buy one gene, get one 30 free - wesley ob/gyn · -- if polyp not adenomatous, assess whether...
TRANSCRIPT
BUY ONE GENE, GET
ONE 30 FREE !G E N E P A N E L T E S T I N G F O R H E R E D I T A R Y C A N C E R :
G E T T I N G I T R I G H T
THIS COULD BE YOU ONE DAY SOON:
Starting out in your new
OB/Gyn practice
You meet Lori, a new
patient, for her annual
well-woman visit:
LORI:
37-year old Caucasian female
good general health
family history:
mother: HTN, osteopenia dx’ed 65
father: colon polyps dx’ed 68
PGM: breast cancer dx’ed 55
sister: recently dx’ed with breast cancer at 42
FUN FACT #1:F A M I LY H I S T O R Y W A S T H E F I R S T G E N E T I C T E S T.
CASE #1 – LORI’S PEDIGREE
Lifestyle
Genes
Environment
Family histor
y
Cancer
Risk
FUN FACT #2:A L L C A N C E R I S G E N E T I C ,
BUT
F E W C A N C E R S A R E I N H E R I T E D .
STAGES OF CANCER DEVELOPMENTNormal cell
Increased proliferation
Early neoplasia
Progressive neoplasia
Carcinoma
Metastasis
Mutation in Gene A
Mutation in Gene B
Mutation in Gene C
Continuing
cascade of
mutations
ALL CANCERS HAVE GENETIC ORIGINS
Somatic mutations
Occur in non-germline tissues
(breast, colon, lung, blood, etc.)
Not inherited
“sporadic”
90-97% of all cancers
Germline Mutations
Start out in egg and sperm cells
Heritable
Once inherited, mutation is present in
all cells of the body
3-10% of all cancers
THE WORLD OF CANCER GENETIC TESTING
Direct-to-consumer
Tumor testing (somatic-
based)
Germline genetic testing
not every cancer risk gene is known
possibility of unclear results
cannot prevent / screen for all cancer
risks
more questions than answers
anxiety / distress
GERMLINE GENETIC TESTINGWHO?
– DNA sequencing and deletion/duplication
analysis of genes associated with
inherited cancer syndromes
WHY?
– Myriad, Ambry, GeneDx, Prevention, etc.
WHAT?
– To guide screening, prophylaxis, risk
management, and identify at-risk family
members
LIMITATIONS
CASE #1 – LORI’S PEDIGREE
NATIONAL COMPREHENSIVE CANCER NETWORK www.NCCN.org
Mission statement:
“Our mission, as an alliance of leading
cancer centers devoted to patient care,
research, and education, is improve the
quality, effectiveness, and efficiency of
cancer care so that patients can live better
lives.”
Clinical Practice Guidelines in Oncology
Patient Guidelines
CEU programs
NCCN GUIDELINES FOR HEREDITARY BREAST/OVARIAN ASSESSMENT personal history of ovarian cancer at any age
personal history of breast cancer <45
triple negative breast cancer
two primary breast cancers
two or more family members with breast and/or ovarian
cancer, especially <50
CONSIDER GENETIC TESTING……BUT FOR WHO?
Lori ?
Lori’s sister ??
Someone else???
FUN FACT #3:IDEALLY, GENETIC TESTING
SHOULD BE PERFORMED ON
AN AFFECTED INDIVIDUAL.
SO WHAT TESTING DO WE OFFER THIS FAMILY?
Back in the day (<5 years ago), we had only a small handful of cancer genes
we routinely tested for.
Myriad Labs held the patent on the BRCA1 and BRCA2 genes and was the
only lab who could do the testing.
On June 13, 2013, the Supreme Court struck down the patent, ruling that
genes are not patentable.
On June 14, 2013, every genetic testing laboratory was offering BRCA1 / 2.
Introduction of NGS technologies
NGS MULTIGENE PANELS
Benefits
-- assess any number of genes at once (typically anywhere from 15 – 50)
-- clarify patient’s risk (and those of other carriers of familial variant)
-- guide medical management
Challenges
-- turnaround time may be several weeks delayed decision-making
-- limited literature on many genes / variants
-- interpreting results for unaffected family members
-- variants of unknown significance
-- informed consent
-- follow up in the case of variant reclassification
DISTRIBUTION OF PATHOGENIC VARIANTS IN HBOC FAMILIES
Citation: Castera, L. et al. Next-
generation sequencing for the
diagnosis of hereditary breast and
ovarian cancer using genomic capture
targeting multiple candidate
genes. Eur J Hum Genet. 2014 Feb
19
GENES AND CANCER SITES
FUN FACT #4:I T I S V E R Y U N L I K E LY Y O U W I L L E V E R O R D E R
G E N E T I C T E S T I N G F O R A S I N G L E G E N E /
C A N C E R S Y N D R O M E
CASE #2 – COLON POLYPS
57-year old male
first colonoscopy at 56
-- multiple polyps throughout colon
-- pathology: tubular adenomas and
mucosal polyps with muscle overgrowth
follow-up colonoscopy (6 months later)
-- multiple polyps in each colon segment
-- uncountable polyps in transverse colon
-- pathology: tubular adenomas and
hyperplastic polyps
TESTING STRATEGY
genetics evaluation
if >10 adenomas present, test for FAP / MAP
conventional approach:
-- sequencing and rearrangement testing of APC, MUTYH genes
-- if polyp NOT adenomatous, assess whether patient meets NCCN criteria for
less common polyposis syndrome, such as Cowden, Peutz-Jehger, or Juvenile
Polyposis syndrome.
COLORECTAL CANCERSporadic (70%)
Familial (25%)
- Lynch syndrome (3%)
- FAP (1%)
- MAP (1%)
- Rare CRC syndromes (<1%)
juvenile polyposis
Peutz-Jehgers syndrome
serrated polyposis
PTEN-related syndrome
hereditary diffuse gastric
cancer (HDGC)FAP = Familial adenomatous polyposis
MAP= MUTYH-associated polyposis
LIFETIME RISKS FOR COLORECTAL CANCER
0
10
20
30
40
50
60
70
80
90
100
FAP AFAP MAP General
Population
Can
cer
Ris
k (
%)
APC /
MUTYH
negative
NOW
WHAT?
COLONEXT NGS PANEL (AMBRY)Gene Syndrome CRC Risk Polyposis Other Associated
Cancer(s)
STK11 Peutz-Jeghers Up to 40% Yes Breast, pancreas,
GI, uterine,
cervical
CHEK2 Hereditary
Breast/CRC
Increased No Breast
CDH1 Hereditary Diffuse
Gastric Cancer
Increased No Lobular breast,
diffuse gastric
PTEN Cowden Increased Yes Breast, thyroid,
kidney, uterine
TP53 Li-Fraumeni Increased No Breast, sarcoma,
brain, leukemia
MYH MAP Up to 80% Yes Duodenal, thyroid
APC FAP / AFAP Up to 99% Yes Duodenal, thyroid
MLH1
MSH2
MSH6
PMS2
EPCAM
Lynch Up to 80% No
Stomach, brain,
Uterine, ovarian,
Pancreas, ureter
SMAD4
BMPR1A
Juvenile Polyposis Up to 50% Yes Stomach
THINGS TO CONSIDER BEFORE TESTING - CLINICIAN Gene / syndrome-specific testing is still available and MAY be a reasonable
option in some cases and should be discussed with any patient
MSI / IHC should be utilized when Lynch syndrome is suspected
Large gene panels can take several weeks to several months for results
Large panels may not be feasible when making time-sensitive decisions
THINGS TO CONSIDER BEFORE TESTING - PATIENT
Longer turnaround time may delay treatment / surgery
Testing may find variants with unclear cancer implications
Testing may find variants revealing risk for unrelated cancers
Results may have implications for other family members
PTEN HAMARTOMA TUMOR SYNDROME (PHTS)
– Thyroid cancer (35%)
– Kidney cancer (33%)
– Colorectal cancer (9%)
– Melanoma (6%)
– Breast cancer (60%)
– Endometrial cancer (28%)
– Uterine fibroids
– Hamartomatous polyps
– Macrocephaly
– Thyroid nodules, goiter
– Trichilemmomas, papillomatous papules
– Hyperpigmentation
– Overgrowth
– Fibrocystic breast disease
– Autism spectrum disorder
– Mental retardation (IQ<75)
– Lipomas
Includes: Cowden syndrome, Proteus syndrome, Bannayan-Riley-Ruvalcaba syndrome (BRRS)
Lipomas, HC 63.9 cm
Asperger
syndrome
macrocephaly
LDautism
PTEN HAMARTOMA TUMOR SYNDROME (PHTS)
– Thyroid cancer (35%)
– Kidney cancer (33%)
– Colorectal cancer (9%)
– Melanoma (6%)
– Breast cancer (60%)
– Endometrial cancer (28%)
– Uterine fibroids
– Hamartomatous polyps
– Macrocephaly √
– Thyroid nodules, goiter
– Trichilemmomas, papillomatous papules
– Hyperpigmentation
– Overgrowth
– Fibrocystic breast disease
– Autism spectrum disorder √
– Mental retardation (IQ<75)
– Lipomas √
Includes: Cowden syndrome, Proteus syndrome, Bannayan-Riley-Ruvalcaba syndrome (BRRS)
VARIABLE EXPRESSIVITY
PTEN WORKUP - JW Subtotal colectomy with IRA
– path: colon with multiple tubular adenomas and
hamartomatous polyps
Double balloon enteroscopy
-- glycogenic acanthosis, ileal and jejunal polyps
Thyroid ultrasound
– innumerable nodules
Derm exam
– unremarkable
MRI of the abdomen
– unremarkable
Recommendations:
– Yearly physical
– Yearly thyroid ultrasound
– Yearly derm exam
– Continue GI screening based on polyp burden
– Genetic testing for first degree relatives > age 18
CASE #3 - HBOC
46 year old woman with a newly diagnosed left breast cancer
– ER/PR+ invasive ductal carcinoma
Referred for genetic risk assessment by patient request
-- wants risk estimate to help her decide about bilateral
mastectomy
CANCER RISKS IN HBOC
BRCA1
– Breast cancer: 54-90%
– 2nd breast cancer: 27% within 5 years
– Ovarian cancer: 24-40%
BRCA2
– Breast cancer: 41-87%
– 2nd Breast cancer: 12% within 5 years
– Ovarian cancer: 8.4-18%
CANCER RISKS IN HBOC
FUN FACT #5A LWAY S A S K A B O U T B O T H S I D E S O F
T H E FA M I LY W H E N TA K I N G A FA M I LY
H I S T O RY !
CASE #3 – PEDIGREE
MYRISK (MYRIAD) RESULTS
BOOM! POSITIVE TEST!
Deleterious variant
- MUTYH gene c.1187G>A (p.Gly396Asp)
MUTYH GENE involved in base excision repair
germline MUTYH mutations impair DNA repair of somatic APC mutations leading to a phenotype similar to FAP
RECESSIVE inheritance
biallelic carriers are predisposed to:
– Multiple colorectal adenomas
– upper GI manifestations – stomach cancer, duodenal polyps
– Early onset colon caner
– CHRPE
– Risks for other cancers is unclear (possible increased risk for breast cancer, skin cancer, ovarian cancer)
MUTYH-ASSOCIATED POLYPOSIS MUTYH testing classically bundled with APC
accounts for 1% of all CRC
accounts for up to 3% of CRC under age 50
monoallelic carriers:
- studies conflict on whether cancer risk is
increased
- carrier rate: 1-2% of the general US population
SO, IN OTHER WORDS
Does she have a disease-causing
variant? YES.
Does it explain her cancer? NO.
Does this variant, on its own,
affect her risk for cancer?
Probably not.
MYRISK RESULTS
Deleterious variant
- MUTYH gene c.1187G>A (p.Gly396Asp)
Variants of Uncertain Significance (VUS)
- BRCA2 c.8447G>A (p.Gly2816Asp)
- STK11 c.1062C>G (p.Phe354Leu)
FUN FACT #6:
S O M E T I M E S I N O U R Q U E S T F O R A N S W E R S W E
O N LY F I N D M O R E Q U E S T I O N S .
VARIANT INTERPRETATION
Medical mgmt. based on personal &
family hx. Uncertain results do not
influence recommendations for care.
Medical mgmt. based on
guidelines for gene variant and
its associated syndrome(s).
Citation:
Richards, S., Aziz, N.,
Bale, S., Bick, D., Das, S.,
Gastier-Foster, J., ... &
Voelkerding, K. (2015).
Standards and guidelines
for the interpretation of
sequence variants: a joint
consensus
recommendation of the
American College of
Medical Genetics and
Genomics and the
Association for Molecular
Pathology. Genetics in
Medicine.
RATES OF UNCERTAIN VARIANTS
0.0%
5.0%
10.0%
15.0%
20.0%
25.0%
30.0%
35.0%
40.0%
2002 2006 2008 2012
Decline in Rate of BRCA1/2 Variants of Uncertain Significance
All Patients
Middle Eastern
Asian
African
Native American
Latin American
Central European
Western European
Eggington et. al. Current Variant of Uncertain Significance Rates in BRCA1/2 and Lynch Syndrome Testing (MLH1, MSH2,
MSH6, PMS2, EPCAM), March 2012, ACMG Poster Presentation.
CASE #3 – PEDIGREE
MUTYH-positive
VUS – BRCA2
VUS – STK11
NO BRCA2 VUS
STK11 GENE
associated with Peutz-Jehgers syndrome
autosomal dominant
~50% de novo
characteristic hyperpigmentation of the
mucosa
hamartomatous polyps
CANCER RISKS IN PJS
Breast - 50%
Colorectal - 39%
Pancreatic – 11-36%
Gastric - 29%
Small bowel – 13%
Ovarian - 21%
Cervical – 10%
Uterine - 9%
Lung - 15%
Testicular - ?
RECOMMENDATIONS
currently no genetic indication that PR’s risk for a second breast cancer
is significantly increased.
recommended standard breast treatment, screening, and follow-up
care based on physician recommendations and family history
undergo colonoscopy every 5 years
MYH testing recommended for 1st degree relatives
-- to assess for MAP
-- high US carrier rate (1-2%)
THIS CASE ILLUSTRATES…
complex inheritance patterns with some syndromes
significant risk of variants of uncertain significance
- approximately one-third of panel results
- newer genes, less literature, smaller samples
- reclassification of many VUS with time
challenges for clinicians in sorting out the data
challenges for patients trying to make decisions about care
FUN FACT #7:Y O U D O N ’ T N E E D T O K N O W E V E R Y T H I N G .
Y O U D O N E E D T O K N O W W H E N T O R E F E R .
A GENETIC COUNSELOR CAN HELP YOU
RIGHT PATIENT
RIGHT TEST
RIGHT LAB
RIGHT RESULTS
WHEN TO REFER TO GENETICS triple-negative breast cancer
male breast cancer
ovarian cancer
young onset (< 50)
same/related cancer in relatives
autosomal dominant inheritance
– with rare exceptions
aggressive prostate cancer
- Gleason score ≥ 7
multiple primaries
multifocal / bilateral cancers
rare cancers
unusual non-malignant features (i.e.,
“syndromic”)
confirmed mutation in relative
If uncertain, refer anyway!
LAST FUN FACT:
“ G E N E T I C S A N D O U R U N D E R S TA N D I N G O F
M U TAT I O N S I S E V O LV I N G , S O T O D AY ’ S
G E N E T I C R E S U LT M U S T A L W AY S B E
R E A S S E S S E D A N D I N T E R P R E T E D B A S E D O N
C U R R E N T I N F O R M AT I O N A N D S T U D I E S O F
M O D I F I E R S , P R O P H Y L A X I S O P T I O N S , A N D
P R E V E N T I O N . ”
M I C H A E L H A L L , M D
F O X C H A S E C A N C E R C E N T E R
P H I L A D E L P H I A , P A
QUESTIONS?
My contact information:
Carla Bell, MS, LCGC
Wesley Medical Center
Oncology Department
550 North Hillside
Wichita, KS 67214
Direct phone: 316.361.0991
Fax: 501.222.7753
Email: [email protected]