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BreastTrue® High Risk Panel

Genetic Testing for High Risk Incidences of Breast Cancer

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What Is BreastTrue®
High Risk Panel?

BreastTrue® High Risk Panel is a next-generation sequencing test with deletion/duplication analysis to detect mutations in seven high-risk breast cancer susceptibility genes, including BRCA1, BRCA2 and PALB2.

 

Recent studies of breast cancer survivors have shown that approximately 70 percent of the mutations identified were BRCA1/2 mutations. Approximately 4 percent had germline mutations in other cancer-susceptibility genes, including high-risk genes. These additional high-risk genes include CDH1, PALB2, PTEN, STK11, and TP53. Pathway Genomics’ BreastTrue® High Risk Panel analyzes all of these genes.

BreastTrue_New-England-Journal_Cambridge_Infographic

The Latest Research on PALB2

A new large study published in the New England Journal of Medicine shows that mutations in the PALB2 gene are important contributors to breast cancer risk. Read the abstract…

“Since the BRCA1 and BRCA2 mutations were discovered in the mid-90s, no other genes of similar importance have been found. PALB2 is a potential candidate to be BRCA3.”

Marc Tischkowitz, M.D., Ph.D.
Lead Study Author
Department of Medical Genetics
University of Cambridge

Explore the Genes

Pathogenic variants in BRCA1 and in a related gene, BRCA2, lead to hereditary breast and ovarian cancer syndrome (HBOC) [1, 2]. These pathogenic variants increase an individual’s risk for several cancers, most notably, breast and ovarian cancer. Other cancers associated with HBOC include male breast, prostate, pancreatic, and melanoma [1, 2]. The average lifetime risks in those who carry a BRCA1 pathogenic variant are 57-73% for breast cancer and up to 41% for ovarian cancer [1, 3-7]. Women in the general population have only a 12.3% lifetime risk of breast cancer and a 1.4% lifetime risk of ovarian cancer; meaning that 1 in 8 women will develop breast cancer and 1 in 71 women will develop ovarian cancer sometime during their lives [8].
The BRCA1 (breast cancer 1, early onset) gene encodes a multifunctional protein that interacts with tumor suppressors, DNA repair proteins, cell cycle regulators, RNA polymerase II holoenzyme, transcription factors, corepressors, chromatin remodeling enzymes, and RNA processing factors. BRCA1, therefore, has a critical role in maintaining genomic stability and is involved in many cellular processes important in tumor biology, including DNA repair, cell cycle progression, and transcriptional regulation [9-15]. Loss or inactivation of one copy of BRCA1 is thought to result in accumulation of pathogenic variants and structural changes in the genome, thereby increasing the risk of cancer [1].
Pathogenic variants in BRCA2 and in a related gene, BRCA1, lead to hereditary breast and ovarian cancer syndrome (HBOC) [1, 2]. These pathogenic variants increase an individual’s risk for several cancers, most notably, breast and ovarian cancer. Other cancers associated with HBOC include male breast, prostate, pancreatic, and melanoma [1, 2]. The average lifetime risks in those who carry a BRCA2 pathogenic variant are 45-55% for breast cancer and 11-18% for ovarian cancer [1, 3-7]. Women in the general population have a 12.3% lifetime risk of breast cancer and a 1.4% lifetime risk of ovarian cancer; meaning that 1 in 8 women will develop breast cancer and 1 in 71 women will develop ovarian cancer sometime during their lives [8].
The BRCA2 (breast cancer 2, early onset) gene encodes a protein with important roles in the DNA damage response and DNA repair pathways [14]. BRCA2 is a tumor suppressor that mediates recruitment of the RAD51 recombinase protein to DNA double-strand breaks [14]. The primary function of the BRCA2 protein is to facilitate homologous recombination, an important DNA repair mechanism for maintenance of genomic integrity [1, 14]. Loss or inactivation of one copy of BRCA2 is thought to result in accumulation of pathogenic variants and structural changes in the genome, thereby increasing the risk of cancer [1].
Pathogenic variants in the CDH1 gene are associated with hereditary diffuse gastric cancer syndrome (HDGC). Individuals who carry a pathogenic variant in CDH1 have a high risk of developing lobular breast cancer and diffuse gastric cancer at a relatively young age. Onset occurs anywhere between the ages of 14 to 69 years with an average onset age of 38 years [16]. The lifetime risk for female breast cancer in individuals with HDGC is 39-52% and up to 80% for gastric cancer [17, 18].
The CDH1 (cadherin 1) gene encodes the epithelial cadherin protein (E-cadherin), a member of the trans-membrane glycoprotein family. E-cadherin is expressed on epithelial tissues and is responsible for calcium-dependent cell-cell adhesion. Loss of CDH1 expression is associated with cancer cell invasiveness [18]. Individuals who are carriers of a CDH1 germline pathogenic variant, will develop cancer only when the second copy of the CDH1 gene is somatically inactivated or down regulated [17-20].

Pathogenic variants in PALB2 are associated with elevated risks for both breast and pancreatic cancer [23]. While there are no specific risk estimates for pancreatic cancer, there is an estimated 33-58% risk for breast cancer in individuals who carry a PALB2 pathogenic variant. This risk range is dependent on whether an individual has a significant family history of breast cancer [27]. PALB2 pathogenic variants have been detected in 1-3% of hereditary breast cancer patients who tested negative for BRCA1 and BRCA2 variants [24-27].

The PALB2 (partner and localizer of BRCA2) gene encodes a protein that plays essential roles in homologous recombination (HR)-mediated DNA repair by interacting with BRCA1, BRCA2, and other proteins involved in HR-mediated DNA repair [25, 27]. PALB2 functions as a tumor suppressor gene. Disruption of the PALB2 gene is thought to result in accumulation of pathogenic variants and structural changes in the genome, thereby increasing the risk of cancer [28].

Pathogenic variants in the PTEN gene are associated with PTEN hamartoma tumor syndrome (PHTS), which includes Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, PTEN-related Proteus syndrome, and Proteus-like syndrome (30). Individuals with PHTS develop benign (non-cancerous) tumors called hamartomas in multiple organ systems throughout the body [29, 30]. Individuals with inherited pathogenic variants in the PTEN gene have an elevated risk of breast (85.2% lifetime risk), thyroid (35.2% lifetime risk), endometrial (28.2% lifetime risk) and kidney cancer (33.6% lifetime risk) [31]. These individuals are also prone to developing gastrointestinal polyps and have a slightly elevated lifetime risk for colorectal cancer [30].

The PTEN (phosphatase and tensin homolog) gene encodes a dual-specificity phosphatase that acts on both lipid and protein substrates. The lipid phosphatase activity of the PTEN protein suppresses the PI3K/AKT/mTOR signaling pathway, which regulates cell growth and survival [32]. The importance of PTEN as a tumor suppressor gene is supported by the high frequency of somatic mutations in PTEN found in a variety of sporadic (non-hereditary) human cancers [33].

Pathogenic variants in STK11 are associated with Peutz-Jeghers syndrome (PJS). Individuals with PJS have an increased risk for breast cancer (32-54% lifetime risk), colorectal, gastric, gynecologic, pancreatic and lung cancers, as well as tumors of the testes and gastrointestinal polyps [34-36]. The risks among individuals with PJS for developing any first cancer by ages 20, 30, 40, 50, 60 and 70 years are 2%, 5%, 17%, 31%, 60% and 85%, respectively [37]. In PJS, cancers develop at an average age of 42 years, a younger age compared to the general population [36]. Some individuals with an STK11 pathogenic variant may present with hyperpigmented (dark, freckle-like) spots on mucocutaneous (lips, mouth, nostrils) surfaces that may resolve by adulthood [38].

The STK11 (serine/threonine protein kinase 11) gene encodes a serine-threonine kinase involved in regulation of metabolism, cell differentiation, proliferation, polarity and apoptosis [38, 39]. Most patients who are clinically diagnosed with PJS have a causative mutation in STK11 [40]. Loss of kinase activity is likely responsible for the development of this condition [41].

Pathogenic variants in the TP53 gene are associated with Li-Fraumeni syndrome (LFS). Fifty percent of individuals with a TP53 pathogenic variant will develop cancer by the age of 30 [42-45]. Females who carry a TP53 pathogenic variant have a significant higher risk of developing cancer than male carriers, and a lifetime breast cancer risk of about 70-90% [42, 45-48]. The most common cancers associated with LFS are breast, sarcoma, brain tumors and adrenocortical carcinoma. Other cancers include leukemia, choroid plexus papilloma, Wilms tumor, and gastric, colorectal and pancreatic cancer [49].

The TP53 (tumor protein p53) gene encodes a transcription factor (p53 protein) that is involved in cellular responses to environmental and genotoxic stress [50]. The p53 tumor suppressor protein binds consensus DNA in the responsive elements of several hundreds of genes [51]. Approximately 95% of p53 pathogenic variants are localized in the DNA-binding domain of the p53 protein [51].

 

Testing Options

Below are the next-generation sequencing tests that Pathway Genomics offers for risk of hereditary breast cancer:
  1. BRCATrue®
  2. BRCATrue® Ashkenazi Jewish (3-Site)
  3. BRCATrue® Hispanic (8-Site)
  4. BreastTrue® High Risk Panel
  5. Single Site Testing

Reflex Options

  1. BRCATrue® with reflex to BreastTrue® High Risk Panel
  2. BRCATrue® Ashkenazi Jewish (3-Site) with reflex to BRCATrue®
  3. BRCATrue® Ashkenazi Jewish (3-Site) with reflex to BreastTrue® High Risk Panel
  4. BRCATrue® Hispanic (8-Site) with reflex to BRCATrue®
  5. BRCATrue® Hispanic (8-Site) with reflex to BreastTrue® High Risk Panel

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High-Risk Hereditary Breast Cancers

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Clinical Guidelines & Clinical Utility

High Risk Patient Criteria

The test is best suited for individuals with either a history of early onset breast or ovarian cancer or a strong family history of breast and/or ovarian cancer. Individuals with the following medical or family history factors should consider testing:

  • Early onset breast cancer (under 50 years of age)
  • Bilateral or multiple breast cancers
  • Diagnosed with both breast and ovarian cancer
  • Family history of breast and/or ovarian cancer
  • Male breast cancer within family
  • Ashkenazi Jewish ethnic background

Clinical Utility

  • Guide decisions on prevention strategies (e.g. chemoprevention, prophylactic surgery)
  • Increase surveillance for breast cancer
  • Inform treatment decisions
  • Identify family members at increased risk

Acceptable Sample Types

Saliva

The saliva sample collection kit includes one saliva collection device. Fill each tube up to the notch in the collection device.

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Blood

The blood sample collection kit includes one 4ml lavender blood tube.

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For more information about the sample collection kits listed above, please contact our client services department at (877) 505-7374 or clientservices@pathway.com. To order sample collection kits, complete our online order form.

References

References

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  2. Smith, E.C., An overview of hereditary breast and ovarian cancer syndrome. J Midwifery Womens Health, 2012. 57(6): p. 577-84.
  3. Ford, D., et al., Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet, 1998. 62(3): p. 676-89.
  4. Antoniou, A., 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): p. 1117-30.
  5. Brose, M.S., et al., Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program. J Natl Cancer Inst, 2002. 94(18): p. 1365-72.
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  42. Hwang, S.J., et al., Germline p53 mutations in a cohort with childhood sarcoma: sex differences in cancer risk. Am J Hum Genet, 2003. 72(4): p. 975-83.
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  46. Chompret, A., et al., P53 germline mutations in childhood cancers and cancer risk for carrier individuals. Br J Cancer, 2000. 82(12): p. 1932-7.
  47. Kamihara, J., H.Q. Rana, and J.E. Garber, Germline TP53 mutations and the changing landscape of Li-Fraumeni syndrome. Hum Mutat, 2014. 35(6): p. 654-62.
  48. Mai, P.L., et al., Li-Fraumeni syndrome: report of a clinical research workshop and creation of a research consortium. Cancer Genet, 2012. 205(10): p. 479-87.
  49. Ariffin, H., et al., Li-Fraumeni syndrome in a Malaysian kindred. Cancer Genet Cytogenet, 2008. 186(1): p. 49-53.
  50. Krypuy, M., et al., High resolution melting for mutation scanning of TP53 exons 5-8. BMC Cancer, 2007. 7: p. 168.
  51. Malcikova, J., et al., Analysis of the DNA-binding activity of p53 mutants using functional protein microarrays and its relationship to transcriptional activation. Biol Chem, 2010. 391(2-3): p. 197-205.