Download ASIP 2016 Journal CME Programs JMD 2016 CME Program in

ASIP 2016 Journal CME Programs
JMD 2016 CME Program in Molecular Diagnostics
American Society for Investigative Pathology and the
Association for Molecular Pathology
The Journal of Molecular Diagnostics, Volume 18, Number 5 (September 2016)
www.asip.org/CME/journalCME.htm
Mark E. Sobel, MD, PhD, Director of Journal CME Programs
CME September Questions # 1-8
A Review article on the molecular pathology of gliomas and an article on the comprehensive analysis of FMR1 alleles were
selected for the September 2016 JMD CME Program in Molecular Diagnostics. The authors of the referenced articles, the
planning committee members, and staff have no relevant financial relationships with commercial interests to disclose.
Questions #1-6 are based on: Rodriguez FJ, Vizcaino A, Lin MT: Recent advances on the molecular pathology of glial
neoplasms in children and adults. J Mol Diagn 2016, 18:620-634; http://dx.doi.org/10.1016/j.jmoldx.2016.05.005.
Questions #7-8 are based on: Hayward BE, Zhou Y, Kumari D, Usdin K: A set of assays for the comprehensive analysis of
FMR1 alleles in the fragile X-related disorders. J Mol Diagn 2016, 18:762-774; http://dx.doi.org/10.1016/j.jmoldx.2016.06.001.
Upon completion of this month’s journal-based CME activity, you will be able to:
•
Define glioblastoma, including small cell and giant cell glioblastoma.
•
Understand the first reports from The Cancer Genome Atlas glioblastoma study.
•
Describe primary and secondary type glioblastoma.
•
Define low-grade glioma.
•
Understand the prevalence of EGFR mutations in glioblastoma.
•
Describe the molecular characteristics of high-grade gliomas in children.
•
Explain fragile X-related disorders.
•
Describe repeat number (RPT-PCR) assays.
1. Glial neoplasms encompass a heterogeneous group characterized predominantly by an astrocytic or
oligodendroglial structural characteristic. Based on the referenced Review article, select the ONE statement that is
NOT true: [See J Mol Diagn 2016, 18:620-634.]
a.
b.
c.
d.
Glioblastoma is a morphologically heterogeneous neoplasm, with several variants and patterns.
The epidermal growth factor receptor (EGFR) gene is amplified in 100% of small cell astrocytoma pattern
glioblastoma.
Giant cell glioblastoma is characterized by voluminous cell size and frequent TP53 mutations (83%) and aurora
kinase B (AURKB) overexpression.
Epithelioid glioblastoma may resemble a variety of non-central nervous system (CNS) tumor types and has B-Raf
proto-oncogene, serine/threonine kinase (BRAF) p.V600E mutations in approximately half of the cases.
2. One of the most important developments in the neuro-oncology community was the selection of glioblastoma as
the model for The Cancer Genome Atlas (TCGA) first study. Based on the referenced Review article, select the ONE
statement that is NOT true: [See J Mol Diagn 2016, 18:620-634.]
a.
b.
c.
d.
An early report was published in 2008, which included gene expression data and DNA copy number and methylation
in 206 glioblastomas.
The 2008 study described standard gene sequencing on approximately 600 candidates in a representative group of
tumors.
The 2008 study validated well-recognized glial oncogenes (EGFR, CDK4, PDGFRA, MDM4, MET) and tumor
suppressor genes (CDKN2A/B, PTEN, RB1) that were altered at variable rates.
A total of five molecular core pathways (ie, Ras, RB1, TP53, receptor tyrosine kinase, and NFκB) were elucidated as
aberrant in most tumors studied.
© The American Society for Investigative Pathology
JMD 2016 CME Program in Molecular Diagnostics
The Journal of Molecular Diagnostics, Volume 18, Number 5, September 2016
3. From clinical presentation, glioblastomas have been broadly separated into primary and secondary types. Based
on the referenced Review article, select the ONE statement that is NOT true: [See J Mol Diagn 2016, 18:620-634.]
a.
b.
c.
d.
Primary glioblastomas are by far the most common (>90%) and are characterized by a short clinical evolution
without evidence of a precursor lesion.
Secondary glioblastomas represent a minority of the tumors (<10%), and by definition develop from a clinical or
pathologically verified lower grade precursor.
Known alterations in secondary glioblastoma include TP53 (approximately 50%) and ATRX (approximately 25%).
IDH mutations have emerged as robust molecular markers for secondary glioblastoma.
4. The TCGA effort has also focused on the group of tumors labeled lower grade glioma. Based on the referenced
Review article, select the ONE statement that is NOT true: [See J Mol Diagn 2016, 18:620-634.]
a.
b.
c.
d.
Lower grade glioma includes grade II and III astrocytomas, oligoastrocytomas and oligodendrogliomas, that is,
diffuse gliomas other than glioblastomas.
The most consistent molecular finding in lower grade tumors is the high frequency of TERT promoter mutations and
hypermethylation of the MGMT gene promoter.
Lower grade gliomas cluster in three main molecular subgroups, which are more strongly associated with prognosis
than traditional histology.
The molecular groups have intrinsic importance, not only related to their robust prognostic power but also because
they identify biologically separate disease entities, based on their distinct patterns of somatic alterations, epigenetic
alterations, and gene expression.
5. EGFR is almost always active or overexpressed in high-grade astrocytomas. Based on the referenced Review
article, select the ONE statement that is NOT true: [See J Mol Diagn 2016, 18:620-634.]
a. EGFRvIII is an EGFR variant III deletion mutation, occurs in approximately 20% of glioblastomas, leads to a
truncated protein lacking the extracellular domain, and is frequently associated with amplification.
b. Somatic EGFR alterations lead to constitutive activation of several signaling pathways critical for gliomagenesis,
including MAPK and PI3K/Akt, ultimately promoting tumor growth.
c. EGFR is one of the most frequently altered genes in glioblastoma (approximately 75% of tumors), with
approximately 25% of tumors demonstrating amplification.
d. A variety of noncanonical recurrent EGFR mutations may be identified in glioblastoma, including C-terminal
deletions and alternative intragenic alterations.
6. The World Health Organization (WHO) classification does not necessarily separate high-grade gliomas in children
and adults. Based on the Review referenced article, select the ONE statement that is NOT true: [See J Mol Diagn
2016, 18:620-634.]
a.
b.
c.
d.
The number of coding gene mutations in high-grade gliomas in children is higher than lower grade examples and
much higher than high-grade adult counterparts in some data sets.
Integrated molecular profiling of pediatric glioblastomas has generated distinct subgroups with prognostic relevance,
with tumors containing oncogene amplifications and/or H3F3A p.K27M mutations, in particular, having the worst
outcome.
H3F3A p.K27M mutations have a predilection for diffuse astrocytomas involving midline structures, including diffuse
intrinsic pontine gliomas in children as well as high-grade astrocytomas occurring in the spinal cord in both children
and adults.
Other pediatric high-grade gliomas occurring outside of the pons/midline may contain alternative H3F3A mutations
(p.G34R or p.G34V).
7. The fragile X-related disorders are diseases resulting from the expansion of a CGG/CCG-repeat tract in the 5’
untranslated region of the FMR1 gene. Based on the referenced article, select the ONE statement that is NOT true:
[See J Mol Diagn 2016, 18:762-774]
a. These disorders include fragile X-associated primary ovarian insufficiency and fragile X-associated tremor/ataxia
syndrome that are seen in carriers of alleles with 55 to 200 repeats, so-called permutation (PM) alleles.
b. Fragile X syndrome is seen in carriers of full mutation (FM) alleles that have >400 repeats.
c. The differences in pathology seen in carriers of FM and PM alleles stem from the fact that fragile X-associated
tremor/ataxia syndrome and fragile X-associated primary ovarian insufficiency arise from some as yet unresolved
deleterious consequence of the expression of FMR1 transcripts with large repeat numbers, whereas fragile X
syndrome results from repeat-mediated gene silencing.
d. The repeat tract is unstable, undergoing expansions and contractions in both the germline and somatic cells.
© The American Society for Investigative Pathology
JMD 2016 CME Program in Molecular Diagnostics
The Journal of Molecular Diagnostics, Volume 18, Number 5, September 2016
8. Repeat number (RPT-PCR) assays can readily detect alleles with >900 repeats, even in samples with multiple large
alleles. Based on the referenced article, select the ONE statement that is NOT true: [See J Mol Diagn 2016, 18:762774.]
a.
b.
c.
d.
RPT-PCR is sensitive enough to detect 25% of FM alleles present in a mixture of normal or PM alleles.
RPT-PCR is robust enough to be used on samples like saliva with minimal purification.
The ability to use saliva samples simplifies sample collection in the field and is particularly advantageous for
collecting DNA from FM carriers who often find blood draws difficult.
TP_RPT-PCR allows the unambiguous determination of the AGG interspersion pattern that is particularly useful for
males.
© The American Society for Investigative Pathology
JMD 2016 CME Program in Molecular Diagnostics
The Journal of Molecular Diagnostics, Volume 18, Number 5, September 2016