Name : DUMMY N210 Collected : 29/07/2020 Lab No. : 153672450 Age: 35 years Gender: Male Received : 29/07/2020 Status : F Ref By : UNKNOWN Reported : 01/08/2020 Page 1 of 21 CLINICAL INDICATION Breast Cancer GENOMIC HIGHLIGHTS Pathways driving cancer Cell cycle control pathway Beta catenin/ Wnt signaling pathway DNA damage/ repair pathway DNA mismatch repair pathway Receptor tyrosine kinase pathway Driver mutations BRCA2, TP53, APC, POLE, PMS2, BAP1, NTRK1, STK11 and NF1 genes Gene variants with therapy BRCA2 (A2513E) and TP53 (C238F) Tumor Mutation Burden (TMB) Low TMB score, which is associated with better response rate with immune-checkpoint inhibitor. Microsatellite Instability (MSI) MSI STABLE, which represents phenotypic evidence that DNA mismatch repair (MMR) is functioning normally. Clinically actionable mutation We found FDA-approved therapies with the drugs, Olaparib and Bevacizumab, as maintenance treatment for Ovarian cancer. Clinical trial We found a clinical trial investigating the action of high- dose alkylating chemotherapy in patients with oligo- metastatic breast cancer harboring homologous recombination deficiency. ONCOPRO TMB & MSI PROFILE No clinically actionable mutations or driver mutations identified
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
Name : DUMMY N210 Collected : 29/07/2020 Lab No. : 153672450 Age: 35 years Gender: Male Received : 29/07/2020 Status : F Ref By : UNKNOWN Reported : 01/08/2020
Gene variants with therapy BRCA2 (A2513E) and TP53 (C238F)
Tumor Mutation Burden (TMB) Low TMB score, which is associated with better response
rate with immune-checkpoint inhibitor.
Microsatellite Instability (MSI)
MSI STABLE, which represents phenotypic evidence that DNA
mismatch repair (MMR) is functioning normally.
Clinically actionable mutation We found FDA-approved therapies with the drugs, Olaparib and
Bevacizumab, as maintenance treatment for Ovarian cancer.
Clinical trial
We found a clinical trial investigating the action of high- dose
alkylating chemotherapy in patients with oligo- metastatic breast
cancer harboring homologous recombination deficiency.
ONCOPRO TMB & MSI PROFILE
No clinically actionable mutations or driver mutations identified
Name : DUMMY N210 Collected : 29/07/2020 Lab No. : 153672450 Age: 35 years Gender: Male Received : 29/07/2020 Status : F Ref By : UNKNOWN Reported : 01/08/2020
Page 2 of 21
IMPLICATION TO IMMUNOTHERAPY
VARIANTS WITH CLINICALLY RELEVANT THERAPIES
Summary of Relevant Therapies in same cancer type
Gene Therapy Evidence Reference
BRCA2(A2513E) Carboplatin, Thiotepa, and Cyclophosphamide Late trials NCT01646034
Summary of Relevant Therapies in other cancer types
Gene Therapy Cancer type Evidence Reference
BRCA2
(A2513E)
Olaparib Ovarian cancer FDA FDA guidelines
Olaparib; Bevacizumab Ovarian cancer FDA FDA guidelines
TP53
(C238F)
Olaparib; Adavosertib Ovarian cancer Early trials NCT02576444
Cetuximab Colorectal Carcinoma Late trials NCT02942706
Pembrolizumab Gastro-esophageal Junction
Adenocarcinoma
Early trials NCT02589496
Adavosertib; Paclitaxel Early trials NCT02448329
Tumor mutational burden Tumor mutational burden (TMB) is a measure of the mutation load in a tumor sample. TMB for this tumor sample is determined to fall in the Low TMB category. High TMB is associated with production of more neo-antigens which may be recognized by the immune system and inciting an anti-tumor response. High TMB is associated with better response rate with immune-checkpoint inhibitor
Microsatellite Instability
Microsatellite Instability (MSI) refers to a type of genomic instability in tumor tissue caused by the failure of the DNA mismatch repair system to repair errors during DNA replication. This process results in accumulation of various mutations including alterations in the length of small repetitive microsatellite sequences. MSI for this tumor sample is found to fall in the MSI-Stable category.
Name : DUMMY N210 Collected : 29/07/2020 Lab No. : 153672450 Age: 35 years Gender: Male Received : 29/07/2020 Status : F Ref By : UNKNOWN Reported : 01/08/2020
Page 3 of 21
CLINICAL TRIAL We found a clinical trial investigating the effect of high-dose alkylating chemotherapy compared with
standard chemotherapy as part of a multimodality treatment approach in patients with oligo-metastatic breast cancer harboring homologous recombination deficiency.
These high- alkylating chemotherapy regimens contain potent inducers of DNA double-strand breaks (DSB), which are highly effective in tumors with an inadequate DNA repair system. The tumor suppressor genes BRCA1 and BRCA2 are involved in the repair of DNA DSB via homologous recombination. When this mechanism is inactivated, tumor cells rely on less adequate repair mechanisms. This is called homologous recombination deficiency (HRD) and causes genome instability and consequently apoptosis of tumor cells. Hence, targeting BRCA2 mutation with an altered chemotherapy regime is recommended to treat breast cancer.
Name : DUMMY N210 Collected : 29/07/2020 Lab No. : 153672450 Age: 35 years Gender: Male Received : 29/07/2020 Status : F Ref By : UNKNOWN Reported : 01/08/2020
Page 4 of 21
CLINICAL TRIAL
Study Title
High-dose Alkylating Chemotherapy in Oligo-metastatic Breast Cancer Harboring Homologous
Recombination Deficiency
Brief Summary
This study investigates the effect of high-dose alkylating chemotherapy compared with standard
chemotherapy as part of a multimodality treatment approach in patients with oligo-metastatic breast
cancer harboring homologous recombination deficiency.
Study phase Phase 3
Condition
Breast cancer
NCT Number NCT01646034
Intervention
Experimental: intensified alkylating chemotherapy
a course chemotherapy with high dose cyclophosphamide, G-CSF and peripheral blood progenitor cell (PBPC) harvest followed by tandem intermediate-dose alkylating therapy (miniCTC, carboplatin 800 mg/m2, thiotepa 240 mg/m2, and cyclophosphamide 3000 mg/m2) with PBPC-reinfusion.
Intervention: Drug: carboplatin, thiotepa, and cyclophosphamide
Active Comparator: three cycles of chemotherapy
three cycles of chemotherapy depending on previously received agents
chemotherapy naïve;three cycles of docetaxel, doxorubicin, and cyclophosphamide previously received anthracyclines without taxanes;three cycles of carboplatin and paclitaxel previously received anthracyclines and taxanes;three cycles of carboplatin and gemcitabine
Name : DUMMY N210 Collected : 29/07/2020 Lab No. : 153672450 Age: 35 years Gender: Male Received : 29/07/2020 Status : F Ref By : UNKNOWN Reported : 01/08/2020
Page 5 of 21
RELEVANT THERAPIES IN SAME CANCER TYPE
BRCA2 – Breast cancer 2
Variant details
Drug details –
Carboplatin, Thiotepa, and Cyclophosphamide
This study investigates the effect of high-dose alkylating chemotherapy compared with standard chemotherapy as part of a multimodality treatment approach in patients with oligo-metastatic breast cancer harboring homologous recombination deficiency.
Studies have shown that patients with high-risk breast cancer and a BRCA1- or BRCA2-like profile derive important benefit from high-dose, alkylating chemotherapy in comparison to conventional chemotherapy (hazard ratio (HR) for overall survival: 0.19, 95% confidence interval (CI): 0.08 to 0.48). It is suggested that selecting oligo-metastatic patients based on HRD for high-dose chemotherapy can improve outcome for more patients.
BRCA2 – Breast cancer 2
Variant details Gene Genomic alteration Impact Mutation ID Clinical significance
Name : DUMMY N210 Collected : 29/07/2020 Lab No. : 153672450 Age: 35 years Gender: Male Received : 29/07/2020 Status : F Ref By : UNKNOWN Reported : 01/08/2020
Page 6 of 21
On December 19, 2018, the Food and Drug Administration approved olaparib (LYNPARZA®, AstraZeneca
Pharmaceuticals LP) for the maintenance treatment of adult patients with deleterious or suspected deleterious
germline or somatic BRCA-mutated (gBRCAm or sBRCAm) advanced epithelial ovarian, fallopian tube or primary
peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy.
Olaparib (AZD-2281, MK-7339 trade name Lynparza) is an FDA-approved targeted therapy for cancer. It is a PARP inhibitor, inhibiting poly ADP ribose polymerase (PARP), an enzyme involved in DNA repair. Adavosertib (AZD1775) is a first-in-class, potent, and selective inhibitor of WEE1 with proof of chemo- potentiation in p53-deficient tumors in preclinical models. (Chen, Dongshao, 2018)
Name : DUMMY N210 Collected : 29/07/2020 Lab No. : 153672450 Age: 35 years Gender: Male Received : 29/07/2020 Status : F Ref By : UNKNOWN Reported : 01/08/2020
Page 7 of 21
Given that PARP inhibition by olaparib results in DNA double-strand breaks in S phase, it is hypothesized that combined Wee1 kinase and PARP inhibition could induce tumor cell death. Remarkable synergy was observed using an AZD1775/olaparib combination in small-cell lung cancer (SCLC) xenograft models (O’Connor, EORTC 2015).
Cetuximab
This study aims at evaluating the effect of cetuximab monotherapy as maintenance treatment, versus continuation after 8 courses of
induction therapy with cetuximab plus standard chemotherapy regimen (FOLFIRI or mFOLFOX6)in metastatic colorectal cancer (mCRC) patients.
The maintenance treatments are continued until disease progression or untolerated toxicity. The aim of this study is to demonstrate that cetuximab monotherapy is non-inferior to continuation treatment, in those mCRC patients who responded to induction therapy (SD, PR, or CR), and carry biomarker-panels (KRAS, NRAS, BRAF, and PIK3CA) favor EGFR antibody. (Details of clinical trial on page 4) (NCT02942706)
Pembrolizumab
Pembrolizumab is a highly selective IgG4-kappa humanized monoclonal antibody against PD-1 receptor. Pembrolizumab targets and blocks a protein called PD-1 on the surface of certain immune cells called T-cells. Blocking PD-1 triggers the T-cells to find and kill cancer cells. Pembrolizumab is very well tolerated so many patients who have difficulty tolerating chemotherapy may be able to handle this medication,
In the phase Ib KEYNOTE-012 study which evaluated pembrolizumab monotherapy at 10 mg/kg ever 2 weeks in patients with gastric cancer were recently reported. Most patients had two or more prior lines of therapy. In the study, 41% of evaluable patients showed tumor shrinkage. The overall response rate in 39 patients were 31%.
Adavosertib, Paclitaxel
This study is a single arm, single center phase II study of AZD1775 in combination with paclitaxel in patients with
advanced gastric adenocarcinoma harboring TP53 mutation as a second-line chemotherapy.
AZD1775 is an inhibitor of Wee1, a protein tyrosine kinase. Wee1 phosphorylates and inhibits cyclin- dependent
kinases 1 (CDK1) and 2 (CDK2), and is involved in regulation of the intra-S and G2 cell cycle checkpoints.
In in-vitro and in-vivo preclinical models, AZD1775 selectively enhanced chemotherapy induced death of cells deficient in p53 signaling. Tumor context-specific sensitization to the DNA damaging agents, gemcitabine and platinum, was observed in TOV21G (ovarian carcinoma) cell lines matched for wild type and knock down of p53
Name : DUMMY N210 Collected : 29/07/2020 Lab No. : 153672450 Age: 35 years Gender: Male Received : 29/07/2020 Status : F Ref By : UNKNOWN Reported : 01/08/2020
Page 8 of 21
DRIVER MUTATIONS
GENES OVERVIEW
Variant details
TP53 – Tumor suppressor protein 53
TP53 is a well-known tumor suppressor gene and has various mechanisms of anticancer function and plays
significant role in maintenance of genome integrity, apoptosis, genomic stability, and inhibition of angiogenesis
etc. Loss of TP53 function allows deregulated survival of genetically impaired abnormal cells which can lead to
neoplastic conversion of later on. It is altered in 39.49% of all cancers with mutations in 32.77% of breast carcinoma patients.
Name : DUMMY N210 Collected : 29/07/2020 Lab No. : 153672450 Age: 35 years Gender: Male Received : 29/07/2020 Status : F Ref By : UNKNOWN Reported : 01/08/2020
Page 9 of 21
APC- Adenomatous polyposis coli
APC is a gene that encodes a tumor suppressor protein that acts as an antagonist of the Wnt signaling pathway.
It is also involved in other processes including cell migration and adhesion, transcriptional activation, and
apoptosis .Defects in this gene cause familial adenomatous polyposis (FAP), an autosomal dominant pre-
malignant disease that usually progresses to malignancy. APC also play a rate-limiting role in the majority of
sporadic colorectal cancers.
APC is altered in 10.55% of all cancers with mutations in 2.04% of breast carcinoma patients.
BRCA2 – Breast cancer 2
BRCA2 is a gene that encodes a protein that functions in maintaining genomic stability and as a tumor suppressor.
BRCA2 is a mediator of the core mechanism of homologous recombination. BRCA2 loss- of-function truncation
mutant display some defects in replication and checkpoint control.
BRCA2 alterations allow cells to bypass checkpoint controls and evade apoptosis, and thereby initiate
tumorigenesis. BRCA2 is altered in 4.63% of all cancers with mutations in 3.95% of breast carcinoma patients.
POLE – Polymerase (DNA directed), epsilon, catalytic subunit
POLE is a gene that encodes a protein that is a catalytic component of DNA polymerase epsilon. The enzymatic
protein functions in DNA repair and chromosomal DNA replication. Polε is also involved in DNA repair pathways
such as mismatch repair (MMR), base excision repair (BER), nucleotide excision repair (NER) or double-strand
break repair. (Guerro J et al, 2017)
Pathogenic somatic mutations in the proofreading domain of POLE have been found in some tumour types at
moderate or rare frequencies. Some mutations in the polymerase domain have been suggested to be drivers.
POLE is altered in 3.43% of all cancers with mutations in 1.78% of breast carcinoma patients
PMS2 – Post-meiotic segregation increased 2
PMS2 is a gene that encodes a protein that functions in DNA mismatch repair that functions to correct DNA
mismatches and small insertions and deletions that can occur during DNA replication and homologous
recombination. Also implicated in DNA damage signalling, a process which induces cell cycle arrest and can lead
to apoptosis in case of major DNA damages.
PMS2 is altered in 1.38% of all cancers with mutations in 0.81% of breast carcinoma patients.
Name : DUMMY N210 Collected : 29/07/2020 Lab No. : 153672450 Age: 35 years Gender: Male Received : 29/07/2020 Status : F Ref By : UNKNOWN Reported : 01/08/2020
Page 10 of 21
BAP1 – BRCA1 associated protein 1
BAP1 is a tumor suppressor gene important to the development and prognosis of many cancers, especially uveal
melanoma (UM). BAP1 is a scavenger protein that regulates cell cycle, cellular differentiation, and DNA damage
response. BAP1 was first shown to act as a tumor suppressor in cultured cells, where its deubiquitinase (UCH)
domain and nuclear localization sequences were required for BAP1 to suppress cell growth. BAP1 is altered in
2.04% of all cancers.
NTRK1 – Neurotrophic receptor tyrosine kinase 1
The NTRK1 gene provides instructions for making a protein that is essential for the development and survival of
nerve cells (neurons), especially those that transmit information about sensations such as pain, temperature,
and touch (sensory neurons). The NTRK1 protein is found on the surface of cells, particularly sensory neurons.
Trk (neurotrophin) receptors are single transmembrane catalytic receptors with intracellular tyrosine kinase
activity.
NTRK1 is altered in 2.21% of all cancers with mutations in 1.71% of breast carcinoma patients.
STK11- Serine/threonine kinase 11
STK11 is a gene that encodes a protein that belongs to the serine/threonine kinase family. The protein functions
in the regulation of cell polarity and is also a tumor suppressor. STK11 has been reported to play a critical role in
P53-mediated cell apoptosis. STK11 gene is involved in cell cycle regulation and apoptosis, whose abnormality
can induce and promote tumorigenesis.
STK11 is altered in 2.56% of all cancers with mutations in 1.23% of breast carcinoma patients.
NF1 – Neurofibromin 1
NF1 is a gene that codes for neurofibromin, a tumor suppressor protein. NF1 suppresses the function of the Ras
protein, which promotes cell growth and differentiation. In cancer, the tumor suppression function of the gene
is impaired, leading to conditions favorable for uncontrolled cell growth. NF1 mutations have been observed in
multiple cancer types, including myelodysplastic syndromes.
NF1 is altered in 6.78% of all cancers with mutations in 4.83% of breast carcinoma patients.
Name : DUMMY N210 Collected : 29/07/2020 Lab No. : 153672450 Age: 35 years Gender: Male Received : 29/07/2020 Status : F Ref By : UNKNOWN Reported : 01/08/2020
Page 11 of 21
Cell Cycle Control Pathway
GENES OVERVIEW
CDK4/6 inhibitors
targeting
pathway -
CDK1 inhibitors,
CDK2 inhibitors,
CDK inhibitors,
Genomic alteration in TP53
gene
Pathway driving cancer- Cell
Cycle Control
Pathway
Name : DUMMY N210 Collected : 29/07/2020 Lab No. : 153672450 Age: 35 years Gender: Male Received : 29/07/2020 Status : F Ref By : UNKNOWN Reported : 01/08/2020
Page 12 of 21
Beta-catenin/ Wnt Signaling Pathway
DNA Damage/Repair Pathway
FZD inhibitors
GSK inhibitors
targeting Therapies
pathway –
Genomic alteration in
APC gene
Pathway driving cancer-
Beta catenin/ Wnt
signaling pathway
Name : DUMMY N210 Collected : 29/07/2020 Lab No. : 153672450 Age: 35 years Gender: Male Received : 29/07/2020 Status : F Ref By : UNKNOWN Reported : 01/08/2020
Page 13 of 21
DNA Damage/Repair Pathway
Genomic alteration in
BRCA2 and POLE genes
Pathway driving cancer- DNA damage/
repair pathway Therapies pathway – targeting
PARP inhibitors
Name : DUMMY N210 Collected : 29/07/2020 Lab No. : 153672450 Age: 35 years Gender: Male Received : 29/07/2020 Status : F Ref By : UNKNOWN Reported : 01/08/2020
Page 14 of 21
DNA Mismatch repair pathway
PARP inhibitors
targeting
pathway -
Genomic alteration in
PMS2 gene
Pathway driving cancer-
DNA mismatch repair
Pathway
Name : DUMMY N210 Collected : 29/07/2020 Lab No. : 153672450 Age: 35 years Gender: Male Received : 29/07/2020 Status : F Ref By : UNKNOWN Reported : 01/08/2020
Name : DUMMY N210 Collected : 29/07/2020 Lab No. : 153672450 Age: 35 years Gender: Male Received : 29/07/2020 Status : F Ref By : UNKNOWN Reported : 01/08/2020
Page 16 of 21
REFERENCES
Abotaleb, M., Kubatka, P., Caprnda, M., Varghese, E., Zolakova, B., Zubor, P., & Büsselberg, D. (2018). Chemotherapeutic
agents for the treatment of metastatic breast cancer: An update. Biomedicine & Pharmacotherapy, 101, 458-477.
Bagrodia A, Lee BH, Lee W, et al. Genetic Determinants of Cisplatin Resistance in Patients With Advanced Germ Cell
Name : DUMMY N210 Collected : 29/07/2020 Lab No. : 153672450 Age: 35 years Gender: Male Received : 29/07/2020 Status : F Ref By : UNKNOWN Reported : 01/08/2020
Page 17 of 21
Hientz, K., Mohr, A., Bhakta-Guha, D., & Efferth, T. (2017). The role of p53 in cancer drug resistance and targeted
chemotherapy. Oncotarget, 8(5), 8921.
Kamel, Dalia, et al. "PARP inhibitor drugs in the treatment of breast, ovarian, prostate and pancreatic cancers: an update
of clinical trials." Current drug targets 19.1 (2018): 21-37.
Kamps, Rick et al. “Next-Generation Sequencing in Oncology: Genetic Diagnosis, Risk Prediction and Cancer
Classification.” International journal of molecular sciences vol. 18,2 308. 31 Jan. 2017,
doi:10.3390/ijms18020308
Leijen, Suzanne, et al. "Phase II study of WEE1 inhibitor AZD1775 plus carboplatin in patients with TP53-mutated ovarian
cancer refractory or resistant to first-line therapy within 3 months." Journal of Clinical Oncology 34.36 (2016): 4354-4361.
Li, Marilyn M., et al. "Standards and guidelines for the interpretation and reporting of sequence variants in cancer: a joint
consensus recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and
College of American Pathologists." The Journal of molecular diagnostics 19.1 (2017): 4-23.
Meyer, Matthias, and Martin Kircher. "Illumina sequencing library preparation for highly multiplexed target capture and
sequencing." Cold Spring Harbor Protocols 2010.6 (2010): pdb-prot5448.
Muller, P. A., & Vousden, K. H. (2014). Mutant p53 in cancer: new functions and therapeutic opportunities. Cancer cell,
25(3), 304-317.
Nykamp, K., Anderson, M., Powers, M., Garcia, J., Herrera, B., Ho, Y. Y. Topper, S. (2017). Sherloc: a comprehensive
refinement of the ACMG-AMP variant classification criteria. Genetics in medicine: official journal of the American College
of Medical Genetics, 19(10), 1105–1117. doi:10.1038/gim.2017.37
Park, Ji Hyun, Jin-Hee Ahn, and Sung-Bae Kim. "How shall we treat early triple-negative breast cancer (TNBC): from the
current standard to upcoming immuno-molecular strategies." ESMO open 3.Suppl 1 (2018): e000357.
Parrales, A., & Iwakuma, T. (2015). Targeting oncogenic mutant p53 for cancer therapy. Frontiers in oncology, 5, 288.
Patnaik, Amita, et al. "Efficacy and safety of abemaciclib, an inhibitor of CDK4 and CDK6, for patients with breast cancer,
non–small cell lung cancer, and other solid tumors." Cancer discovery 6.7 (2016): 740-753.
Rivlin, N., Koifman, G., & Rotter, V. (2015, June). p53 orchestrates between normal differentiation and cancer. In Seminars
in cancer biology (Vol. 32, pp. 10-17). Academic Press.
Roy, Rohini et al. “BRCA1 and BRCA2: different roles in a common pathway of genome protection.” Nature reviews. Cancer
Salama, Joseph K., and Steven J. Chmura. "The role of surgery and ablative radiotherapy in oligometastatic breast cancer."
Seminars in Oncology. Vol. 41. No. 6. WB Saunders, 2014.
Schouten, Philip C., et al. "Breast cancers with a BRCA1-like DNA copy number profile recur less often than expected after
high-dose alkylating chemotherapy." Clinical Cancer Research 21.4 (2015): 763-770.
Schrama, J. G., et al. "Phase II study of a multi-course high-dose chemotherapy regimen incorporating cyclophosphamide,
thiotepa, and carboplatin in stage IV breast cancer." Bone marrow transplantation 28.2 (2001): 173-180.
Soussi, T., & Béroud, C. (2001). Assessing TP53 status in human tumours to evaluate clinical outcome. Nature Reviews
Cancer, 1(3), 233.
Steenbruggen TG, Linn SC, Rodenhuis S, Sonke GS. Ongoing Remission Nineteen Years after High-dose Chemotherapy for
Oligometastatic Breast Cancer; What Can We Learn from this Patient?. Cureus. 2015;7(12):e433. Published 2015 Dec 24.
doi:10.7759/cureus.433
Name : DUMMY N210 Collected : 29/07/2020 Lab No. : 153672450 Age: 35 years Gender: Male Received : 29/07/2020 Status : F Ref By : UNKNOWN Reported : 01/08/2020
Page 18 of 21
The AACR Project GENIE Consortium. AACR Project GENIE: powering precision medicine through an international
consortium. Cancer Discovery. 2017;7(8):818-831.
The UniProt Consortium. UniProt: a worldwide hub of protein knowledge. Nucleic Acids Research. 2019;47:D506-D515.
Vollebergh, Marieke A., et al. "Genomic patterns resembling BRCA1-and BRCA2-mutated breast cancers predict benefit of
intensified carboplatin-based chemotherapy." Breast Cancer Research 16.3 (2014): R47.
Welch JS, Petti AA, Miller CA, et al. TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes. N
Name : DUMMY N210 Collected : 29/07/2020 Lab No. : 153672450 Age: 35 years Gender: Male Received : 29/07/2020 Status : F Ref By : UNKNOWN Reported : 01/08/2020
Page 19 of 21
TEST DESCRIPTION
Somatic Genomic Test- Target Focus is a Next Generation Sequencing based test which identifies genetic alterations in a comprehensive panel of well curated 352 tumor genes which can impact response to approved therapy for a particular cancer type. Some of the alterations detected may have bearing on prognosis and/or therapeutic options and may provide relevant information that allows doctor to consider various lines of targeted treatment for the patient.
Sample preparation and Library preparation:
DNA isolated from FFPE or any other fresh tumor tissue source was used to perform targeted gene capture using a custom capture kit. The libraries were sequenced to mean >100X coverage on Illumina sequencing platform.
Bioinformatics Analysis and Reporting:
The sequences obtained are aligned to human reference genome (GRCh37/hg19) and variant analysis was performed using set of Bioinformatics Pipeline. Clinically relevant mutations were annotated using published variants in literature and a set of databases – ClinVar, COSMIC Drugs and Clinical Trials, FDA Approval Drugs. Common variants are filtered based on allele frequency in 1000 Genome Phase 3, ExAC, EVS, dbSNP147, etc. Non-synonymous variants effect is calculated using multiple algorithms such as PolyPhen-2, SIFT, MutationTaster2, Mutation Assessor and LRT. Only non-synonymous and splice site variants found in the clinical exome panel consisting of specific set of genes were used for clinical interpretation. Silent variations that do not result in any change in amino acid in the coding region are not reported.
Tumor Mutation Burden (TMB) is an evolving and promising biomarker for predicting a response to immunotherapy treatment. TMB is calculated by estimating the somatic non synonymous coding mutation as identified by Whole Exome Sequencing. A sample is categorized as High TMB if the TMB is found to be ≥20 mutations / megabase.
Name : DUMMY N210 Collected : 29/07/2020 Lab No. : 153672450 Age: 35 years Gender: Male Received : 29/07/2020 Status : F Ref By : UNKNOWN Reported : 01/08/2020
Page 20 of 21
LIMITATIONS AND DISCLAIMER
DNA studies do not constitute a definitive test for the selected condition(s) in all individuals. It should be
realized that there are possible sources of error. Errors can result from trace contamination, rare technical errors,
rare genetic variants that interfere with analysis, recent scientific developments, and alternative classification
systems. This test should be one of the many aspects used by the healthcare provider to help with a diagnosis and
treatment plan.
The contents of this test should be carefully assessed by the treating physician and further interpreted
along with clinical, histopathological findings, contraindications and guidelines before deciding the course of
therapy.
Most recent block is recommended for testing as the mutation profile may change in response to treatment
and hence differ at different sampling points.
Somatic Genomic Test has not been cleared or approved by the FDA.
Large deletions of more than 10 bp or copy number variations /chromosomal rearrangements cannot be
assessed using this method.
Certain genes may not be covered completely, and few mutations could be missed. A negative result
cannot rule out the possibility that the tested tumor sample carries mutations not previously associated with
cancer and hence not included in the panel.
The following table represents the panel of 352 genes, evaluated in the Target Focus test, commonly known to be
associated with different cancers and cancer syndromes.
Name : DUMMY N210 Collected : 29/07/2020 Lab No. : 153672450 Age: 35 years Gender: Male Received : 29/07/2020 Status : F Ref By : UNKNOWN Reported : 01/08/2020