Dr. Riegert-Johnson's presentation for Mayo Clinic's Center for Individualized Medicine Grand Rounds.

1. 2020 UPDATE
HEREDITARY CANCER
SYNDROMES
Douglas Riegert-Johnson, MD
Clinical Genomics and Gastroenterology

2. Conflicts of Interest
No conflicts of interest to report.
No off label drug use reviewed.

3. 2020 is the year of the HCS! “MORE.”
More testing.
More different tests.
More diagnoses.
More natural history data.
More treatments.

4. 2020 is the year of the HCS!
• HCS Background - HCS at Mayo Clinic Florida
• Diagnosis
• Panel testing
• Accessibility
• Accuracy (DNA + mRNA sequencing)
• Clarifying the natural history
• PALB2
• Lynch syndrome
• Pheochromocytoma and paraganglioma syndromes
• Management

5. Hereditary Cancer Syndromes (HCS)
• MCs INTERCEPT trial recently tested about 3,000 newly
diagnosed cancer patients for a HCS. PI Dr. Samadder (MCA)
will present those results at a CIM grand rounds later this year.
• HCS are a diverse group of about 100 disorders predisposing
to both benign and malignant tumors. HCS are each
associated with germline pathogenic variants in a single gene
(eg BRCA1). They are usually associated with an increased
risk of cancer from at least two different organ systems. Eg
Lynch syndrome – colon and uterine.
• The population prevalence is about 2%, in individuals with
cancer the overall prevalence is about 10%.

6. High risk HCS (OR >4-5)
are less common than intermediate risk HCS.
High risk syndromes (BRCA1/2) about 1/300.
Intermediate risk syndrome (CHEK2) 1%
PDQ cancer summaries
https://www.ncbi.nlm.nih.gov/books/NBK65761/

7. Hereditary Cancer Syndromes
at Mayo Clinic Florida.
HCS are seen in many clinics, and not all patients are seen in
Cancer Genetics. Cancer Genetics has seen about 800 patients
with about 60 different diagnoses in 12 years.
Mayo Clinic Florida
Cancer Syndrome Patient Panel 779
Lynch syndrome 161
Familial Adenomatous Polyposis 156
BRCA1/2 mutation carriers 127
Peutz Jeghers syndrome 36
CHEK2 38

8. Some HCS are very rare.
Sample of HCS were
Only 1 or 2 patients have been seen (2008-2020)
Gastric adenocarcinoma and proximal
polyposis of the stomach
BAP1
Dyskeratosis congenita HOXB12
RAD51D CEBPA
MITF AXIN2
MODY type 3 NTHL1 Biallelic mutations
Familial esophageal cancer RAD50
Schwanomatosis NBN
Familial CLL CHEK2 pathogenic variant homozygous
Rothmund-Thompson Syndrome Familial esophageal cancer

9. 60
87
115
50
0
20
40
60
80
100
120
140
The number of new HCS patients
increases year on year
2017 20192018 2020

10. DIAGNOSIS
Expanded indications for testing
Accessibility
DNA + RNA sequencing

11. Who to test? Offer testing to all.
In general, clinical decision tools do not have the power to a pathogenic
HCS variant. Said another way, they can not identify a group of patients
with less than a 1% chance of having a positive test.

12. What test to order?
A Large number of Genes.
0
2
4
6
8
10
12
14
16
18
20
Small No. Genes Medium No.
Genes
Large No. Genes
Percentage of Patients with Pathogenic Variant
Large Panel
• Diagnoses more patients
• No difference in OP, TAT
• Lab is probably doing large panel. Easier to have the same workflow on all
patients

13. Case 2020:
Value of Large
HCS Panel.
2 PVS!
• 37 yo female with Stage
IIB breast adenoCA
• BRCA2 PV and
hereditary Pheo/Para
SDHD PV
• PET/CT – Right cartiod
body bifurcation uptake

14. Accessibility
• Accessibility.
• Cost
• Most cancer patients have no out of pocket.
• Out of pocket maximum is $250 for most tests.
• Availability to an ordering provider.
• Color.com and others offer HCS panel testing via mail (saliva kit)
ordered by their providers ($250).
• As testing is ordered by provider after patient initiation, FDA approval is
not needed. Direct to consumer testing (23andme) does need FDA
approval.
• >200,000 ? HCS tests / year
Cynthia Nelson
Multi-Gene Panel Testing of 23,179 Individuals . .
Journal of Molecular Diagnostics 2019

15. RNA testing allows interpretation of splice site variants
and discovery of deep intronic pathogenic variants.
PMS2 c.11C>G
VUS->VLP
ATM c.2466A>G
VUS->VLB
ATM c.3065T>G
VUS->VLP
BRCA2 c.475+4DELT
VUS->VLP
BRCA1 c.81-9C>G
VUS->Pathogenic
BRCA1 c.5152+6T>G
VUS->Pathogenic
APC c.933+829A>G
Pathogenic
ATM
c.2466+1552G
>C
VLP
ATM c.497-2661A>G
VLP
Splicing profile by capture RNA-seq identifies
pathogenic germline variants in tumor
suppressor genes; NPJ Precis Oncol. 2020

16. DNA testing + RNA sequencing
• 1000 clinical samples for testing of 18 tumor suppressor
genes
• DNA testing> 77 pathogenic or likely pathogenic
• DNA + RNA testing> 84 pathogenic or likely pathogenic
(+9.4%).
• Results are used to improve interpretation of follow up
results and also the DNA testing (deep intronic mutations
are added to regular DNA panel)
• RNA testing has not been validated on saliva.
Landrith
Precision Oncology 2020

18. CLARIFYING THE
NATURAL HISTORY
Lynch syndrome
PALB2
Pheochromocytoma and paragangliomas syndromes (SDHx)

19. The Prospective Lynch Syndrome
Database
• About 50,000 years of patient follow up.
• Clinical scenario:
30 yo MSH2 carrier has read that Lynch syndrome is
associated with urinary tract cancers and asks about
having a urinalysis?
Pål Møller
The Prospective Lynch Syndrome Database reports enable evidence-based personal precision health care
Hereditary Care Clin Pract 2020

21. Ampullary Cancer
Prostate cancer
Breast cancer
GBM

22. May 2020 “… correlations between
PALB2 mutations and increased
risks of ovarian cancer, pancreatic
cancer, prostate, and male breast
cancer have been suggested;
however these exact risks are
subject to further study.”

24. SS risk for female breast cancer, male breast
cancer, ovarian cancer and pancreas ID.

25. Germline mutations are not uncommon in
individuals with Pheo/Para
• About 30% of patients will have a germline mutation in
one of ten genes.(Under 10 yo – 90%, Over 60 – 20%)
• In adults, SDH family genes are the most commonly
mutated.
Hartmut Newman and others.
Pheochromocytoma and Paraganglioma.
NEJM 2019

26. Clinical Scenario.
• 39 yo man
• Age 33 resection of HNP
• HCS panel testing found the SDHD P81L founder mutation
• Clinical question,
• What is the risk of a pheochromocytoma or intra adbominal
paraganglioma? How often does he need follow up imaging of the
abdomen?

27. P81L SDHD pathogenic variant carriers are at low risk for
pheochromocytomas and abdominal paragangliomas.
Bayley and others.
Variant type is associated with disease characteristics in SDHB …
J Med Genetics 2020

28. IMPROVED THERAPY

29. Endoscopic Management of
Familial Adenomatous Polyposis
• FAP is associated intestinal polyps, especially
colon polyps, thyroid cancer, desmoid tumors,
osteomas and other tumors.
• Attenuated FAP (aFAP)
• Less than 100 adenomatous polyps.
• Usual treatment for aFAP is a subtotal colectomy (rectum left in
place).
• Classic FAP
• More than 100 adenomatous polyps
• Usual treatment is a total colectomy usually with a J pouch (“new”
rectum created out of ileum.)

30. Endoscopic Management of
Familial Adenomatous Polyposis
• 95 FAP patients who refused surgery managed
endoscopically for mean of 5.1 years.
• Removed 55,701 polyps.
• No invasive cancers.
• 2 patients sent to surgery for carpeting polyposis not
amenable to endoscopic management.
Hideki Ishikawa
Endoscopic Management of Familial Adenomatous Polyposis in Patients Refusing Colectomy
Endoscopy 2016

32. Endoscopic management of AFAP
23 yo (2011) year old patient presented
with retro orbital osteoma.
Year Number of colon polyps removed
2011 30
2012 14
2013 26
2014 15
2015 15
2016 24
2017 31
2018 7 (poor preparation)
2019 35

33. Clinical Scenario
• 43 woman with both BRCA1 and CHEK2 pathogenic
variants. Her mother died of ovarian cancer at 59 years of
age and a maternal aunt died of ovarian cancer at age 50
years of age.
• She has declined RR (risk reducing) BSO due to
concerns of the adverse effects.
• What to do?

34. For BRCA1/2 patients, BS/DO vs RRSO
• BS/DO= Bilateral salpingectomy with delayed
oophorectomy
• RRSO= Risk reducing salpingectomy/oophorectomy
• Current 3.2019 NCCN recommendations are,
• BRCA1 RRSO age 35-40
• BRCA2 RRSO age 40-45

35. Ovarian malignancies in BRCA1/2 carriers usually
originate from ends of the fallopian tubes.
• 2001, 6 of 12 women with BRCA and other ovarian cancer
predispositions undergoing RRS were found to have
dysplasia at the tips of the fallopian tubes (fimbria).
Piek JM.
Dysplastic changes in prophylactically removed fallopian tubes.
J Pathol (2001)
Patricia Shaw
Candidate Serous Cancer Precursors in Fallopian Tube Epithelium of BRCA1/2 Mutation Carriers
Mod Path 2009
Iiana Cass
A Cautious View of Putative Precursors of Serous Carcinomas in the Fallopian Tubes of BRCA Mutation Carriers
Gyne Oncol 2014
Michael Callahan
Primary Fallopian Tube Malignancies in BRCA-Positive Women Undergoing Surgery for Ovarian Cancer
Journal of Clinical Oncology 2007
Center Year Number of
BRCA1/2 BSO
% with fallopian tube
neoplasia
Toronto 2009 176 8
Brigham & Women’s 2007 122 5.7
Cedars Sinai 2014 78 12

37. Final Results Pending From Prospective Trials
of Risk Reducing Salpingectomy
and Delayed Oophorectomy
Participants choose either standard RRSO within current guidelines (at
age 35-40 years for BRCA1 carriers, age 40-45 years for BRCA2
carriers)
or the innovative RR salinpectomy approach followed by RRO
at up to 5 years after the current guideline age (at age 40-45 years for
BRCA1 carriers, age 45-50 years for BRCA2 carriers).
• WISP - MD Anderson
• 183 patients with BRCA1/2 or other ovarian cancer predisposition genes
• TUBA trial- Launched at 13 Dutch oncology centers in 2015
• Plans to enroll 510 BRCA1/2 mutation carriers.
• NCCN 3.2019 “BS/DO is not the standard of care, as some risk is still
present and in women who have not had RR breast surgery
oophorectomy decreases cancer risk.”

38. Clinical Scenario
• 43 woman with both BRCA1 and CHEK2 pathogenic
variants. Her mother died of ovarian cancer at 59 years of
age and a maternal aunt died of ovarian cancer at age 50
years of age.
• She has declined RR (risk reducing) BSO due to
concerns of the adverse effects.
• What to do?
Patient opted for risk reducing bilateral salpingectomy, with
delayed oophorectomy.

39. Tuberous
Sclerosis
• 34 yo woman with
TSC and numerous
renal
angiomyolipomas,
two > 5 cm.

41. FUTURE: Colon cancer rate still about
1% / year having colonoscopy. Why?

42. 2020 is the year of the HCS! MORE.
• More testing
• Cheaper
• More different tests.
• Large panels.
• RNA testing.
• More diagnoses.
• More natural history data.
• Completion of large studies.
• More treatments.

43. END
Thank you.