1. +
Screening for
Genetic Disease
Douglas Riegert-Johnson, MD
Assistant Professor of Medicine and
Medical Genetics
Mayo Clinic Florida
Amelia
Island
Mayo Clinic
Review
Course
Douglas Riegert- Johnson, MD
Riegertjohnson.douglas@mayo.edu
Mayo Clinic Florida - Jacksonville
Assistant Professor of Medicine and Medical Genetics

2. +
Conflicts of Interest and
off Label Drug Use
None.

3. +
Objectives
What questions do I need to ask as a
primary care provider to screen for genetic
disease?
How do I refer a patient for a genetic
evaluation?
What genetic tests can I order as a non
geneticist?

4. + What questions do I need to ask
to screen for genetic disease?
 Does anyone in your family have
cancer? Breast, ovarian, or colon
cancer?
 At what age were the cancers diagnosed?
Breast cancer 80
Breast cancer 65

5. + What questions do I need to ask
to screen for genetic disease?
 Does anyone in your family have
cancer? Breast, ovarian, or colon
cancer?
 At what age were the cancers diagnosed?
Compliance with
cancer family history in
oncology practices
77% of medical records
reviewed documented
presence or absence of
CFH in first-degree
relatives.
Of patients with increased
risk for hereditary cancer,
52% of patients with Breast
CA and 26% of those with
Colorectal CA were referred
for GC/GT.
Quality of Cancer Family History and Referral for
Genetic Counseling and Testing Among Oncology
Practices: A Pilot Test of Quality Measures As Part of
the American Society of Clinical Oncology Quality
Oncology Practice Initiative J Clinical Oncology 2014
Breast cancer 80 41
Breast cancer 65 50

6. + Age of diagnosis and presence of an affected
family member changes the odds of a
hereditary cancer syndrome diagnosis
Myraid Genetics BRCA mutation prevalence tables
Personal history No family history of
breast or ovarian
cancer
Family history of first
degree relative with
breast cancer dx < 50
yo
Breast CA > 50yo 2.2% 8.0%
Breast CA < 50 yo 4.7% 21.2%
Male breast CA 6.9% 36.6%
Ovarian CA 7.7% 27.4%
* Not applicable to Ashkenzai Jewish populations.

7. + Age of diagnosis and presence of an affected
family member changes the odds of a
hereditary cancer syndrome diagnosis
Myraid Genetics BRCA mutation prevalence tables
Personal history No family history of
breast or ovarian
cancer
Family history of first
degree relative with
breast cancer dx < 50
yo
Breast CA > 50yo 2.2% 8.0%
Breast CA < 50 yo 4.7% 21.2%
Male breast CA 6.9% 36.6%
Ovarian CA 7.7% 27.4%
* Not applicable to Ashkenazi Jewish populations.

8. + Treatment is different for BRCA1/2
patients:
Bilateral mastectomy prolongs survival in patients with
BRCA1/2 mutations.
Contralateral mastectomy and survival after breast cancer in carriers of BRCA1 and BRCA2 mutations. BMJ 2013.
390 women
with stage 1
or stage 2
breast
cancer. All
with a
mutation in
the BRCA ½
genes.
181 bilateral
mastectomy
88% survival
209 unilateral
mastectomy
66% survival
* Survival at 20 years. Reduction in risk hazard ratio 0.52, 95%
confidence interval 0.29 to 0.93; P=0.03.

9. +
Hereditary cancer syndrome
patients are not rare!
Location by Zip Code
139 patients
(out of 280)
MCF 6.2014

10. + Selected criteria for referral of the Breast
Cancer patient for genetic evaluation
Refer if patient has any of the following
 Early-age-onset breast cancer (less the 50 yo)
 Breast cancer at any age if,
 Triple negative (ER-, PR-, HER2-) breast cancer
 Two breast primaries at any age
 Personal history of breast cancer and family history of close blood
relative with breast cancer dx <50yo
 Ovarian/fallopian tube/primary peritoneal cancer
 Male breast cancer
NCCN 1.2014

11. + Selected criteria for referral of the Breast
Cancer patient for genetic evaluation
 In unaffected patient if, family history of
 2 breast primaries in single individual close relative
 2 individuals with breast primaries on the same side of family
(maternal or paternal)
 1 ovarian and breast primary from the same side of family (maternal
or paternal)
 First- or second-degree relative with breast cancer 45 y
 1 family member on same side of family with a 1 of the following (especially
if early onset): pancreatic cancer, aggressive prostate cancer (Gleason
score 7) sarcoma, adrenocortical carcinoma, brain tumors, endometrial
cancer, leukemia/lymphoma; features of Cowden syndrome.
 From a population at increased risk (Ashkenazi Jewish)
NCCN 1.2014

12. +
Simplified criteria for referring Colon
Cancer patients for genetic evaluation.
(Lynch syndrome)
NCCN 2.2014
 All patients with colon cancer or endometrial cancer under the age
of 50.
 All patients with metachronous or synchronous colon cancer.
 Any patient with colon cancer who has a family member with colon
or endometrial cancer.*
 Any patient with a specific colon cancer pathology
 tumor-infiltrating lymphocytes,
 Crohn's-like lymphocytic reaction,
 mucinous/signet-ring differentiation,
 or medullary growth pattern
 Any patient with >10 cumulative colon adenomas
* Revised Bethesda criteria in supplemental slides.

13. + Lynch Syndrome: Frequent colonoscopy is
protective for a colon cancer diagnosis (but does
not prevent all cases)
Järvinen HJ, Gastroenterology 2000.
90 Lynch syndrome
patients
44 Colonoscopy (every 3 years)
46 No colonoscopy
15 years
Outcome Colonoscopy No colonoscopy
Colon cancer dx 8 (18%) 19 (41%)
Colon cancer deaths 0 4
Total deaths 4 (9%) 12(26%)

14. + Lynch syndrome polyps are often flat and
difficult to detect. Indigo carmine chromoendoscopy 45 year old
female Lynch syndrome patient (MLH1): Ascending colon polyp before
injection with saline.

15. + Overlooked polyps. Indigo carmine chromoendoscopy 45 year
old female Lynch syndrome patient (MLH1): Ascending colon polyp after
injection with saline.

16. +
2014 NCCN recommends all patients with colon
cancer be screened for Lynch syndrome by tumor
testing.
Protocol screen testing on
tumors
Immunohistochemistry
(4 Lynch syndrome genes)
Genetic testing on blood
(germline)
Colon cancer patients MCF
154
22
4
10
14 LS ptsIdentify family members

17. +
How do I refer a patient
for genetic evaluation?

18. + www.nsgc.org

19. +

20. Genetic Counseling as a medical speciality
Under Graduate 4 years + Post Graduate 2 years
Specialty n
Internists 189,587
Family medicine specialists 114,000
GI 12,398
Genetic counselors 2,573
Medical geneticists 1,509 (all time)

21. + NEXT GENeration Sequencing
Name for numerous
technologies used for
high through put
relatively low cost DNA
sequencing
 Illumina – HiSeq
 Ion torrent
Conceivable to
sequence 1 DNA base,
but usually used for
panels of genes
Ion torrent

22. +
BRCA1
BRCA2
ATM
BARD1
MSH2
MSH6 MLH1
Some of the genes included on
Next Generation panels for breast cancer
PALB2
NF1
CHEK2
CDH1
TP53
RAD50
PMS2

23. + Case presentation: Family with
breast cancer, but no BRCA1/2
mutation
30
62 40
22 2
Changes to medical
care:
Consider prophylactic
mastectomy of females
Pancreas cancer screening
22

24. +
What genetic tests I can
perform as a non
geneticist?

25. +
Genetic tests commonly ordered.
 Would not recommend ordering any Next Gen
testing: Billing and interpretation too complex.
 Hemochromatosis HFE gene test
 Indication: Elevated ferritin
 Factor V Leiden in PTE
 16% One copy: Recurrence risk VTE OR 1.56
 ?1-2% Two copies: Recurrence risk VTE OR 2.56
 At this time no convincing evidence testing changes should
change duration of therapy.
 No randomized controlled trials have shown any benefit to
testing.
Testing for Inherited Thrombophilia.Thrombosis and Hemostasis 2014.

26. + The new standard for genetic testing:
Randomized double blind controlled trials.
Discovery Medicine 2013.
51 patients with
depression
26 Treatment guided by
pharmacogenetics
25 Treatment as usual

27. +
Summary
 Cancer Family History should include cancer diagnosis and age
of diagnosis.
 Which patients should be referred for genetic counseling?
 All breast, colon and endometrial cancer patients diagnosed under
the age of 50.
 All ovarian and male breast cancer patients regardless of age.
 Newsflash: Screening of all colon cancers for Lynch syndrome is
recommended and being implemented.
 How to refer: Directory of genetic counselors at www.nsgc.org.
 Genetic testing is maturing. The efficacy of genetic tests are
being evaluated by DB RCTs. DRJ: I predict with further
development of Next Generation sequencing DB RCTs will
show utility in genetic testing in common diseases.

28. + The
End

29. +
Supplemental slides
Douglas Riegert-Johnson, MD

30. +
Revised Bethesda Criteria
 1.Colorectal cancer diagnosed under the age of 50 years of
age.
 2. Presence of synchronous, metachron ous colorectal, or other
HNPCC- associated tumors * , regardless of age.
 3. Colorectal cancer with the MSI-H † histology € diagnosed in
a patient who is less than 60 years of age.
 4. Colorectal cancer diagnosed with one or more first-degree
relatives with an HNPCC-related tumor, with one of the
cancers being diagnosed under age 50 years.
 5. Colorectal cancer diagnosed in two or more first or second
degree relatives with HNPCC-related tumor, regardless of age.
Used to identify colorectal cancers for Lynch
syndrome tumor testing.

31. +
Revised Bethesda Critieria
 * Hereditary Nonpolyposis Colorectal Cancer (HNPCC)-related tumors include
colorectal, endometrial, stomach, ovarian, pancreas, bladder, ureter and renal
pelvis, biliary tract, brain (usually glioblastoma as seen in Turcot Syndrome),
sebaceous gland adenomas and keratoacanthomas in Muir-Torre syndrome,
and carcinoma of the small bowel.
 † MSI-H = high microsatellite in stability in tumors refers to
 changes in two or more of the five NCI-recommended panels of microsatellite
markers. MSI-L = low microsatellite instability in tumors refers to changes in
only one of the five NCI-recommended panels of microsatellite markers.
 € Presence of tumor infiltrating lymphocytes, Crohn's-like lymphocytic reaction,
mucinous/signet ring differentiation, or medullary growth pattern. There was no
consensus on whether to include the age criteria
 in point (3) above; participants voted to keep age 60 years in the guidelines.
Continued

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