Download Many of our patients should have already had germline testing

Germline testing
Susan Domchek, MD
University of Pennsylvania
Key issues
• Do oncologists underestimate the power of germline
genetics?
Predictive testing can prevent disease – in our patients and their
family members
– It is important and valuable in its own right
– Germline findings can have therapeutic implications on their
own
– Many of our patients should have already had germline testing
before they developed cancer
Germline testing is standard of care
• Many diseases in which all patients should be offered germline
testing
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Adrenocortical
Pheochromocytoma
Paraganglioma
Ovarian cancer
Triple negative breast cancer <60
Diffuse gastric cancer <40
Medullary thyroid cancer
Etc etc
Hampell Gen Med et al 2015
Case 1: Germline testing can prevent disease
BRCA1 C61G
This woman would have been
aided much more by predictive
germline testing and risk
reducing salpingo-oophorectomy
than somatic sequencing of the
tumor she developed
Key issues
• There are several ways to do tumor testing: do patients and
providers understand germline implications of each method?
– Paired germline/somatic vs somatic with germline subtracted vs
somatic only
– Understand strengths and weaknesses
– Develop strategies so that data can be used
– Appropriate consent
Case 2: Does anyone understand what we are doing?
Technical aspects of germline sequencing
• Rationale for germline sequencing are different and
sensitivity for mutations is not necessarily the same
– Identification of cancer susceptibility variants vs.
comparison to a tumor sequence
– Sensitivity of deletion/duplication? Uniform coverage?
– Current standard remains to do germline testing if
indicated regardless of somatic results
Key issues
• Reporting:
– Differential level of variant review and annotation for germline and somatic
– Testing is done for different reasons – and may have different thresholds
– Not everything needs to be further evaluated in the germline (VUS/benign in
ClinVar)
– Clarification of reporting
• Founder mutations
• Allelic frequency?
• Beyond cancer related genes?
Case 3: Multiple reporting confusions
• Oncologist at Penn had received germline and somatic
testing reports and “it is very weird but the patient has
different mutations in germline and tumor”
– BRCA1 C61G, c.181T>G: They are the same
• Patient – very concerned because her uncle has a different
germline mutation than she does – does she need to be
retested?
– BRCA1 187delAG (also known as BRCA1 185delAG and
c.68_69delAG)
– Common Ashkenazi Jewish founder mutation
Case 4: Variants of Uncertain Significance
• Not infrequent that findings on somatic reports are
“unimportant” in ClinVar
– VUS: When found in the germline – we do not act on these,
management is based on family history
– GENIE and other initiatives
– May be particularly important in loss of function
– For alternations that on the germline side would be VUS at best
– this may “dilute” the study, as we may not expect responses
Key issues
• Somatic only – the de facto standard in the
community at this time
– What results should trigger rapid and low barrier
referral for germline testing? Why does this matter?
– Extending beyond the traditional model - cancer
community has create new models
Case 5: Why do germline testing once we have somatic results?
Somatic sequencing in the mother’s ovarian
tumor:
BRCA2 6014_6017delATAG
Testing in the two daughters is
uninformative without knowing if the
mutation is germline in the mother
Irish/English, no AJ
We were able to obtain a sample while
proband was on hospice: no germline
mutation was detected
Best practice list: Somatic sequencing findings with
consideration for gemline testing
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Tumors with a pathogenic or likely pathogenic BRCA1, BRCA2, MLH1,
MSH2, or MSH6 mutations
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Pathogenic variants in BRIP1, PALB2, RAD51C, RAD51D
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Founder mutations (which will be specified in report)
•TP53 R337H; ATM V2424G;
•APC I1307K; CHEK2 1100delC, I157T, S428F will have explanatory text (as
moderate prevalence founder/common mutations)
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Pathogenic variants in genes for which your patient appears to have an
associated clinical phenotype (See checklist )
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Patients whose personal or family history is suggestive of a hereditary
cancer syndrome should be referred regardless of somatic testing results
D Clark, K Maxwell, K Nathanson, S Domchek, J Morrissette
Considerations
• Embrace the germline: risk prediction and prevention for
patients and family members – as well as targeted therapy
• Consent, disclosure, and data usage
• Clarity of testing and reporting for providers and patients
• Novel models for consent and information dissemination
Suggestions from the clinical oncologist
1.
Encourage use of germline testing early in disease in appropriate
candidates
2.
Clarify reporting: Type of testing and reporting of results
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3.
Clearly identify type of testing
Clearly identify founder mutations
Develop consistent reporting across germline and somatic
sequencing
Develop a best practice list of which somatic results should be
promptly referred to germline testing
Recommendations from the germline panel
1. Encourage analysis of the germline
2. Improve annotation and reporting
3. Evolve paradigms for consent and return of
results
4. Provide guidance for community oncologist
for inferences of germline in somatic testing