Diagnostics

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Pan Cancer Panel

The Pan Cancer Panel is a comprehensive next-generation sequencing (NGS) panel that analyzes genes associated with increased risks for hereditary breast, colon, gastric, uterine, ovarian, brain, nervous system, renal, urinary tract, prostate, and pancreatic cancers.

Breast cancer occurs frequently in the general population, with the average woman’s lifetime risk of developing breast cancer being approximately 12% (SEERP). Although the majority of breast cancer is not related to heritable factors, in approximately 5-10% cases breast cancer is caused by a specific genetic change. Women who carry these genetic changes may be at significantly increased risk of developing breast cancer in their lifetime. The majority of hereditary breast cancer is caused by mutations in the BRCA1 and BRCA2 genes, which can lead to lifetime breast cancer risks of 46-87% (Ford et al, 1994; Antoniou et al, 2003; Petrucelli et al, 1998), and other, rarer genes can cause similar or higher breast cancer risks. Frequently, changes in genes that result in increased risks for breast also predispose individuals to increased risks for other cancers.

Colorectal cancer occurs frequently in the general population, with the average person’s lifetime risk of developing colorectal cancer being approximately 5% (SEERP). Although the majority of colorectal cancer is not related to heritable factors, in approximately 5-10% cases colorectal cancer is caused by a specific genetic change (Bogaert and Prenen, 2014). Individuals who carry these genetic changes may be at significantly increased risk of developing colorectal cancer in their lifetime. The majority of hereditary colorectal cancer is caused by mutations in the MLH1, MSH2, MSH6, PMS2, and EPCAM genes, which can lead to lifetime colorectal cancer risks of up to 82%, and other, rarer genes are also associated with an increased risk for malignancy (Kohlmann and Gruber, 2004).

Ovarian cancer affects approximately 1% of women during their lifetime, and uterine cancer affects approximately 2% of women (SEERP). Although the majority of ovarian and uterine cancer is not related to heritable factors, approximately 5% of uterine cancer (Gruber and Thompson, 1996) and at least 10-15% of ovarian cancer is caused by a specific genetic change (Pal et al, 2005) . Individuals who carry these genetic changes may be at significantly increased risk of developing ovarian and uterine cancer in their lifetime. The majority of hereditary uterine is caused by mutations in the EPCAM, MLH1, MSH2, PMS2, and MSH6 genes, related to Lynch syndrome, while the majority of hereditary ovarian cancer is caused by mutations in the BRCA1/2 genes related to hereditary breast and ovarian cancer syndrome. Individuals who carry disease causing changes in these genes, and other, rarer genes, are at increased lifetime risks for uterine cancer (up to 60%) and ovarian cancer (up to 63%) (Kohlmann and Gruber, 2004; Petrucelli et al, 1998).

Pancreatic cancer affects approximately 1.5% of individuals in their lifetime (SEERP). Although the majority of pancreatic cancer is not related to heritable factors, in approximately 5-10% cases pancreatic cancer may be hereditary (Shi et al, 2009). Individuals who carry disease causing genetic changes may be at significantly increased risk of developing pancreatic cancer in their lifetime. For example, individuals with a pathogenic BRCA1/2 mutation have up to 7% lifetime risk for pancreatic cancer (Petrucelli et al,1998), while individuals with STK11 or CDKN2A mutations have up to 36% and 17% lifetime risks for pancreatic cancer, respectively (van Lier et al, 2010; Vasen et al, 2000).

Thyroid cancer affects approximately 1.2% of individuals in their lifetime (SEERP). Although the majority of thyroid cancer is not related to heritable factors, approximately 25% of medullary thyroid cancer and 5-15% of non-medullary thyroid cancer is related to heritable factors (Nose, 2011). Individuals who carry disease causing genetic changes may be at significantly increased risk of developing thyroid cancer in their lifetime. For example, individuals with a pathogenic RET mutation have >95% lifetime risk to develop medullary thyroid cancer (Marquard et al, 1999).

Brain and nervous system cancer affects approximately .6% of individuals in their lifetime (SEERP). Although the majority of brain and nervous system cancer cases are not related to heritable factors, approximately 5% of central nervous system cancers are associated with underlying genetic conditions (Bleeker et al, 2014). Individuals who carry disease causing genetic changes may be at significantly increased risk of developing brain or nervous system cancer in their lifetime; for example, individuals with pathogenic VHL changes have a 60-80% risk to develop hemangioblastoma (Wind and Lonser, 2011).

Renal cancer affects approximately 1.6% of individuals in their lifetime, and bladder cancer affects approximately 2.6% of individuals in their lifetime (SEERP). Although the majority of renal and urinary tract cancer cases are not related to heritable factors, approximately 3-5% of renal cell carcinoma is due to genetic changes (Coleman and Russo, 2009). Individuals who carry disease causing genetic changes may be at significantly increased risk of developing renal or urinary tract cancer in their lifetime. For example, individuals with a pathogenic VHL mutation have up to a 70% risk for renal cancer (Frantzen et al, 2000; Houweling et al, 2011).

Frequently, changes in genes that result in increased risks for one type of cancer also predispose individuals to increased risks for other malignancies.

Included Disorders

This panel includes genes associated with:

  • Hereditary breast and ovarian cancer syndrome
  • Familial adenomatous polyposis
  • Lynch syndrome (hereditary non-polyposis colon cancer)
  • Peutz-Jeghers syndrome
  • Li-Fraumeni syndrome
  • Von-Hippel-Lindau syndrome
  • Hereditary diffuse gastric cancer
  • Cowden syndrome
  • Neurofibromatosis type1
  • Neurofibromatosis type 2
  • Tuberous sclerosis complex
  • Multiple endocrine neoplasia type I
  • Multiple endocrine neoplasia type II
  • Ataxia telangiectasia
  • Bloom syndrome
  • Retinoblastoma
  • Simpson-Golabi-Behmel syndrome
  • Nevoid basal cell carcinoma
  • Juvenile polyposis syndrome
  • Nijmegen breakage syndrome
  • MUTYH-associated polyposis

Inheritance

The inheritance of genes included in the panel is typically autosomal dominant, although several of the genes on this panel are associated with recessive genetic conditions:

  • MLH1, MSH2, PMS2, and MSH6 are associated with constitutional mismatch repair deficiency
  • ATM is associated with ataxia telangiectasia
  • BRCA2, BRIP1, FANCC, PALB2, and RAD51C are associated with Fanconi anemia.
  • MUTYH is associated with MUTYH-associated polyposis
  • NBN is associated with Nijmegen breakage syndrome
  • BLM is associated with Bloom syndrome
  • GPC3 is inherited in an X-linked fashion.

Indications for Testing

  • A personal history of early cancer
  • A personal history of multiple primary cancers
  • A family history suggestive of a hereditary cancer syndrome, including multiple individuals on the same side of a family diagnosed with cancer, especially at ages below population averages
  • Risk assessment for asymptomatic family of members of proband with molecular diagnosis of a hereditary cancer syndrome

Methodology

Next-generation sequencing technology is used to test clinically relevant portions of each gene, including coding exons, adjacent flanking bases, and selected introns/noncoding variants. Pathogenic and likely pathogenic variants are confirmed by orthogonal methods. Copy number variants, including intragenic deletions and duplications are detected to a resolution of a single exon. To request analysis of a specific single exon copy number variant, please contact our Client Services team prior to ordering.

Included Genes (83)

AIP ALK APC ATM AXIN2 BAP1
BARD1 BLM BMPR1A BRCA1 BRCA2 BRIP1
CASR CDC73 CDH1 CDK4 CDKN1B CDKN1C
CDKN2A CEBPA CHEK2 DICER1 DIS3L2 EGFR
EPCAM FANCC FH FLCN GATA2 GPC3
GREM1 HOXB13 HRAS KIT MAX MEN1
MET MITF MLH1 MSH2 MSH6 MUTYH
NBN NF1 NF2 PALB2 PDGFRA PHOX2B
PMS2 POLD1 POLE POT1 PRKAR1A PTCH1
PTEN RAD50 RAD51C RAD51D RB1 RECQL4
RET RUNX1 SDHA SDHAF2 SDHB SDHC
SDHD SMAD4 SMARCA4 SCARCB1 SMARCE1 STK11
SUFU TERC TERT TMEM127 TP53 TSC1
TSC2 VHL WRN WT1 XRCC2

Additions to the Pan Cancer Panel:

Emerging evidence genes can also be added onto the Pan Cancer panel. These genes do not have a clear association with hereditary brain and nervous system cancer, but emerging evidence suggests that they may play a role in disease pathogenesis.

Emerging Evidence Genes (31)

AKT1 BUB1B CEP57 CFTR CTRC ENG ERCC4 DKC1
EZH2 FAM175A FANCA FANCB FANCD2 FANCE FANCF FANCG
FANCI FANCL FANCM GALNT12 KIF1B MLH3 MRE11A PALLD
PIK3CA PRSS1 PTCH2 RINT1 SLX4 SPINK1 TINF2

References:

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