Typically somatic or mosaic only	Association with MLH1 promoter hypermethylation in colon cancer when somatic, and Cardiofaciocutaneous syndrome when mosaic or heterozygous	20301365
BRCA1	BRCA1-associated protein complex	Breast, Ovarian	Hereditary breast and ovarian cancer	22006311, 2270482, 7545954
BRCA2	Fanconi/BRCA	Breast, Ovarian	Hereditary breast and ovarian cancer, Fanconi anaemia FA-D1 (recessive)	22006311, 8524414
BRIP1	Fanconi/BRCA	Breast, Ovarian	Fanconi anaemia FA-J (recessive)	22006311, 17033622, 21964575
BUB1B	Spindle assembly checkpoint	Prostate, Melanoma, Colon	Mosaic variegated aneuploidy syndrome (AR)	27239782, 9521327 15475955
CDC73	Tumor suppressor	Parathyroid, Benign tumors	Hyperparathyroidism-jaw tumor syndrome (HPT-JT)	14985403, 20301744
CDH1	Cell adhesion	Breast, Gastric	Hereditary diffuse gastric cancer	20301318
CDK4	Cell cycle	Melanoma	Familial melanoma	19585149
CDK12	MAP kinase regulation	Breast, ovarian cancer, frequently somatic	Hereditary breast and ovarian cancer	24554720, 29906450, 24240700
CDKN1B	Cyclin-dependent kinase inhibitor 1B	Parathyroid, Pituitary	Multiple endocrine neoplasia, type IV	37733893
CDKN2A	Cell cycle	Pancreatic, Melanoma	Familial melanoma and pancreatic cancer	19585149
CEBPA	Tumor suppressor	Leukemia	Familial AML	35178345
CHEK2	Double stranded break repair	Breast	Hereditary breast cancer	11967536
CTNNA1	Beta-catenin, e-cadherin complex	Gastric	Hereditary diffuse gastric cancer	23208944
CTNNB1	WNT signaling	Typically somatic only	Colon cancer, endometrial cancer, desmoid tumors, colon adenomas	33115416, 37048063
DDX41	Splicing regulation	Leukemia, MDS	Familial MDS, AML	26712909, 34723452
DICER1	Tumor suppressor	Wilms tumor, pleuropulmonary blastoma	DICER1 syndrome	29343557, 28960912, 23625684
EIF6	Cell signaling pathway activation	Somatic only
EGFR	Epidermal growth factor receptor	Lung	Familial lung cancer	37274482
ELANE	Inflammation modulation	Leukemia, MDS	ELANE-related neutropenia	10581030, 20301705
ELOC	RNA polymerase II transcription	Kidney, Hemangioblastomas, Pheochromocytomas	von Hippel-Lindau	35323939
EPCAM	Deletions inactivate MSH2, mismatch repair	Colon, Ovarian, Endometrial	Lynch syndrome	23938213
ERCC6L2	DNA repair (non-homologous end joining)	Leukemia, MDS	ERCC6L2-associated bone marrow failure (AR)	36790458
ETV6	Transcription factor in hemopoietic regulation	Leukemia, MDS	Familial thrombocytopenia, MDS, acute leukemia	28555414
EXT1	Heparan sulfate synthesis	Chondrosarcoma	Hereditary multiple osteochondromas	8981950
EXT2	Heparan sulfate synthesis	Chondrosarcoma	Hereditary multiple osteochondromas; EXT2-related neurodevelopmental disorder (AR)	8782816
FANCM	Fanconi/BRCA	Breast	Fanconi anemia (recessive)	25288723
FH	Tumor suppressor	Renal	Hereditary leiomyomatosis and renal cell cancer	25018647, 11865300, 25004247
FLCN	Tumor suppressor	Renal	Birt-Hogg-Dube syndrome, primary spontaneous pneumothorax.	12204536, 19659657
GATA2	Transcription factor in hemopoietic regulation	Leukemia, MDS	Familial leukemia, MDS, immunodeficiency	38660832, 364555197
GEN1	Double stranded break repair	Breast	Hereditary breast cancer	2052659
GREM1	BMP antagonist	Colon	Hereditary mixed polyposis syndrome	22561515
HOXB13	Sequence-specific transcription factor which binds preferentially to methylated DNA	Prostate	Familial prostate cancer	36446039, 34799695, 34059701
HSD3B1	Aldosterone production	Prostate, Breast	Hereditary breast, prostate cancer	34520399, 38506808
KDM3B	Gene transcription regulation	Wilms tumor, Leukemia	Diets-Jongmans syndrome; KDM3B-related Wilms tumor	20301471
KIF1B	Tumor suppressor	Neuroblastoma	Hereditary neuroblastoma	18334619, 24469107, 30859632
KIT	Proto-oncogene which encodes a tyrosine-protein kinase that acts as a cell-surface receptor for cytokine KITLG/SCF	Gastrointestinal stromal tumors (GIST), Acute myelogenous leukemia (AML)	Hereditary GIST and AML	36351335, 35821557
LZTR1	RAS ubiquitination/MAPK signaling	Schwannomatosis	Schwannomatosis, Noonan syndrome	24362817, 25335490
MAX	MYC signaling	Pheochromocytoma, Paraganglioma	Hereditary pheochromocytoma and paraganglioma (parent-of-origin effect)	21685915, 22452945
MBD4	Mismatch DNA repair	Uveal Melanoma, myelodysplastic disease, colon polyposis	Polyposis, multi-organ tumor predisposition (recessive)	32239153, 35460607
MECOM	Hematopoietic stem cell maintenance	Leukemia, MDS	MECOM-associated syndrome	38662475
MEN1	Gene expression regulation	Endocrine	Multiple endocrine neoplasia type 1	9215689
MET	Tyrosine Kinase receptor	Kidney, Squamous cell carcinomas	Hereditary papillary renal cell carcinoma	11551094, 9140397, 27330189
MITF	Melanocyte inducing transcription factor	Kidney, Melanoma	MITF-related melanoma and renal cell carcinoma predisposition	24290354, 22012259
MLH1	Mismatch DNA repair	Colon, Ovarian, Endometrial	Lynch syndrome	20301390
MLH3	Mismatch DNA repair	Polyposis (recessive)	unknown	30573798
MSH2	Mismatch DNA repair	Colon, Ovarian, Endometrial	Lynch syndrome	20301390
MSH3	Mismatch DNA repair	Polyposis	Familial adenomatous polyposis 4 (recessive)	27476653, 35675019, 38243056
MSH6	Mismatch DNA repair	Colon, Endometrial	Lynch syndrome	20301390
MUTYH	DNA repair	Colon (homozygotes)	MUTYH-associated polyposis	20301519, 21952991
NBN	Double stranded break repair	Breast	Nijmegen breakage syndrome (recessive)	15185344, 9590180
NF1	MAPK signaling	Optic Glioma, Peripheral Nerve Sheath, Breast	Neurofibromatosis	2114220, 23165953, 20301288
NF2	Cellular regulation	Acoustic neuromas, Vestibular Schwannomas	Neurofibromatosis 2	20301380
NTHL1	Base excision repair	Colon	Polyposis (recessive)	25938944, 26431160
NYNRIN	Stem cell homeostasis	Wilms tumor	NYNRIN-related Wilms tumor (AR)	20301471
PALB2	Fanconi/BRCA	Breast, Pancreatic	Fanconi anaemia FA-N (recessive)	17200668, 17200671, 25099575
PDGFRA	Protein tyrosine kinase	GIST	Familial, sporadic GIST	25975287, 23036227
PHOX2B	Tumor suppressor	Neuroblastoma	Hereditary neuroblastoma	17637745, 28674118
PIK3CA	AKT signaling	Breast, Thyroid	Cowden-like	22729224, 23246288
PMS2	Mismatch DNA repair	Colon, Endometrial	Lynch syndrome	20301390
POLD1	DNA Polymerase	Colon, Endometrial	Familial polyposis, colorectal cancer	23263490, 23770608
POLE	DNA Polymerase	Colon	Familial polyposis, colorectal cancer	23263490
POLQ	DNA polymerase, double-strand break repair	Breast, Ovarian, Colorectal, Pancreatic	Hereditary colorectal, breast, ovarian cancer	27264557
POT1	Telomere maintenance	Melanoma, CLL, Sarcoma, Glioma, Colon, Thyroid, Breast	Multi-organ tumor predisposition	23502782, 24686849, 28853721
PRKAR1A	cAMP signaling	Endocrine	Carney complex (recessive)	4010501
PTCH1	Hedgehog	Basal cell carcinoma, PNET	Nevoid basal cell-carcinoma syndrome	8681379, 8658145, 20301330
PTEN	PI3K/MAPK Signaling	Breast	Cowden syndrome	20301661
RAD51B	Double stranded break repair	Unknown	Hereditary breast and ovarian cancer	24139550
RAD51C	Fanconi/BRCA	Ovarian, Breast	Fanconi anaemia FA-O (recessive)	22006311, 22538716
RAD51D	Fanconi/BRCA	Ovarian, Breast	Fanconi anaemia (recessive)	21822267, 22415235
RB1	Tumor suppressor	Retinoblastoma, Sarcoma, Melanoma	Hereditary retinoblastoma	25621664, 22355046, 20301625
RECQL	DNA repair	Breast	Hereditary breast cancer	25915596
RECQL4	Telomere maintenance	Osteosarcoma, Leukemia, MDS	Rothmund-Thomson syndrome (AR), Baller-Gerold (AR) syndrome	35219053
RET	Receptor Tyrosine Kinase	Endocrine	Multiple endocrine neoplasia type 2	20301434
REST	Transcription repressor	Wilms tumor	REST-related Wilms tumor	20301471
RINT1	DNA checkpoint regulation	Breast, Colon	Multi-organ tumor predisposition	25050558
RNF43	WNT signaling	Colon	Sessile Serrated Polyposis	27329244, 27081527
RPS19	Protein synthesis	Leukemia, MDS, Sarcoma, Lung, Colon, Cervix	Diamond-Blackfan anemia	17726054, 20301769
RPS20	Ribosomal protein	Colon	unknown	24941021
RSPO3	WNT signaling	Typically somatic only	Colon cancer	29127379, 37048063
RTEL1	Telomere maintenance	Leukemia, MDS, Thyroid, Melanoma	Dyskeratosis Congenita and Telomere Biology disorders (DC/TBD), Revesz syndrome	15210109, 20301779
RUNX1	Hematopoietic stem cell regulation (transcription factor)	myelodysplastic syndrome and acute myeloid leukemia	RUNX1-familial platelet disorder	21148331
SBDS	Ribosomal RNA processing	Leukemia, MDS, Colon	Shwachman-Diamond syndrome (AR)	41155398
SDHA	Succinate dehydrogenase complex	Pheochromocytoma, Paraganglioma	Hereditary paraganglioma-pheochromoctyoma	20484225, 21752896
SDHAF2	Succinate dehydrogenase co-factor	Pheochromocytoma, Paraganglioma	Hereditary paraganglioma-pheochromoctyoma	20301715
SDHB	Succinate dehydrogenase complex	Pheochromocytoma, Paraganglioma	Hereditary paraganglioma-pheochromoctyoma	11404820
SDHC	Succinate dehydrogenase complex	Pheochromocytoma, Paraganglioma	Hereditary paraganglioma-pheochromoctyoma	11062460
SDHD	Succinate dehydrogenase complex	Pheochromocytoma, Paraganglioma	Hereditary paraganglioma-pheochromoctyoma	10657297
SMAD4	TGF-beta signaling	Colon	Juvenile polyposis	20301642
SMARCA4	SWI/SNF complex	Ovarian	Hereditary small cell carcinoma of the ovary, hypercalcemic	24658002
SMARCB1	ATP-dependent SWI/SNF chromatin remodeling complex	Schwannoma, Pediatric Rhabdoid Tumors (Kidney, CNS, Soft Tissue), Meningioma,	Schwannomatosis, rhabdoid tumor predisposition syndrome type 1	28109176, 29706634
SMARCE1	DNA repair and replication	Spinal meningioma	Familial spinal meningioma	23377182
STK11	Tumor suppressor	Breast, Colon, Pancreatic, Gastric, Hamartomas	Peutz-Jeghers syndrome	20301443
TINF2	Telomere maintenance	Leukemia, MDS, Thyroid, Melanoma	Dyskeratosis Congenita and Telomere Biology disorders (DC/TBD), Revesz syndrome	18669893
SUFU	Hedgehog Signaling	Basal cell carcinoma, medulloblastoma, meningioma, gonadal tumours	Nevoid basal cell-carcinoma syndrome (Gorlin syndrome)	19533801, 35768194
TMEM127	Tumor suppressor	Pheochromocytoma, Paraganglioma	Hereditary paraganglioma-pheochromocytoma	20301715
TP53	Cell growth	Breast, Ovarian	Li-Fraumeni syndrome	22006311,20301488
TRIM28	Cell growth and differentiation, pluripotency, apoptosis, DNA repair	Wilms tumor	TRIM28-related Wilms tumor	20301471
TRIM37	Cell division regulation, centrosome stability	Wilms tumor, Breast	Mulibrey nanism (AR)
TSC1	Cell growth	Hamartomas	Tuberous sclerosis complex	10227394, 9924605, 17287951
TSC2	Cell growth	Hamartomas	Tuberous sclerosis complex	8825048, 9829910
VHL	p53 regulation	Kidney, Neuroendocrine	von Hippel-Lindau syndrome	20301636
WT1	WT1 transcription factor	Wilms tumor	Wilms tumor	15150775

References

1. Jacobson AL, et al. Utility of adenomatous polyp testing for detection of constitutional mosaic APC mutations in unexplained polyposis patients. Collaborative Group of Americas on Inherited Gastrointestinal Cancer, 2021 Annual Meeting, plenary abstract presentation
2. Pritchard CC, et al. ColoSeq provides comprehensive lynch and polyposis syndrome mutational analysis using massively parallel sequencing. J Mol Diagn 2012, 14:357-66. 22658618
3. Walsh T, et al. Detection of inherited mutations for breast and ovarian cancer using genomic capture and massively parallel sequencing. Proc Natl Acad Sci U S A 2010, 107:12629-33. 20616022
4. Nord AS, Lee M, King MC, and Walsh T. Accurate and exact CNV identification from targeted high-throughput sequence data. BMC Genomics 2011, 12:184. 21486468
5. Metzker ML. Sequencing technologies - the next generation. Nat Rev Genet 2010, 11:31-46. 19997069
6. Li J et al. Point Mutations in Exon 1B of APC Reveal Gastric Adenocarcinoma and Proximal Polyposis of the Stomach as a Familial Adenomatous Polyposis Variant. Am J Hum Genet 2016 May, 5;98(5):830-842. 27087319

Forms & Requisitions

Requisition Form and Ordering Instructions:

1. Fill out a Genetics Requisition form

2. Under “Check Test Requested,” check: "ColoSeq™ – Polyposis/CSQP"

Genetics Preauthorization Form (preauthorization is only available for providers who are external to the UW system).

Synonyms

AIP, AKT1, ALK, AMER1, APC, ATM, ATR, AXIN2, BAP1, BARD1, BMPR1A, BRAF, BRCA1, BRCA2, BRIP1, BUB1B, CDC73, CDH1, CDK12, CDK4, CDKN1B, CDKN2A, CEBPA, CHEK2, colon polyposis, constitutional mosaicism, CTNNA1, CTNNB1, DDX41, DICER1, EGFR, EIF6, ELANE, ELOC, EPCAM, ERCC6L2, ETV6, EXT1, EXT2, familial adenomatous polyposis, FANCM, FAP, FH, FLCN, GATA2, GEN1, germline mosaicism, GREM1, HOXB13, HSD3B1, KDM3B, KIF1B, KIT, LZTR1, MAX, MBD4, MECOM, MEN1, MET, MITF, MLH1, MLH3, mosaicism, MSH2, MSH3, MSH6, MUTYH, MYH-associated polyposis, NBN, Next-generation sequencing, NF1, NF2, NTHL1, NYNRIN, paired tissue testing, paired tumor testing, PALB2, PDGFRA, PHOX2B, PIK3CA, PMS2, POLD1, POLE, POLQ, polyps, POT1, PRKAR1A, PTCH1, PTEN, RAD51B, RAD51C, RAD51D, RB1, RECQL, RECQL4, REST, RET, RINT1, RNF43, RPS19, RPS20, RSPO3, RTEL1, RUNX1, SBDS, SDHA, SDHAF2, SDHB, SDHC, SDHD, SMAD4, SMARCA4, SMARCB1, SMARCE1, STK11, SUFU, TINF2, TMEM127, TP53, TRIM28, TRIM37, TSC1, TSC2, VHL, WT1 Colon cancer

Components

Code	Name
CSQPGS	ColoSeq Genes Sequenced
CSQPRE	ColoSeq Result
CSQPIN	ColoSeq Interpretation
CSQPCH	ColoSeq Clinical History
CSQPMT	ColoSeq Method
CSQPDI	ColoSeq Director