CustomNext-Cancer

CustomNext-Cancer is a next generation sequencing panel that analyzes up to 67 genes of your choosing associated with increased risks for breast, colon, ovarian, pancreatic, kidney, uterine, and many other cancers.

 

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CustomNext-Cancer is a next generation sequencing panel that analyzes up to 67 genes of your choosing associated with increased risks for breast, colon, ovarian, pancreatic, kidney, uterine, and many other cancers.

 

Ambry utilizes next generation sequencing (NGS) to offer CustomNext-Cancer, a customizable hereditary cancer panel of up to 67 genes. Gene options for this panel include: AIP, ALK, APC, ATM, BAP1, BARD1, BLM, BRCA1, BRCA2, BRIP1, BMPR1A, CDH1, CDK4, CDKN1B, CDKN2A, CHEK2, DICER1, EPCAM, FANCC, FH, FLCN, GALNT12, GREM1, HOXB13, MAX, MEN1, MET, MITF, MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, NF1, NF2, PALB2, PHOX2B, PMS2, POLD1, POLE, POT1, PRKAR1A, PTCH1, PTEN, RAD50, RAD51C, RAD51D, RB1, RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, SMAD4, SMARCA4, SMARCB1, SMARCE1, STK11, SUFU, TMEM127, TP53, TSC1, TSC2, VHL, XRCC2.

Disease Name 
Breast cancer
Brain tumors
Colorectal cancer
Hereditary cancer
Kidney cancer
Melanoma
Ovarian cancer
Pancreatic cancer
Paraganglioma
Pheochromocytoma
Prostate cancer
Stomach cancer
Uterine cancer
Disease Information 

CustomNext-Cancer includes genes related to breast, colorectal, kidney, melanoma, ovarian, pancreatic, paraganglioma, pheochromocytoma, uterine, and other cancers. For more information specific to each gene and disease type, click here.

CustomNext-Cancer Gene Options:

CustomNext-Cancer has 67 genes to choose from, including all of the BrainTumorNext and MelanomaNext  genes and all 49 genes on CancerNext-Expanded. Specific Site Analysis is available for individual gene mutations identified in a family.

Additional CustomNext-Cancer Genes

BLM is a gene associated with Bloom syndrome, a rare autosomal recessive condition affecting multiple body systems. Studies have demonstrated an increased risk for breast cancer in women who carry a Slavic founder mutation (p.Q548*) in BLM, including a meta-analysis of BLM mutations that suggested a two- to five-fold increased risk for female breast cancer in carriers. 1-2 Additionally, BLM mutations have also been associated with an increased risk for colorectal cancer; however, exact cancer risks are not currently available. 3-4

DICER1 mutations have been shown to cause a tumor predisposition syndrome associated with an increased risk for various benign and malignant tumors. Studies have demonstrated an increased risk for tumors including pleuropulmonary blastoma, cystic nephroma, ovarian sex cord stromal tumors (primarily Sertoli-Leydig cell tumors), multinodular goiter and thyroid cancer, embryonal rhabdomyosarcomas, ciliary body medulloepithelioma, nasal chondromesenchymal hamartomas, and pituitary blastoma, as well as various other tumor types. At this time, lifetime risks for each tumor type have not been well described.5-7

FANCC is a gene involved in the Fanconi anemia pathway, critical for DNA repair by homologous recombination. Carriers of FANCC mutations have been identified in high-risk breast cancer families.8 A study found an increased risk for breast cancer in female relatives of patients with Fanconi anemia type C (FA-C) who carried a FANCC mutation.9 Other studies have identified FANCC mutations in patients with apparently sporadic, early-onset pancreatic cancer. 10-12 Lifetime cancer risk estimates are not currently available for mutation carriers.

GALNT12 mutations have been identified in individuals with colorectal cancer and polyps. Carriers ofGALNT12 mutations may be at an increased lifetime risk for colorectal cancer; however, lifetime cancer risk estimates are not currently available. 13-14

HOXB13 encodes a transcription factor involved in epidermal differentiation and prostate gland development. Multiple studies have associated a recurrent HOXB13 mutation, p.G84E, with an increased risk for early-onset prostate cancer, however, lifetime cancer risk estimates are not currently available for mutation carriers.15-17 Data are insufficient to support increased cancer risks for other HOXB13 alterations at this time.

XRCC2 is a gene involved in the Fanconi anemia pathway, critical for DNA repair by homologous recombination. Female and male individuals with breast cancer have been found to carry monoallelic mutations in XRCC218-20 Currently, breast cancer lifetime risk estimates are not available for mutation carriers.

Testing Benefits & Indication 

Indications for Testing

CustomNext-Cancer may be appropriate to consider in the following situations, combined with common red flags for hereditary cancer and clinician discretion:

  • Your patient's complex personal and and/or family history requires a unique panel of genes to assess (not found in an existing panel)
  • You/your patient would like to learn about fewer genes than those currently found on existing panels
  • You/your patient would like to learn about more genes than those currently found on existing panels

Common Red Flags for Hereditary Cancer

  • Cancer diagnosed at a younger age than expected for the general population (≤ 50 years, for most cancers)
  • Cancer diagnosed across generations, and in multiple generations within a family, especially when diagnosed younger than average*
  • Individual with multiple primary cancers (either in paired organs or in different organs)
  • A pattern of cancer in the family that is typical of a known cancer predisposition syndrome (for example colon and uterine cancer in Lynch syndrome, or breast and pancreatic cancer with PALB2 mutations)

*On the same side of the family

If increased risk of a hereditary cancer syndrome is suspected, the American Congress (formerly College) of Obstetricians and Gynecologists (ACOG) recommends referral to a specialist in cancer genetics or a healthcare provider with expertise in genetics for complete hereditary cancer risk assessment, which may lead to genetic testing.21 Establishing a molecular diagnosis can help guide preventive measures, direct surgical options and estimate personal and familial cancer risk. 

Benefits of Testing
Identifying patients with an inherited susceptibility for certain cancers can help with medical management. For example, this information can:

  • Modify cancer surveillance options and age of initial screening
  • Suggest specific risk-reduction measures (e.g. considering prophylactic oophorectomy, after childbearing is complete, for women with increased risk for breast/ovarian cancer)
  • Clarify and stratify familial cancer risks, based on gene-specific cancer associations, such as risk for uterine, colon, and ovarian cancer with MLH1 mutations
  • Offer treatment guidance (e.g. avoidance of radiation-based treatment methods for individuals with aTP53 mutation)
  • Identify other at-risk family members
  • Provide guidance with new gene-specific treatment options and risk reduction measures as they emerge
Test Description 

CustomNext-Cancer analyzes up to 67 genes (listed above) selected by the ordering healthcare provider. All selected genes (excluding EPCAM and GREM1) are evaluated by next generation sequencing (NGS) or Sanger sequencing of all coding domains, and well into the flanking 5’ and 3’ ends of all the introns and untranslated regions. In addition, sequencing of the promoter region is performed for the following genes, if selected: PTEN (c.-1300 to c.-745), MLH1 (c.-337 to c.-194), and MSH2 (c.-318 to c.-65). For POLD1 and POLE, missense variants located outside of the exonuclease domains (codons 311-541 and 269-485, respectively) are not routinely reported. For MITF, only the status of the c.952G>A (p.E318K) alteration is analyzed and reported. When applicable, the inversion of coding exons 1-7 of the MSH2 gene and the BRCA2 Portuguese founder mutation, c.156_157insAlu (also known as 384insAlu) are detected by NGS and confirmed by PCR and agarose gel electrophoresis. For ALK, only variants located within the kinase domain (c.3286-c.4149) are reported. For PHOX2B, the polyalanine repeat region is excluded from analysis. Clinically significant intronic findings beyond 5 base pairs are always reported. Intronic variants of unknown or unlikely clinical significance are not reported beyond 5 base pairs from the splice junction. Additional Sanger sequencing is performed for any regions missing or with insufficient read depth coverage for reliable heterozygous variant detection. Reportable small insertions and deletions, potentially homozygous variants, variants in regions complicated by pseudogene interference, and single nucleotide variant calls not satisfying 100x depth of coverage and 40% het ratio thresholds are verified by Sanger sequencing.22  Gross deletion/duplication analysis is performed for the covered exons and untranslated regions of all ordered genes (excluding MITF) using read-depth from NGS data with confirmatory multiplex ligation-dependent probe amplification (MLPA) and/or targeted chromosomal microarray. For GREM1, only the status of the 40kb 5’ UTR gross duplication is analyzed and reported, when applicable. For APC, all promoter 1B gross deletions as well as single nucleotide substitutions within the promoter 1B YY1 binding motif are analyzed and reported. If a deletion is detected in exons 13, 14, or 15 of PMS2, double stranded sequencing of the appropriate exon(s) of the pseudogene, PMS2CL, will be performed to determine if the deletion is located in the PMS2 gene or pseudogene.

Mutation Detection Rate 

CustomNext-Cancer can detect >99.9% of described mutations in the included genes listed above, when present (analytic sensitivity).

Specimen Requirements 

Complete specimen requirements are available here or by downloading the PDF found above on this page.

Turnaround Time 
TEST CODE TECHNIQUE CALENDAR DAYS
9510 CustomNext-Cancer 14-21

 

Specialty 
Genes 
AIP
ALK
APC
ATM
BAP1
BARD1
BLM
BRCA1
BRCA2
BRIP1
BMPR1A
CDH1
CDK4
CDKN1B
CDKN2A
CHEK2
DICER1
EPCAM
FANCC
FH
FLCN
GALNT12
GREM1
HOXB13
MAX
MEN1
MET
MITF
MLH1
MRE11A
MSH2
MSH6
MUTYH
NBN
NF1
NF2
PALB2
PHOX2B
PMS2
POLD1
POLE
POT1
PRKAR1A
PTCH1
PTEN
RAD50
RAD51C
RAD51D
RB1
RET
SDHA
SDHAF2
SDHB
SDHC
SDHD
SMAD4
SMARCA4
SMARCB1
SMARCE1
STK11
SUFU
TMEM127
TP53
TSC1
TSC2
VHL
XRCC2
References 
  1. Sokolenko AP, et al. High prevalence and breast cancer predisposing role of the BLM c.1642C>T (Q548X) mutation in Russia. Int J Cancer. 2012. 130(12):2867-73.
  2. Prokofyeva D, et al. Nonsense mutation p.Q548X in BLM, the gene mutated in Bloom’s syndrome, is associated with breast cancer in Slavic populations. Breast Cancer Res Treat. 2013. 137(2):533-9.
  3. Gruber SB, et al. BLM heterozygosity and the risk of colorectal cancer. Science. 2002. 297(5589):2013.
  4. de Voer RM, et al. Deleterious germline BLM mutations and the risk for early-onset colorectal cancer. Sci Rep. 2015. 5:14060.
  5. Slade I, et al. DICER1 syndrome: clarifying the diagnosis, clinical features and management implications of a pleiotropic tumour predisposition syndrome. J Med Genet. 2011. 48(4):273-8.
  6. Schultz KA, et al. DICER1-pleuropulmonary blastoma familial tumor predisposition syndrome: a unique constellation of neoplastic conditions. Pathol Case Rev. 2014. 19(2):90-100.
  7. de Kock L, et al. Pituitary blastoma: a pathognomonic feature of germline DICER1 mutations. Acta Neuropathol. 2014. 128(1):111-22.
  8. Thompson ER, et al. Exome sequencing identifies rare deleterious DNA repair genes FANCC and BLM as potential breast cancer susceptibility alleles. PLos Genet. 2012. 8(9):e1002894
  9. Berwick M, et al. Genetic heterogeneity among Fanconi anemia heterozygotes and risk of cancer. Cancer Res. 2007. 67(19):9591-6.
  10. van der Heijden MS, et al. Fanconi anemia gene mutations in young-onset pancreatic cancer. Cancer Res. 2003. 65(10):2585-8.
  11. Rogers CD, et al. The genetics of FANCC and FANCG in familial pancreatic cancer. Cancer Biol Ther.2004. 3(2):167-9.
  12. Couch FJ, et al. Germline Fanconi anemia complementation group C mutations and pancreatic cancer. Cancer Res. 2005. 65(2):383-6.
  13. Guda K, et al. Inactivating germline and somatic mutations in polypeptide N-acetylgalactosaminyltransferase 12 in human colon cancers. Proc Natl Acad Sci U.S.A. 2009. 106(31):12921-5.
  14. Clarke E, et al. Inherited deleterious variants in GALNT12 are associated with CRC susceptibility. Hum Mutat. 2012. 33(7):1056-8.
  15. Ewing CM, et al. Germline mutations in HOXB13 and prostate cancer risk. N Engl J Med. 2012. 366(2):141-9.
  16. Lin X, et al. A novel germline mutation in HOXB13 is associated with prostate cancer risk in Chinese men. Prostate. 2013. 73(2):169-75.
  17. Maia S, et al. Identification of two novel HOXB13 germline mutations in Portuguese prostate cancer patients. PLoS One. 2015. 10(7):e0132728.
  18. Kuschel B, et al. Variants in DNA double-strand break repair genes and breast cancer susceptibility. Hum Mol Genet. 2002. 11(12):1399-407.
  19. Park DJ, et al. Rare mutations in XRCC2 increase the risk of breast cancer. Am J Hum Genet. 2012. 90(4):734-9.
  20. Couch FJ, et al. Inherited mutations in 17 breast cancer susceptibility genes among a large triple negative breast cancer cohort unselected for family history of breast cancer. J Clin Oncol. 2015. 33(4):304-11.
  21. American Congress of Obstetricians and Gynecologists Committee on Genetics. Committee Opinion No. 634: Hereditary cancer syndromes and risk assessment. Obstet Gynecol. June 2015. 125(6):1538-1543.
  22. Mu W, et al. Sanger confirmation is required to achieve optimal sensitivity and specificity in next-generation sequencing panel testing. J Mol Diagn. 2016. 18(6):923-932.