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SNOMED CT
Content Improvement Project
Combined Inception and Elaboration phases
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Date 20140425
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Art227316
Malignant neoplasm with <gene
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20140425
James Campbell
Revised from inception document on advice of
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© International Health Terminology Standards Development Organisation 2012. All rights reserved.
SNOMED CT® was originally created by the College of American Pathologists.
The International Release of SNOMED CT® is distributed by the International Health Terminology Standards Development Organisation
(IHTSDO), and is subject to the IHTSDO’s SNOMED CT® Affiliate Licence. Details of the SNOMED CT® Affiliate Licence may be found at
http://www.ihtsdo.org/our-standards/licensing/.
No part of this document may be reproduced or transmitted in any form or by any means, or stored in any kind of retrieval system, except by
an Affiliate of the IHTSDO in accordance with the SNOMED CT® Affiliate Licence. Any modification of this document (including without
limitation the removal or modification of this notice) is prohibited without the express written permission of the IHTSDO.
Any copy of this document that is not obtained directly from the IHTSDO [or a Member of the IHTSDO] is not controlled by the IHTSDO, and
may have been modified and may be out of date. Any recipient of this document who has received it by other means is encouraged to obtain
a copy directly from the IHTSDO [or a Member of the IHTSDO. Details of the Members of the IHTSDO may be found at
http://www.ihtsdo.org/members/].
Combined Inception and Elaboration phases
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Table of Contents
1 Glossary ................................................................................................................................ 5
1.1 Domain Terms............................................................................................................................. 5
2 Introduction............................................................................................................................ 6
2.1 Purpose....................................................................................................................................... 6
2.2 Audience and stakeholder domain .............................................................................................. 6
2.2.1 Input from stakeholders ........................................................................................................................... 6
2.2.2 Degree of consensus on the statement of problem ................................................................................. 6
3 Statement of the problem or need ......................................................................................... 7
3.1 Summary of problem or need, as reported .................................................................................. 7
3.2 Summary of requested solution ................................................................................................... 7
3.3 Statement of problem as understood........................................................................................... 7
3.4 Detailed analysis of reported problem, including background ...................................................... 7
3.5 Subsidiary and interrelated problems .......................................................................................... 8
4 Risks / Benefits...................................................................................................................... 9
4.1.1 Risks of not addressing the problem ....................................................................................................... 9
4.1.2 Risks of addressing the problem ............................................................................................................. 9
5 Requirements: criteria for success and completion ............................................................. 10
5.1 Criteria for success/completion ................................................................................................. 10
5.2 Strategic and/or specific operational use cases ......................................................................... 10
5.2.1 Use case 1 ............................................................................................................................................. 10
5.2.2 Use case 2… ......................................................................................................................................... 10
6 Solution Development ......................................................................................................... 12
6.1 Initial Design ............................................................................................................................. 12
6.1.1 Outline of initial design........................................................................................................................... 12
6.1.2 Significant design or implementation decisions / compromises ............................................................ 14
6.1.3 Evaluation of Design .............................................................................................................................. 14
6.2 Iteration One ............................................................................................................................. 14
6.2.1 Outline of revised design ....................................................................................................................... 14
6.2.2 Significant design or implementation changes ...................................................................................... 14
6.2.3 Evaluation of Revised Design ................................................................................................................ 14
6.3 Iteration Two .. .......................................................................................................................... 14
7 Recommendation ................................................................................................................ 15
7.1.1 Detailed design final specification ......................................................................................................... 15
7.1.2 Iteration plan .......................................................................................................................................... 15
8 Quality program criteria ....................................................................................................... 16
8.1 Quality metrics .......................................................................................................................... 16
Combined Inception and Elaboration phases
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8.1.1 Quality metric 1 ...................................................................................................................................... 16
8.1.2 Quality metric 2 ...................................................................................................................................... 16
8.2 Use case scenarios ................................................................................................................... 16
8.2.1 Scenario One ......................................................................................................................................... 17
8.2.2 Scenario Two ......................................................................................................................................... 17
8.2.3 Scenario … ............................................................................................................................................ 17
8.3 Test cases................................................................................................................................. 17
9 Project Resource Estimates ................................................................................................ 18
9.1 Scope of construction phase ..................................................................................................... 18
9.2 Projection of remaining overall project resource requirements .................................................. 18
9.2.1 Expected project resource requirement category.................................................................................. 18
9.2.2 Expected project impact and benefit ..................................................................................................... 18
9.2.3 Indicative resource estimates for construction, transition and maintenance: ........................................ 18
Combined Inception and Elaboration phases
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1 Glossary
1.1 Domain Terms
Genome
In modern molecular biology and genetics, the genome is the genetic material of an organism. It is
encoded either in DNA or, for RNA viruses, in RNA. The genome includes both the genes and the
non-coding sequences of the DNA/RNA.[Wikipedia]
Phenome
A phenome is the set of all phenotypes expressed by a cell, tissue, organ, organism, or
species.[Wikipedia]
Malignant genome
The genetic material of a malignant population of cells (cancer) within a host
Anaplastic lymphoma Anaplastic lymphoma kinase (ALK) also known as ALK tyrosine kinase receptor or CD246 (cluster of
kinase (ALK tyrosine differentiation 246) is an enzyme that in humans is encoded by the ALK gene.[Wikipedia]
kinase)
Oncogene
A gene that has the potential to cause cancer. In tumor cells they are often mutated or expressed at
high levels (Wikipedia) Examples include BRAF and ALK
EML4-ALK
fusion An abnormal configuration of DNA wherein the echinoderm microtubule-associated protein-like 4
gene
(EML4) gene is fused to the anaplastic lymphoma kinase (ALK) gene. This abnormal gene fusion
leads to the production of a protein (EML4-ALK) that appears, in many cases, to promote and
maintain the malignant behavior of the lung cancer cells.[Wikipedia]
BRAF
BRAF is a human gene that makes a protein called B-Raf. The gene is also referred to as protooncogene B-Raf and v-Raf murine sarcoma viral oncogene homolog B, while the protein is more
formally known as serine/threonine-protein kinase B-Raf.[Wikipedia]
BRAF V600E
Valine to glutamic acid mutation at position 600 of the BRAF gene demonstrated to be an oncogene
for some malignancies and characterizing malignancies sensitive to treatment with Vemurafenib
[mycancergenome.org]
Personalized
An emerging practice of medicine that uses an individual's genetic profile to guide decisions made in
medicine
regard to the prevention, diagnosis, and treatment of disease. [NLM; National Human Genome
Research Institute]
Tumor suppressor A gene that protects a cell from one step on the path to cancer (Wikipedia) Examples include
gene (Antioncogene) BRCA1 and BRCA2
Combined Inception and Elaboration phases
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2 Introduction
2.1 Purpose
The purpose of this project is to consider content model enhancements and or template guidance to
be developed in order to properly record diagnostic assessments regarding cancer with specific
findings of cancer mutant gene expression. The proffered content request relates to genome of a
malignant neoplasm but hereditary cancer predisposition of the patient, including oncogenetic findings
of the patient genome overlap the semantic use case.
SNOMED CT projects transition from Inception Phase  Elaboration Phase  Construction Phase 
Transition Phase. This document combines the documentation of the Inception and Elaboration
Phases.
The Inception Phase focuses on understanding the problem and its scope, identifying stakeholders
and their requirements, and identifying risks.
The purpose of the Elaboration Phase is to develop, document and test one (or more) possible
technical solutions, and to reach a recommendation and provide a detailed specification of a preferred
solution to be taken forward to the construction phase.
2.2 Audience and stakeholder domain
2.2.1 Identification of stakeholders
Oncologists, molecular biologists, geneticists, genomic pathologists, cancer genomics researchers;
Cancer institutes within member countries; American Cancer Society and similar across members;
Wellcome Trust Sanger Institute: Cancer Genome Project; HUGO Gene Nomenclature Committee;
National Center for Biotechnology Information (Database of Genomic Structural Variation); Directors
of molecular genetics labs; lab LOINC committee
iPaLM input: 1) Association for Molecular Pathology; 2) College of American Pathologists:
Personalized Healthcare Committee, Biomarker Template Committee, Cancer Biomarker Reporting
Committee; contacts Alexis Carter and Mary Kennedy; 3) AMIA: Translational Bioinformatics Working
Group; 4) American College of Medical Genetics; 5) American Society of Human Genetics; Transplant
Medicine- 6) American Society of Histocompatibility in Human Genetics
2.2.2 Input from stakeholders
4/21/2015 Meeting with iPaLM SIG: additional stakeholders identified and initial review of
Observable/Observation result model for genotypic/phenotypic observations
2.2.3 Degree of consensus on the statement of problem
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3 Statement of the problem or need
3.1 Summary of problem or need, as reported
Two requests for SNOMED CT content for clinical statements: “Non-small cell lung cancer, anaplastic
lymphoma kinase-positive (disorder)” and “Malignant melanoma with BRAF V600E mutation
(disorder)”. Such requests are expected to become increasingly frequent as cancer genomic research
matures and the diagnostic, prognostic and therapeutic implications of genotypic and phenotypic
variants of cancer genomes are studied. This pattern of finding statement is stated as related to
412734009|BRCA1 gene mutation positive (finding)|. (BRCA mutation identifies a patient with a
genetic finding of abnormal tumor suppressor function which normally promotes DNA repair and
prevent cancer development). Concept model additions or revisions are suggested as likely.
3.2 Summary of requested solution
Requests addition of two new concepts of format Malignant neoplasm with <gene mutation in
neoplasm> with attention to escalation of requests and similarity to Predisposition to malignant
neoplasm due to <gene mutation in patient>
3.3 Statement of problem as understood
The index cases presented for the project are of the form Finding = <<363346000|Malignant neoplasm
(disorder)| + named expression of gene mutation. This includes a specific genetic sequence or
molecular finding regarding the genome or phenome of the malignancy(abnormally mutated
morphology) that has been diagnosed in the patient. It may or may not represent a mutation in a
premorbid oncogene but is identified presumably for clinical implications of therapeutics.
Related examples cited in the request such as 412734009|BRCA1 gene mutation positive (finding)|
are statements of findings regarding the genome or phenome of the patient, in this case identifying an
abnormal tumor suppressor gene which is associated with lifetime risk of breast and ovarian cancers.
This aligns closely with <artf228474> regarding Hereditary predisposition to cancer. These cases
would represent genotypic and phenotypic observations regarding the patient who is found as carrier
of a proto-oncogene, oncogene or mutation of a tumor suppressor gene. Historically these may be
named syndromes but are now increasingly identified as manifestations of specific and sometimes
named genetic findings.
3.4 Detailed analysis of reported problem, including background
The international release contains fewer than 100 findings of genetic mutations involving the patient,
mostly as named syndromes but a dozen or two with non-specific named gene mutations. I can
identify no findings of genetic or phenotypic observations on neoplastic morphology. Molecular
biology and molecular genetics laboratory procedures number fewer than 100 with one or two dozen
procedures assessing named mutations. In the substance hierarchy I find fewer than 50 named
molecular biology proteins or receptors.
Combined Inception and Elaboration phases
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In contrast to SNOMED findings and substances, a review of the census of cancer related genetic
abnormalities from Sanger showed 141,212 discrete mutations documented in over 500,000 tumors in
April 2015.
In short, the number of unique genetic or phenotypic findings for cancer morphology is very large and
growing with an increasing fraction characterized as clinically significant. There is little current content
in SNOMED CT addressing these findings. There is substantial overlap with the LOINC harmonization
efforts in progress and development of the observables/laboratory procedure concept model since the
content reflects specific genotypic or phenotypic observations from molecular genetics and related
laboratory disciplines.
3.5 Subsidiary and interrelated problems
Reviewing laboratory LOINC version 2.50 currently undergoing harmonization with SNOMED CT
observables, I find 900+ named or identified genetic mutation observables and 1500+ phenotypical
molecular pathology observables.
Observables and Investigation procedure redesign (artf6283) is an IHTSDO project with direct
relationship to this request since design of the ‘Observation result’ will necessarily guide the full
definition of the content proposed for addition
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4 Risks / Benefits
4.1.1 Risks of not addressing the problem
With completion of the Human Genome project and rapidly diminishing costs of genomic analysis,
personalized medicine has been declared a national imperative in the US as it is receiving increased
attention around the world. The EHR will increasingly require the recording of detailed genetic
findings for treatment of cancer, infectious disease, to quantitate and manage patient risk and more. If
SNOMED CT does not meet the challenge of expanding the concept model to record and fully define
these findings and support clinically relevant query and decision support use cases, it will fail in its
mission.
4.1.2 Risks of addressing the problem
The science in this area is rapidly developing new knowledge although classifications of genetic
findings is becoming more mature given a decade of work since the human genome was finally
sequenced. The science is evolving from named clinical syndromes through phenotypic testing for
diagnosis and treatment toward direct observation of genomic and phenomic data for making
diagnoses (cancer and infectious disease) and guiding treatment (personalized medicine). Risks to
SNOMED CT concept model development to support these genomic/phenomic testing innovations
would arise primarily from not effectively dialoguing with the research and clinical community and
harmonizing the concept model with the appropriate employment of reference classifications and
ontologies. This raises the issue of identifying emerging standard ontologies and terminologies
relevant to this domain and creating useful and appropriate harmonization activity where important
collaborations are identified.
Combined Inception and Elaboration phases
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5 Requirements: criteria for success and completion
5.1 Criteria for success/completion
5.1.1 Develop and achieve customer consensus on template model for recording of
genotypic/phenotypic observation results, observables and laboratory
procedures. Identify valuesets relevant to template attributes for this domain
and any harmonization activities that might apply.
5.1.2 Add, release for comment and publish limited SNOMED CT content to meet
existing user requests and sample of LOINC material
5.1.3 Develop specific advice document for the reproducible and useful modeling of
future content requests in this domain
5.2 Strategic and/or specific operational use cases
Make it easier to use SNOMED CT for priority use cases: in this case clinical and public health data in
support of personalized medicine, phenotypic and genotypic clinical findings.
Facilitate use of SNOMED CT with other international standards: Laboratory LOINC harmonization
activities
5.2.1 Use case 1
Model and deploy content requests as primitive content within observables, observation results and
observation procedures as primitive content without full definition. This would lead to content addition
of a moderate (1-3K concepts) body of LOINC concepts in this domain without fully specifying defining
features of the observables concept model development currently under discussion
5.2.1.1 Fit with IHTSDO strategy
This fits with roadmap for harmonization of LOINC content with SNOMED CT but falls short in not
deploying a harmonized content model which captures the nuance and detail of molecular genetic
testing.
5.2.2 Use case 2
Develop consensus with stakeholder communities regarding the utility and clarity of an
observables/observation result/observation procedure template proposal for SNOMED CT recording of
laboratory-based genotypic and phenotypic testing of patient and tumor morphologies. Test requested
material and a sample of related LOINC observables within the International release. Prepare a
guidance package for reproducible development of future SNOMED CT content in this domain.
Develop a content deployment roadmap for the remainder of the LOINC material with the Content
manager.
5.2.2.1 Fit with IHTSDO strategy
This interdigitates with a commitment to LOINC harmonization and proceeds with testing and limited
deployment of molecular genetics tests in order to address content requests originating this ticket. It
Combined Inception and Elaboration phases
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further incorporates evaluation and testing of the template and guidance for scaled up inclusion of
genetic testing data in SNOMED CT.
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6 Solution Development
6.1 Initial Design
6.1.1 Outline of initial design
Apply the proposed Observables model to use cases proposed by this ticket and generalize to
molecular genetic testing
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“BRCA1 gene mutation positive”
“450910000|ALK positive large B-cell lymphoma(body structure)| (primitive)”
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6.1.2 Significant design or implementation decisions / compromises
6.1.3 Evaluation of Design
6.1.3.1 Exceptions and Problems
6.1.3.2 Design strengths
6.1.3.3 Design Weakness
The templates relate to an emerging technology that will evolve. Domain knowledge is limited within
terminology communities and there are risks of inconsistent application of template guidance, placing
reproducibility at risk.
6.1.3.4 Design Risks
Description of risk
Importance
Mitigation plan
6.2 Iteration One
6.2.1 Outline of revised design
Redesign the Solution Identify objectives of iteration, and the major changes to previous design
Communicate the revised design
6.2.2 Significant design or implementation changes
6.2.3 Evaluation of Revised Design
6.2.3.1 Exceptions and Problems
6.2.3.2 Design Strengths
6.2.3.3 Design Weakness
6.2.3.4 Design Risks
Description of risk
Importance
Mitigation plan
6.3 Iteration Two ..
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7 Recommendation
7.1.1 Detailed design final specification
Design the Solution Identify major design elements and how they collaborate to realize the scenario
Communicate the design
7.1.2 Iteration plan
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8 Quality program criteria
8.1 Quality metrics
8.1.1 Quality metric 1
Component Characteristic and Description
Logic definitions of
Char:
sufficiently defined
-
concepts in
<domain>
Metric
Descr:
Concept logic definitions should
-
be “defined” not “primitive”
Target
Result
Proportion
sufficiently defined 95%
Numerator: count of
those defined.
Denominator: count
of all concepts
under <concept
nnnnn>
8.1.2 Quality metric 2
Component Characteristic and Description
Fully specified
Char:
Adherence to terming guidelines
Descr:
The fully specified name should
names in <domain>
Metric
-
Target
Result
Proportion meeting
guidelines, based 100%
on manual review
adhere to terming guidelines
listed in the editorial guide,
sections <list sections>
8.2 Use case scenarios
Create Test Cases: Review the requirements to be tested as set out in the Inception Phase document.
Identify and outline relevant Test Cases. Identify test data needs. Share and evaluate the Test Cases
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8.2.1 Scenario One
8.2.1.1 Expected Setting
8.2.1.2 Data capture requirement
8.2.1.3 Data retrieval requirement
8.2.2 Scenario Two
8.2.2.1 Expected Setting
8.2.2.2 Data capture requirement
8.2.2.3 Data retrieval requirement
8.2.3 Scenario …
8.3 Test cases
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9 Project Resource Estimates
Estimate project size; Forecast project velocity and duration
Evaluate risks; Establish costs and articulate value; Plan deployment; Outline project lifecycle
9.1 Scope of construction phase
Optionally:
Skills required
Solution Specification (Elaboration)
Implementation
Outline of work packages
Preventing recurrence of problem
Division of project into stages
9.2 Projection of remaining overall project resource requirements
9.2.1 Expected project resource requirement category
Is it “fast track” or does it require project management?
9.2.2 Expected project impact and benefit
Updated view of impact and benefit, organized by stage if the project is to be staged
9.2.3 Indicative resource estimates for construction, transition and maintenance:
Construction and transition phase:
100-200 new concepts to be authored
Maintenance phase:
500-1000 new ‘frequent usage’ concept requests in 1st 3 years
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10 Appendices
10.1 Related user requests
<art227316>
Title: Malignant neoplasm with <gene mutation>
Description: Submitter requests two new concepts:
1. Non-small cell lung cancer, anaplastic lymphoma kinase-positive (disorder) - Requesting a new
disease concept for non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)positive. XALKORI® (crizotinib) was FDA-approved in 2011 for this indication
2. Malignant melanoma with BRAF V600E mutation (disorder) - Requesting a new disease concept for
malignant melanoma with BRAF V600E mutation. ZELBORAF® (vemurafenib) was FDA-approved in
2011 for this indication.
--Currently SNOMED CT has a small number of similar concepts. These concepts are primitive.
BRCA1 gene mutation negative (finding)
BRCA2 gene mutation negative (finding)
BRCA1 gene mutation positive (finding)
BRCA2 gene mutation positive (finding)
Non-small cell lung cancer, negative for epidermal growth factor receptor expression (disorder)
Non-small cell lung cancer, positive for epidermal growth factor receptor expression (disorder)
There is a potential for a large number of similar requests and the concept model is not adequately
developed for this content. These requests also relate to the following artifacts:
<artf6220 : malignant neoplasm, primary malignant neoplasm
Title: malignant neoplasm, primary malignant neoplasm
Description: Issue of how to handle existing Malignant neoplasm of X and Primary malignant
neoplasm of X content. If default context of Malignant neoplasm of X means Primary malignant
neoplasm of X, then these two concepts would be duplicates. Also, if Malignant neoplasm of X means
Primary malignant neoplasm of X, then it cannot be supertype of secondary malignant
neoplasm of X as is currently the case in SNOMED. There are about 3700 concepts with associated
morphology of Malignant neoplasm of primary, secondary, or uncertain origin (morphologic
abnormality) or a descendant.>
artf7618 : Negation and Context
artf6812 : <procedure> result positive
artf6813 : <procedure> result negative
It is suggested that these two requests be placed on Await policy under artf6812 but that these
requests be linked to those artifacts so that the solution proposed to those artifacts also considers this
content.>
JRC: My review of current content requests identified these possibly related artifacts:
<Artf6328: Title: how to model "carrier of X"
Combined Inception and Elaboration phases
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Need text definition of "carrier" and logic model:
A carrier of infectious organism may not have an infectious disease. Or they may have an
asymptomatic disease. Are all carriers "silent carriers"? (Is everyone with strep pharyngitis also a
carrier of strep?)
What about genetic carriers? Same or different from heterozygous state of a disease that is
homozygous? What about female carriers of X-linked, and those who are homozygous but the disease
has incomplete penetrance?>
<Artf228474Title: hereditary cancer predisposition syndrome
Description: Recent genetic studies have expanded the understanding of the genetic basis of cancer
predisposition / susceptibility. A number of syndromes have been identified. For example, Lynch
syndrome, formerly called HNPCC, includes multiple different genetic defects that predispose to
colorectal and also other cancers.
HNPCC (hereditary nonpolyposis colorectal cancer) is an ambiguous code/concept for two reasons:
(1) does the code imply that the patient has actual colorectal cancer or just the predisposition
conferred by the presence of the inherited genetic defect? and
(2) does the code imply presence of colorectal cancer, or might it be one of the other cancers to which
the genetic defect predisposes?
Similarly for all cancer presdisposing syndromes, we need "hereditary cancer predisposition
syndrome" and "hereditary malignancy" (the latter defined as malignancy in a hereditary cancer
predisposition syndrome>
Inventory of concepts now in the International release
450910000|ALK positive large B-cell lymphoma(body structure)| (primitive)
448212009|Anaplastic large cell lymphoma, ALK negative(disorder)|(primitive)
53237008|Anaplastic large cell lymphoma CD30+(body structure)|(primitive)
441420000|Homozygous prothrombin G202100A mutation(disorder)|
441421001|Heterozygous prothrombin G202100A mutation(disorder)|
440989002|Prothrombin G202100A mutation(disorder)|
421617007|RET proto-oncogene mutation analysis(procedure)|
10.2 References
Sanger Institute Cancer Genome Project http://cancer.sanger.ac.uk/cosmic
Futreal PA, Coin L, Down T, Hubbard T,Wooster R, Rahman N, Stratton MR. A census of human
cancer genes. Nature Reviews Cancer; 4,177-183.
Combined Inception and Elaboration phases
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