Welcome to Strand Genomics-A Monthly E-zine from Strand Life Sciences
Genomic Footprint of Breast and Ovarian Cancer: BRCA1/2 and Accessory Genes
– Dr. Shefali Sabharanjak
Strand Life Sciences
- Diagnosis of HBOC should include screening for non-BRCA1/2 genes, in addition to BRCA1/21–3.
- Mutations in PALB2, TP53, CHEK2, ATM and PTEN, in addition to BRCA1/2 are found in Asian breast and ovarian cancer patients.
- TP53 mutations are not evident in non-BRCA1/2 breast cancer patients from North America3.
- Mutations in non-BRCA 1/2 genes are not as strongly associated with phenotypic markers like early age of onset of breast cancer and Ashkenazi Jew ancestry, as are BRCA1/2 mutations. DNA-based diagnostic screening is the only method to detect these mutations and determine a patient’s risk.
- Prevalence of pathogenic mutations associated with HBOC, in genes other than BRCA 1/2, can be higher amongst Asian women2. The predominance of BRCA 1/2 in breast cancer patients is observed in patients from North America.
Hereditary breast and ovarian cancer (HBOC) is evident amongst Indian women, typically in women who are diagnosed with either of these ailments at a young age1,2. A reckoning of family history of incidence of breast and ovarian cancer is used as a preliminary screening tool.
In Caucasian populations, the Icelandic BRCA2 999 del 5 mutation, 3 BRCA1 (exons 2,11,20 mutations) and 3 BRCA2 (exons 10,11, 25 mutations) which are known as founder mutations in Ashkenazi Jews, have been identified as definite markers of predisposition towards hereditary breast and ovarian cancer.
Genetic analyses of breast and ovarian cancer biopsies from Indian patients have revealed that BRCA1 mutations may be considered as the founder mutations for familial breast and ovarian cancer. The principal concern in the Indian population is the high mortality rate of breast and ovarian cancer patients in India. Although the total number of newly diagnosed cases of breast and ovarian cancer is higher in USA and European Union, the mortality of breast and ovarian cancer patients is highest (nearly 50% of the affected cohort) in India1. Efficient as well as early genomic screening can be instrumental in increasing survival of hereditary breast and ovarian cancer patients.
In a recent study, genomic analyses of breast and ovarian cancer biopsies from 141 patients has yielded a long list of mutations that function as founder mutations of familial breast and ovarian cancer1. These results have been confirmed with a larger cohort of 1000 clinical samples as well (Strand Life Sciences, unpublished data). Pathogenic mutations were identified in 36.9 % of the samples with 19 amongst these, being novel mutations associated with HBOC.
Frequency of Selected Gene Mutations of Breast Cancer Patients in India1, Singapore2, and North America3
As can be seen clearly, BRCA1 mutations are the principal driver mutations in familial breast and ovarian cancer in India. However, mutations in other genes can also play a role in the initiation and progression of breast and ovarian cancer. An examination of a panel of genes other than BRCA1 and BRCA2 is vital in the diagnosis of breast and ovarian cancers in Indian women.
Genomic profiling of breast and ovarian cancer in a Singapore cohort has yielded similar results. Wong, Shekar, Domestici et. al. have profiled tumor samples from 220 Asian women in Singapore, using a 25 gene panel in addition to assessing for BRCA1 and BRCA2 deletions. This cohort had a significant history of familial as well as early onset (less than 40 years) breast and ovarian cancer. A set of 62 mutations were detected in this cohort; 19 in BRCA1 and 16 in BRCA2. Mutations in PALB2 (7), PTEN( 2), TP53 (6), CDH1 (2) as well as in other genes like ATM, RAD51C, RAD51D and BRIP1 were also identified in this study2.
An interesting feature of this study is the fact that 47.8 % of pathogenic gene variants were identified in genes other than BRCA1 and BRCA2.
47.8% of pathogenic gene variants were identified in genes other than BRCA1 and BRCA22.
Genomic analysis of 488 North American patients enrolled in another study has also shown that mutations in non BRCA1/2 genes are pathogenic in breast and ovarian cancer. In this study, traditional factors like Ashkenazi Jew ancestry, early onset breast and ovarian cancer, family history of these cancers and incidence of triple-negative breast cancers were found to be associated closely with mutations in BRCA1/2 than with non-BRCA1/2 genes3. Mutations in genes like PALB2 (1), CHEK2 (10), ATM (4), PTEN (1), RAD51C, RAD51D, MSH6 and BRIP1 were also identified in this study.
Genomic profiles of breast and ovarian cancer patients are similar in Indian and South-East Asian women.
Genomic footprint of breast and ovarian cancer in Asian women are different from that seen in North American women.
Screening for hereditary breast and ovarian cancer, in Asian women should include BRCA1/2 as well as other genes like TP53, PTEN, ATM, and PALB2.
1 Mannan, A. U. et al. Detection of high frequency of mutations in a breast and/or ovarian cancer cohort: implications of embracing a multi-gene panel in molecular diagnosis in India. J. Hum. Genet. 61, 515–22 (2016).
2 Wong, E. S. Y. et al. Inherited breast cancer predisposition in Asians: multigene panel testing outcomes from Singapore. npj Genomic Med. 1, 15003 (2016).
3 Tung, N. et al. Frequency of Germline Mutations in 25 Cancer Susceptibility Genes in a Sequential Series of Patients With Breast Cancer. J Clin Oncol 34, 1460–1468(2016).
Mortality Ratio of Breast Cancer (2012)
A comparison of statistics from USA, India and China shows that India has the highest mortality ratio amongst these three countries. Approximately 50% of the Indian breast cancer patients are lost to breast cancer due to diagnoses at later stages. Enhanced awareness coupled with early diagnosis of breast cancer are the need of the hour.
Strand Life Sciences Offers World-Class Quality in Genomic Analyses of Cancer Tissues
– Dr. Shefali Sabharanjak
Strand Life Sciences
- Strand Life Sciences is a class-leading company, in India, that offers DNA-based diagnostic services. We have developed NGS-based sequencing technologies for genomic profiling as well as designed customized analytical software for gene annotations.
- Our StrandAdvantage gene panel was benchmarked against three other gene panels offered by US companies.
- The performance of StrandAdvantage tests was found to be on par with the leading US company – Foundation Medicine1.
- Strand Life Sciences tests can help to identify actionable gene variants that allow for patient-wise modulation of chemotherapy and radiotherapy.
Strand Life Sciences is a global genomic profiling & bioinformatics company focusing on the use of precision medicine diagnostics aimed at cancer care and inherited diseases. Strand works with physicians and hospitals to enable faster clinical decision support for accurate molecular diagnosis, prognosis, therapy recommendations, and clinical trials. The Strand Center for Genomics & Personalized Medicine is a CAP & NABL accredited NGS laboratory. For more details, visit: www.strandls.com
Benchmarking of Strand Life Sciences Test against International Competitors
A comparative evaluation of the use of genetic analysis in the diagnosis of cancer was undertaken by CHI Institute for Research and Innovation, Center for Translational Research, Baltimore, USA, earlier in 20161. The participants of this benchmarking exercise were Foundation Medicine Inc. (Cambridge, MA), Strand Genomics Inc (Aurora, CO – a wholly-owned subsidiary of Strand Life Sciences, Bangalore, India), Mayo Medical Laboratories at Mayo Clinic (Rochester, MN) and Knight Diagnostic Laboratory, at the Oregon Health and Science University (Portland, OR). Gene panels – Foundation One, StrandAdvantage, CANCP and GeneTrails were the gene panels provided by each company, respectively. The benchmarking exercise was designed to understand the coherence and accuracy of the gene panels tested, for an identical set of breast and colorectal cancer samples. A set of five breast cancer and five colorectal cancer tissue samples were provided to each diagnostic laboratory, in a blinded fashion.
Results of the Benchmarking Exercise
Ten identical tumor samples were sent to each participant company by CHI Institute. Extraction of high-quality DNA from the samples, in a form that could be subjected to NGS analysis was the first criterion monitored.
Foundation Medicine Inc, Strand Life Sciences and Mayo Clinic were able to provide DNA analyses for 9 out of ten samples, each. Knight Diagnostic laboratory reported results for 8 out of 10 samples.
The genetic variants identified by every company were stratified into four actionability categories:
- Targeted therapy approved for a given type of tumor (Column 1, Figure 2)
- Targeted therapy approved for another tumor type (Column2, Figure 2)
- Targeted therapy in clinical trials (Column3, Figure 2)
- Modulations to efficacy / toxicity of chemotherapy and radiotherapy (Column4, Figure 2)
The StrandAdvantage test panel identified gene variants in each of these four categories. Interestingly, Strand Life Sciences was the only company to identify gene mutations that were bucketed into category IV- mutations that can guide customization of established chemotherapy and radiotherapy options for every patient.
Figure 2. Categories of Gene Variants Reported1
The StrandAdvantage test provided the maximum number of gene annotations in the category that is most relevant for therapeutic intervention (Category 4, Figure 2). The gene variants identified in this category allowed for modulation of pre-existent chemotherapeutic and radiotherapeutic treatments. Interestingly, other tests were oriented towards identifying gene targets for which drugs were in clinical trials (Category 3, Figure 2). However, the Strand Advantage test was the only test in his exercise that helped to identify gene variants that could help address the therapeutic needs of patients, using established therapies.
Figure 3. Category IV Actionable Gene Variants1
Strand Life Sciences is a class-leading company, in India, that offers DNA-based diagnostic services. We have developed NGS-based sequencing technologies for genomic profiling as well as designed customized analytical software for gene annotations.
The StrandAdvantage gene panel was benchmarked against three other gene panels offered by US companies. A significant differentiator of the Strand Advantage test is the identification of gene variants that allow modulation of existent chemotherapeutic and radiotherapeutic options. Gene tests from other companies were oriented towards identifying suitable drugs that were in various stages of clinical trials.
The performance of StrandAdvantage tests was found to be on par with the leading US company- Foundation Medicine.
Strand Life Sciences tests can help to identify actionable gene variants that allow for patient-wise modulation of chemotherapy and radiotherapy. This is a unique feature of the analytical software that has been organically built and designed by experts at Strand Life Sciences.
1 Mori, Y., Levenson, V. & Otto, J. Tumor Genomic Profiling Reports from Different Vendors: A Comparison with Respect to Clinical Action Ability of the Provided Data.