Diagnostics

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Common/High-Risk Cancer Panel

The Common/High-Risk Cancer Panel is a comprehensive next-generation sequencing (NGS) panel that analyzes genes associated with increased risks for hereditary breast, colon, uterine, ovarian, 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%, and other, rarer genes are also associated with an increased risk for malignancy.

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 cases are 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 cancer cases are caused by mutations in the EPCAM, MLH1, MSH2, PMS2, and MSH6 genes, related to Lynch syndrome, while the majority of hereditary ovarian cancer cases are 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).

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 (HBOC)
  • 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
  • MUTYH-associated polyposis
  • Muir-Torre syndrome

Inheritance

The cancer risks associated with the genes are typically inherited in an autosomal dominant manner, 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, PALB2, and RAD51C are associated with Fanconi anemia.
  • MUTYH is associated with MUTYH-associated polyposis
  • NBN and RAD50 are associated with Nijmegen breakage syndrome and Nijmegen breakage syndrome-like disorder

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 (32)

APC ATM BAP1 BARD1 BMPR1A BRCA1 BRCA2 BRIP1
CDH1 CDK4 CDKN2A CHEK2 EPCAM GREM1 MITF MLH1
MSH2 MSH6 MUTYH NBN PALB2 PMS2 POLD1 POLE
PTEN RAD50 RAD51C RAD51D SMAD4 STK11 TP53 VHL

References:

  • Antoniou A, Pharoah PD, Narod S, et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet. 2003;72(5):1117-30.
  • Bogaert J, Prenen H. Molecular genetics of colorectal cancer. Annals of Gastroenterology. 2014;27(1):9-14.
  • Gruber SB, Thompson WD. A population-based study of endometrial cancer and familial risk in younger women. Cancer and Steroid Hormone Study Group. Cancer Epidemiol Biomarkers Prev. 1996;5(6):411–417.
  • Ford D, Easton DF, Bishop DT, Narod SA, Goldgar DE. Risks of cancer in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Lancet. 1994;343(8899):692-5.
  • Kohlmann W, Gruber SB. Lynch Syndrome. 2004 Feb 5 [Updated 2014 May 22]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1211/
  • Pal T, Permuth-Wey J, Betts JA. BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases. Cancer. 2005; 104(12):2807-16.
  • Petrucelli N, Daly MB, Pal T. BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer. 1998 Sep 4 [Updated 2016 Dec 15]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1247/
  • Surveillance, Epidemiology, and End Results Program (SEERP). Cancer Stat Fact Sheets [Accessed April 20, 2017]. Available from: http://seer.cancer.gov/
  • Shi C, Ralph H. Hruban, and Alison P. Klein (2009) Familial Pancreatic Cancer. Archives of Pathology & Laboratory Medicine: March 2009, Vol. 133, No. 3, pp. 365-374.
  • Van lier MG, Wagner A, Mathus-vliegen EM, Kuipers EJ, Steyerberg EW, Van leerdam ME. High cancer risk in Peutz-Jeghers syndrome: a systematic review and surveillance recommendations. Am J Gastroenterol. 2010;105(6):1258-64.
  • Vasen HF, Gruis NA, Frants RR, Van der velden PA, Hille ET, Bergman W. Risk of developing pancreatic cancer in families with familial atypical multiple mole melanoma associated with a specific 19 deletion of p16 (p16-Leiden). Int J Cancer. 2000;87(6):809-11.