Access the Next-Generation of Cancer Diagnostics

One of the major challenges in diagnosing hematological and solid tumor cancers is the high degree of tumor heterogeneity. Mutations that have critical clinical implications may only be present in very low levels, making detection of these mutations difficult. Detection of such mutations is especially important in hematological and solid tumor malignancies, where tumors show a great deal of heterogeneity and accurate prognosis is essential to identifying patient with more aggressive disease. Next-generation sequencing (NGS) helps respond to these challenges by providing a comprehensive view of the tumor’s genomic profile. Importantly, NGS can detect multiple mutations present at very low levels within the tumor.

for Hereditary Breast & Ovarian Cancer Syndrome (HBOC)

Hereditary Breast and Ovarian Cancer Syndrome (HBOC) is caused by deleterious loss of function mutations in a number of genes, most commonly BRCA1 or BRCA2. HBOC syndrome manifests clinically as a significantly increased lifetime risk of breast cancer in both females and males, an increased lifetime risk of ovarian cancer in females, as well as increased risk of prostate and pancreatic cancers. Pathogenic germline mutations in BRCA1 or BRCA2 impart a 40-80% increased lifetime risk of breast cancer, 10-40% for ovarian cancer, up to 40% for prostate cancer, and approximately 5% for pancreatic cancer.

Women with personal or family histories of HBOC should be tested for pathogenic mutations in BRCA1 and BRCA2. Many screening algorithms exist to assist primary care providers in determining who should be tested. The following criteria are suggestive of a diagnosis of HBOC:

  • Breast cancer diagnosis at a young age (<50 years old)
  • Bilateral breast cancer
  • Multiple primary BRCA-related cancers (ovarian and breast)
  • BRCA-related cancers in close relatives
  • Males with breast cancer

More extensive algorithms with specific testing guidelines have been published by ACOG, the American Society of Breast Surgeons as well as the National Comprehensive Cancer Network.

The mutations responsible for HBOC syndrome are inherited in an autosomal dominant manner, with development of cancer determined by somatic loss of function of the second allele. These pathogenic mutations are typically single nucleotide variants (SNVs) or small insertions or deletions (indels), however a minority of BRCA1 and BRCA2 mutations are large (exon level) indels.

Beyond BRCA1 and BRCA2, there are numerous genes in which mutations have been associated with increased risk for breast and ovarian cancers. Mutations in these genes are typically SNVs and small indels, and like BRCA 1/2, the increased cancer risk is inherited in an autosomal dominant manner. Sequencing these genes in a given patient increases the clinical sensitivity for overall increase in breast and ovarian cancer risk.

The genes sequenced by the Focus::HERSite™ NGS panel are listed below with estimated lifetime cancer risk by cancer type:

GENE BREAST CANCER OVARIAN CANCER
ATM 20-50% No Increased Risk
BRCA1 40-80% 10-40%
BRCA2 40-80% 10-40%`
BRIP1 10-20% 8%
CDH1 40-50% No Increased Risk
CHEK2 20-50% No Increased Risk
MLH1 No Increased Risk 5-10%
MSH2 No Increased Risk 5-10%
MSH6 No Increased Risk Elevated Risk
PALB2 20-40% No Increased Risk
PMS2 No Increased Risk Elevated Risk
PTEN 80-85% No Increased Risk
RAD51C Slightly Increased Risk 6%
RAD51D No Increased Risk 7%
STK11 40-50% ~20%
TP53 Greatly Increased Risk Slightly Increased Risk

 

Note: The general population lifetime risk for developing female breast cancer is ~10% and for ovarian cancer is ~1%.


Many of the genes listed above are also associated with their own clinical syndromes (e.g. TP53 and Li Fraumeni syndrome). These syndromes contribute indirectly to breast and ovarian cancer risk, and are often associated with greatly increased risk of developing other cancer types. And while Focus::HERSite™ is targeted for hereditary breast and ovarian cancer risk, the mutations responsible for these other syndromes may be incidentally identified as well.

In clinical practice, the information regarding the mutation status of these genes is used similarly to BRCA data. Patients may be identified for active surveillance and increased clinical monitoring, family members may be tested, and even prophylactic surgery may be performed based on these results. Because mutations in these genes are rarer than deleterious BRCA1 and BRCA2 variants, extended panels are often utilized after BRCA1 and BRCA2 mutations have been excluded. However, it is sometimes prudent and more cost-effective to analyze numerous genes simultaneously. Furthermore, details of family history may implicate a specific gene over BRCA1 and BRCA2 in certain circumstances. Therefore, the Focus::HERSite™ NGS panel sequences BRCA1, BRCA2, and 14 additional genes in a single reaction.


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