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:

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.

  1. Ahmed M, Rahman N. ATM and breast cancer susceptibility. Oncogene. 2006 25:5906-11. PMID: 16998505.
  2. Breast Cancer Case-Control Consortium. CHEK2*1100delC and susceptibility to breast cancer. Am J Hum Genet. 2004 Jun;74(6):1175-82. PubMed PMID: 15122511.
  3. Bubien V, et al. High cumulative risks of cancer in patients with PTEN hamartoma tumour syndrome. J Med Genet. 2013 Apr;50(4):255-63. PubMed PMID: 23335809.
  4. Burt RW et al. NCCN Clinical Practice Guidelines in Oncology® Colorectal Cancer Screening. V 2.2013. July 1. Available at
  5. Casadei S, et al. Contribution of inherited mutations in the BRCA2-interacting protein PALB2 to familial breast cancer. Cancer Res. 2011 71:2222-9. PMID: 21285249
  6. Chompret A, et al. p53 germline mutations in childhood cancers and cancer risk for carrier individuals. Br J Cancer. 2000 82:1932-7. PMID: 10864200.
  7. Daly M et al. NCCN Clinical Practice Guidelines in Oncology®: Genetic/Familial High-Risk Assessment: Breast and Ovarian. V 1.2014. Feb 28. Available at
  8. Erkko H, et al. A recurrent mutation in PALB2 in Finnish cancer families. Nature. 2007 446:316-9. PMID: 17287723.
  9. Kaurah P, Huntsman DG. Hereditary Diffuse Gastric Cancer. In: Pagon RA, et al., editors. GeneReviews. 2011 Available from PMID: 20301318.
  10. Kohlmann W, Gruber SB. Lynch syndrome. 2004 Feb 05 [Updated 2012 Sep 20]. Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP, editors. GeneReviews. Seattle: Univ of Washington PMID: 20301390.
  11. Lin KM, et al. Colorectal and extracolonic cancer variations in MLH1/MSH2 hereditary nonpolyposis colorectal cancer kindreds and the general pop. Dis Colon Rectum. 1998 Apr;41(4):428-33. PMID: 9559626.
  12. Loveday C, et al. Germline RAD51C mutations confer susceptibility to ovarian cancer. Nat Genet. 2012 44:475-6. PMID: 22538716.
  13. Meijers-Heijboer H, et al. CHEK2-Breast Cancer Consortium. Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1/2. Nat Gen ‘02 May;31(1) :55-9. PMID: 11967536.
  14. Meindl A, et al. Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. Nat Genet. 2010 42:410-4.PubMed PMID: 20400964.
  15. Pharoah PD, et al. Intern’l Gastric Cancer Linkage Cons. Incidence of gastric cancer and breast cancer in CDH1 from hereditary diffuse gastric cancer families. Gastroent. 2001 121:1348-53. PMID: 11729114.
  16. Provenzale D, et al. NCCN Clinical Practice Guidelines in Oncology Genetic/Familial High-Risk Assessment: Colorectal V 1.2014. Feb 24. Available at
  17. Rafnar T, et al. Mutations in BRIP1 confer high risk of ovarian cancer. Nat Genet. 2011 43:1104-7. PMID: 21964575.
  18. Rahman N, et al. Breast Cancer Susceptibility Collaboration (UK). PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat Genet. 2007 39:165-7. PMID: 17200668
  19. Riegert-Johnson DL, et al. Cancer and Lhermitte-Duclos disease are common in Cowden syndrome patients. Hered Cancer Clin Pract. 2010 Jun 17;8(1):6. PubMed PMID: 20565722.
  20. Schneider K, Garber J. Li-Fraumeni Syndrome. In: Pagon RA, et al., editors. GeneReviews. 2010 Available From PubMed PMID: 20301488.
  21. Seal S, et al. Breast Cancer Susceptibility Collab(UK). Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nat Gen. ‘06 38:1239-41. PMID: 17033622.
  22. Swift M, et al. Incidence of cancer in 161 families affected by ataxia-telangiectasia. N Engl J Med. 1991 325):1831-6. PMID: 1961222.
  23. Tan MH,et al. Lifetime cancer risks in individuals with germline PTEN mutations. Clin Cancer Res. 2012 Jan 15;18(2):400-7. PubMed PMID: 22252256; PubMed Central PMCID: PMC3261579.
  24. Thompson D, et al. Cancer risks and mortality in heterozygous ATM mutation carriers. J Natl Cancer Inst. 2005 97:813-22. PMID: 15928302.
  25. Weischer M, et al. CHEK2*1100delC heterozyg in women with breast cancer assoc with early death, breast cancer-specific death, inc risk of 2nd breast cancer. J Clin Onc. ‘12Dec10;30(35):4308-16. PMID: 23109706.
  26. Weischer M,et al. CHEK2*1100delC genotyping for clinical assessment of breast cancer risk: meta-analyses of 26,000 patient cases and 27,000 controls. J Clin Onc. ‘08Feb1;26(4):542-8. Review. PMID: 18172190.
  27. Win AK, et al. Risks of colorectal and other cancers after endometrial cancer for women with Lynch syndrome. J Natl Cancer Inst.’13Feb20;105(4):274-9. doi:10.1093/jnci/djs525. Epub ‘13Feb5. PMID: 23385444.
  28. Win AK,et al. Risks of primary extracolonic cancers following colorectal cancer in lynch syndrome. J Natl Cancer Inst. 2012 Sep 19;104(18):1363-72.PubMed PMID: 22933731.