the evolution of genetic testing for hereditary cancer ......the evolution of genetic testing for...

The Evolution of Genetic Testing for Hereditary Cancer Susceptibility

Meagan Farmer, MS, CGC, MBA

Certified Genetic Counselor

Department of Genetics

University of Alabama at Birmingham

DISCLOSURE

Employed by UAB as clinical genetic counselor

Employed by My Gene Counsel, LLC as

Genetic Counseling Business Manager

LEARNING OBJECTIVES

Differentiate between sporadic, familial, and hereditary

cancer

Understand when to refer for genetic evaluation vs when to

test

Review cancer genetics basics and examples of hereditary

cancer predisposition syndromes

Discuss multigene panel testing using next generation

sequencing (NGS) technology

Understand various approaches to multigene panel testing

Explore the role of cancer genetic counselors and

CANCER CATEGORIES

HEREDITARY CANCER

Cancer at early ages (<50)

Multiple primary cancers in one person

Multiple cases of same or related cancers on the same

side of the family

Rare cancers

Associated benign findings (ex: polyposis)

Ethnic Background

GENETICS REFERRAL/

TESTING CRITERIA

NCCN- WHEN TO REFER TO GENETICS (BR/OV)

NCCN GENETIC TESTING CRITERIA- BR/OV

ASBS FEB 2019- Test All Breast Ca Pts?

Pros Cons

No risk assessm necessary Controversy regarding justifying

data?

Won’t miss lower penetrance

genes

Logistical challenges and risk

of misinterpretation

Won’t miss atypical

presentations

Insurance coverage

NCCN GENETIC RISK ASSESSM-

CRC/POLYPOSIS

NCCN GENETIC TESTING CRITERIA-

CRC/POLYPOSIS

WHEN TO REFER TO GENETICS

(Hampel, Bennett, Buchanan, Pearlman & Wiesner, 2014)

RISK MODELS

Models to estimate cancer risk and/or risk of detecting

a pathogenic variant in select genes

Be sure you know what factors models do/don’t

account for when selecting one

Brief review/table in Forman 2018

CANCER GENETICS

BASICS

Tumor

Suppressor

Gene(s)

PROTECTION

AGAINST TUMOR

DEVELOPMENT

DECREASED

PROTECTION

AGAINST TUMOR

DEVELOPMENT

Tumor

Suppressor

Gene(s) w/

pathogenic

variant(s)

XXX

TUMOR SUPPRESSOR GENES

TEST RESULTS

Pathogenic variant (mutation)

Likely pathogenic variant

Variant of Uncertain Significance (VUS)

Variant, Favor polymorphism

Negative

True negative

Uninformative negative

NEG RESULT INTERPRETATION

Br ca

dx 67

d.80

Br dx

45

d. 25

MVA

d.65

BRCA -

65

NEG RESULT INTERPRETATION

Br ca

dx 67

d.80

Br dx

45

d. 25

MVA

d.65

BRCA +

BRCA -

INHERITANCE

Most hereditary cancer susceptibility syndromes are

autosomal dominant

Some syndromes have significant de novo (new)

mutation rate

If significant de novo rate, lack of suspicious family

history does not rule out condition

Autosomal recessive conditions: MUTYH-

associated polyposis (MAP), CMMR-D, Fanconi

Anemia, Ataxia telangiectasia

HEREDITARY CANCER

SUSCEPTIBILITY

SYNDROME EXAMPLES

BRCA-RELATED

BREAST AND OVARIAN CANCER

Cancer BRCA1 BRCA2 Gen. Pop.

Breast 46-63% 38-53% 12%

Ovarian 34-44% 12-20% 1-2%

Prostate increased 20-30% 16%

Male Breast increased 7% 0.1%

Pancreatic 3-4% 2-5% 0.9%

Melanoma increased increased 2%

(Graeser et al, 2009) (Chen and Parmigiani, 2007) (Liede, 2004) (Breast Cancer

Linkage Consortium, 1999)

*BRCA-related Breast and Ovarian Cancer more common in Ashkenazi

Jewish individuals

51

Br Ca dx

5039d.48

32 2324

2

737570

d.6775 69

d. 77d. 77

d. 88

Br Ca

@ 40s

65 68 d. 67 d. 20s

d. 80s d. 60s

Pancreatic Ca

“TYPICAL BRCA2+ FAMILY?”

48

Br Ca

@ 46

PALB2-ASSOCIATED

BREAST AND PANCREATIC CANCER

Cancer PALB2 risk Gen. Pop.

Breast 24-58% 12-13%

Pancreatic increased < 1%

(Rahman, 2007; Antoniou, 2014; Slater, 2010)

51

Br Ca dx

5039d.48

32 2324

2

737570

d.6775 69

d. 77d. 77

d. 88

Br Ca

@ 40s

65 68 d. 67 d. 20s

d. 80s d. 60s

Pancreatic Ca

PALB2+ PALB2+

PALB2

48

Br Ca

@ 46

LI-FRAUMENI

• Core cancers

• Sarcomas of bone and soft tissue

• Premenopausal breast cancer (can be very early onset)

• Brain tumors

• Adrenocortical carcinoma

• Caused by mutations in TP53 (p53) gene

• < 20% of cases are de novo

• NCCN: TP53 testing should be considered for

women diagnosed with breast cancer < age 30

(Schneider, Zelley, Nichols & Garber, 2013; NCCN 1.2016, 2016)

LI-FRAUMENI

• High risk of early-onset cancer

• Risk of cancer ~50% by age 30, 90% by age 60 (~100% for women)

• 0-10 yrs: soft tissue sarcomas, brain tumors, ACC

• 11-20 yrs: bone sarcomas

• >20 years: breast cancer, brain tumors

• Multiple primaries

• ~ 57% risk of second cancer

• ~ 38% risk for third cancer

• Childhood cancer survivors at highest risk, likely related to treatment

of previous cancers

(Schneider, Zelley, Nichols & Garber, 2013)

2 2

d. 43

Brain tum

@ 43

48

16 17

51

Breast

@ 32

BRCA-

Colon ca

@ 50

49 46 37

75 66

31 29

TP53-

TP53+

TP53- TP53+

d. 4

Brain tum18

Leuk @ 12

TP53+

LI-FRAUMENI

Cancer MLH1/MSH2 Risk MSH6 Risk PMS2 Risk

Colon 40-80% 10-22% 15-20%

Endometrial 25-60% 16-26% 15%

Stomach 1-13% < 3% *

Ovary 4-24% 1-11% *Hepatobil. tract 1-4% Not reported *Urin. tract 1-4% <1% *

Small bowel 3-6% Not reported *CNS 1-3% Not reported *Sebac. Neop. 1-9% Not reported Not reportedPancreas 1-6% Not reported Not reported

* Combined risk 6%

LYNCH SYNDROME

Lynch-associated genes: MLH1, MSH2, MSH6, PMS2, and EPCAM

(NCCN Colorectal 2.2015)

CONSTITUTIONAL MISMATCH

REPAIR-DEFICIENCY

Biallelic pathogenic MMR variants cause CMMR-D, an AR

syndrome with childhood onset

Hematologic cancers (~30%)

Brain tumors (~50%)

GI cancers (~50% risk)

GI polyps (~30% with 10 or more)

Café-au-lait macules

Lynch-associated cancers can be seen

40% risk of second primary cancers

(Wimmer & Kratz, 2010)

d. 49

CRC dx 48

PMS2/PMS2 CMMRD

d. 65

11

Brain tum dx 10

Colon polyps

CALs

8

36

66

3835 33

PMS2/PMS2+

PMS2+ PMS2+

PMS2+

60

44

COWDEN SYNDROME

Associated cancers: breast, thyroid, endometrial, renal, colon,

melanoma

Multiple benign findings:

Characteristic skin findings

Macrocephaly

GI polyps

Thyroid lesions (ex: multinod. goiter)

Autism, ID

Pathogn: Lhermitte Duclos disease

Caused by pathogenic variants in the PTEN gene

(Eng, 2014)

COWDEN CANCER RISKS

General Population Cowden syndrome

Female breast 12% 50-85%

Male breast <1% increased

Thyroid (non-med.) 1% 10-35%

Uterine 3% 10-28%

Renal Cancer 2% 34%

Colon Cancer 6% 9%

Melanoma 2% 6%

(Eng, 2014; NSGC CA SIG, 2013)

51

Br Ca @ 50

polyposis

Macroceph.

54

Br Ca @ 45

d.48

32 29

polyposis

ID

Macrocephaly

2

73

Endo ca

@ 65

d. 25

PTEN+BRCA-

PTEN+32

polyposis

APC-

APPROACHES TO

MULTIGENE PANEL

TESTING

DISEASE-SPECIFIC PANELS

Examples

Breast cancer

Breast/Ovarian cancer

Colorectal cancer/Polyposis

Renal cancer

Allows analysis of most available genes implicated in

susceptibly to specific cancer/finding

Avoids finding variant in gene that is unlikely to explain

history

BREAST PANEL

High Risk Genes Moderate Risk Genes Newer Genes

BRCA1/BRCA2(HBOC: breast, ovary, prostate,

pancreatic)

ATM(breast, colon, pancreatic)

BARD1/BRIP1(breast, ovary)

CDH1(HDGC: breast, gastric, colon)

CHEK2(breast, colon, prostate)

RAD50/RAD51C/RAD51D(breast, ovary)

PTEN(Cowden: breast, thyroid, endometrial)

NF1(breast, neurofibroma)

FANCC(breast, pancreatic)

TP53(LFS: breast, ovary, sarcoma, brain)

NBN(breast, melanoma, NH-lymphoma,

colon)

PALB2(breast, pancreatic)

MRE11A(breast, ovarian)

COLON PANEL


MLH1/MSH2/MSH6/PMS2/

EPCAM(Lynch: colon, endometrial, ovary, etc.)

CHEK2(breast, colon, prostate, ovary)

SCG5/GREM1(colon)

APC(FAP: colon, gastric, thyroid, etc.)


POLD1(colon, endometrial)

MUTYH(MAP: colon, breast)

POLE(colon)

SMAD4/BMPR1A(JPS: colon, gastric, pancreatic)



STK11(PJS: colon, breast, pancreatic, gastric,

etc.)


51

Br Ca @ 50

polyposis

Macroceph.

54

Br Ca @ 45

d.48

32 29

polyposis

ID

Macrocephaly

2

73

Endo ca

@ 65

d. 25

PTEN+BRCA-

PTEN+32

polyposis

APC-

HIGH PENETRANCE GENE PANELS

Includes analysis of genes that cause relatively high

lifetime risk of cancer

Syndromes tested for are well-studied, many with

published management guidelines

Avoids finding pathogenic variant in gene about which

data are limited

Lower likelihood of VUS in comparison to larger panel

HIGH PENETRANCE BREAST PANEL

High Risk Genes

BRCA1/BRCA2(HBOC: breast, ovary, prostate,

pancreatic)




PALB2(breast, ovary, pancreatic)

PAN-CANCER PANELS

Includes analysis of genes implicated in several types

of cancer and polyposis

Does not require selection of individual genes or

disease-specific panel

May include analysis of genes that you would not

expect to find pathogenic variant in based on patient

personal/family history

Vary in size (20 to 80+ genes)

PAN-CANCER PANEL


BRCA1/2(breast, ovary, prostate, pancreatic)


AXIN2(breast, colon)

MLH1/MSH2/MSH6/PMS2/EPCAM(Lynch: colon, endometrial, ovary, etc.)


BARD1 (breast, ovary)

APC/MUTYH(FAP/MAP: colon, gastric, breast, etc.)

BRIP1(ovary, breast)

CDK4/POT1(melanoma)


RAD51C(ovary, breast)



RAD51D(ovary, breast)

NBN(breast, melanoma, NH-lymphoma, colon)


NF1(breast, neurofibroma, brain)

RECQL(breast)

STK11(PJS: colon, breast, pancreatic, gastric, etc.)



POLE(colon)

CDKN2A(FAMMM: melanoma, pancreatic)

GREM1 (SCG5)(colon)

VHL(VHL: neuroendocrine, renal)

HOXB13(prostate)


NTHL1(colon, polyps)

REFLEXIVE TESTING

Analyze most likely gene(s) first and reflex to multigene panel if

initial test negative

Ex: Abnl IHC testing in early-onset crc, Indicated MMR

gene(s) w/ reflex to colon panel

May answer most important question first

Ex: Breast cancer pt making sx decisions, High penetrance

breast gene panel w/ reflex to breast panel

Avoids VUS in multigene panel if initial test positive

May not be appropriate if history characteristic of multiple

conditions or suspicious cancer history in maternal and paternal

relatives

51

Br Ca @ 50

polyposis

Macroceph.

54

Br Ca @ 45

d.48

32 29

polyposis

ID

Macrocephaly

2

73

Uter ca @ 65d. 25

PTEN+BRCA-

PTEN+32

polyposis

APC-

TESTING FOR MULTIPLE CONDITIONS

JUSTIFIABLE

BOTH SIDES OF FAMILY SUSPICIOUS

d. 55

Panc ca

dx 48

40

Br ca dx 40

d. 60

Br ca

dx 35

62

BSO @ 40

d. 49

Ovar ca

dx 48

RECESSIVE CONDITIONS

Pathogenic variants in several genes routinely included in multigene panels can

also cause autosomal recessive conditions. (Implications for family planning)

High Risk Genes Moderat Risk Genes Newer Genes

BRCA1/2(breast, ovary, prostate, pancreatic)


AXIN2(breast, colon)

MLH1/MSH2/MSH6/PMS2/EPCAM(Lynch: colon, endometrial, ovary, etc.)


BARD1 (breast, ovary)

APC/MUTYH(FAP/MAP: colon, gastric, breast, etc.)

BRIP1(ovary, breast)

CDK4/POT1(melanoma)


RAD51C(ovary, breast)



RAD51D(ovary, breast)

NBN(breast, melanoma, NH-lymphoma, colon)


NF1(breast, neurofibroma, brain)

RECQL(breast)

STK11(PJS: colon, breast, pancreatic, gastric, etc.)



POLE(colon)

CDKN2A(FAMMM: melanoma, pancreatic)

GREM1 (SCG5)(colon)

VHL(VHL: neuroendocrine, renal)

HOXB13(prostate)


NTHL1(colon, polyps)

MULTIGENE PANELS

BENEFITS CHALLENGES

More cost-effective and efficient if

considering multiple syndromes.

Insurance may only allow one

genetic test per lifetime.

More expensive than one single

gene/syndrome test

May identify rarer genetic causes of

cancer in an individual/family

May identify pathogenic variant in

gene for which there is limited

info/guidance

• Tumor Spectrum

• Cancer risk estimates

• Management recommendations

May identify genetic causes in “non-

textbook” cases of well known

cancer syndromes

Inconclusive test results more likely

GENETIC COUNSELING

GENETIC COUNSELING

Genetic counseling is the process of helping people understand

and adapt to the medical, psychological and familial

implications of genetic contributions to disease. This process

integrates the following:

Interpretation of family and medical histories

Education about inheritance, testing, management,

prevention, resources and research

Counseling to promote informed choices

(Resta et al.,2006)

GENETIC COUNSELING

• Contracting

• Risk assessment

• Education

• Test selection

• Facilitating decision-making

• Informed consent

• Test coordination (insur. requirements, financ. assist)

• Results

• Medical management recommendations

• Psychosocial assessment/counseling

NSGC- FIND A GC (INCLUDING TELEMED)

UAB TELEGENETICS

Patients complete medical/family history intake paperwork

GC forwards test kits/packaging materials to referring provider

Patient has session through GoToMeeting with GC

Samples taken at local center. Lab performs insurance preverification.

GC forwards clinic note to referring provider and patient

GC calls patient with test results and recommendations and forwards

result/result letter to patient and referring provider

Allows patients access to genetic counseling without cost/time of travel

Can see patients for any cancer genetics indication

UAB Cancer Community Network members have built-in access to

telegenetics.

MY GENE COUNSEL

Genetic test result (From user or via a distribution partner)

Personalized content and interpretation

- Linked to individual gene variants

- Written by clinical genetics experts; vetted by patient advocates

- Translated into patient-friendly language

- Disease risks, management options, implications for family, support

- Third-party unbiased – not interpretation from testing company

As new data unfold, users are alerted via email or text

>>

>>

>

CONFIDENTIAL & PROPRIETARY

TAKE HOME MESSAGE

5-10% of cancers are due to underlying hereditary cause

There are many options for/approaches to cancer multigene panel

testing. Test selection, true informed consent, result interpretation,

and management is challenging.

A GC can review medical and family histories to determine:

whether testing is appropriate

who the best person is to test in a family

what test/test approach is best

how test results and family history may affect medical management of

patient and family

If you don’t have a GC at your institution:

Get one or refer to one.

Think like one

Use other resources- telegenetics, digital resources (mGC)

OTHER AREAS TO EXPLORE

Management of patients with PVs in newer/lower

penetrance genes

Potential germline implications of somatic (tumor)

testing

What to do when patients bring you DTC test results

(e.g. 23andMe) with or w/o raw data analysis (e.g.

Promethease)

Hampel, H., Bennett, R., Buchanan, A., Pearlman, R., & Wiesner, G.

(2014). A practice guideline from the American College of

Medical Genetics and Genomics and the National Society of

Genetic Counselors: referral indications for cancer

predisposition assessment. Genetics In Medicine, 17(1), 70-87.

ACMG/NSGC WHEN TO REFER

REFERENCES

Ambry Genetics. (January 2016). Hereditary Cancer Panels.

http://www.ambrygen.com/sites/default/files/web/cancer/white_papers/cancer_panels_white_paper.pdf

Antoniou, A., Casadei, S., Heikkinen, T., Barrowdale, D., Pylkäs, K., & Roberts, J. et al. (2014). Breast-Cancer

Risk in Families with Mutations in PALB2. New England Journal Of Medicine, 371(6), 497-506.

http://dx.doi.org/10.1056/nejmoa1400382

Breast Cancer Linkage Consortium, T. (1999). Cancer Risks in BRCA2 Mutation Carriers.JNCI Journal Of The

National Cancer Institute, 91(15), 1310-1316. http://dx.doi.org/10.1093/jnci/91.15.1310

Chen, S., & Parmigiani, G. (2007). Meta-Analysis of BRCA1 and BRCA2 Penetrance. Journal Of Clinical

Oncology, 25(11), 1329-1333. http://dx.doi.org/10.1200/jco.2006.09.1066

Eng, C. (2014). PTEN Hamartoma Tumor Syndrome (PHTS). University Of Washington, Seattle. Retrieved

from http://www.ncbi.nlm.nih.gov/books/NBK1488/

Graeser, M., Engel, C., Rhiem, K., Gadzicki, D., Bick, U., & Kast, K. et al. (2009). Contralateral Breast Cancer

Risk in BRCA1 and BRCA2 Mutation Carriers. Journal Of Clinical Oncology, 27(35), 5887-5892.

http://dx.doi.org/10.1200/jco.2008.19.9430

Hampel, H., Bennett, R., Buchanan, A., Pearlman, R., & Wiesner, G. (2014). A practice guideline from the

American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral

indications for cancer predisposition assessment. Genetics In Medicine, 17(1), 70-87.

http://dx.doi.org/10.1038/gim.2014.147

Jasperson, K., & Burt, R. (2014). APC-Associated Polyposis Conditions. University Of Washington, Seattle.

Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK1345/

Liede, A. (2004). Cancer Risks for Male Carriers of Germline Mutations in BRCA1 or BRCA2: A Review of the

Literature. Journal Of Clinical Oncology, 22(4), 735-742. http://dx.doi.org/10.1200/jco.2004.05.055

Muzzey, D., Evans, E., & Lieber, C. (2015). Understanding the Basics of NGS: From Mechanism to Variant

Calling. Curr Genet Med Rep, 3(4), 158-165. http://dx.doi.org/10.1007/s40142-015-0076-8

http://www.ambrygen.com/sites/default/files/web/cancer/white_papers/cancer_panels_white_paper.pdf

http://dx.doi.org/10.1056/nejmoa1400382




REFERENCES

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology.

Genetic/Familial High-Risk Assessment: Breast and Ovarian Version 1.2016. National Comprehensive Cancer

Network. [Available: http://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf]

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology.

Genetic/Familial High-Risk Assessment: Colorectal Version 2.2015. 2015;National Comprehensive Cancer

Network. [Available at www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pd]

Rahman, N., Seal, S., Thompson, D., Kelly, P., Renwick, A., & Elliott, A. et al. (2006). PALB2, which encodes a

BRCA2-interacting protein, is a breast cancer susceptibility gene. Nature Genetics, 39(2), 165-167.

http://dx.doi.org/10.1038/ng1959

Resta, R., Biesecker, B., Bennett, R., Blum, S., Estabrooks Hahn, S., Strecker, M., & Williams, J. (2006). A

New Definition of Genetic Counseling: National Society of Genetic Counselors’ Task Force Report. Journal Of

Genetic Counseling, 15(2), 77-83. http://dx.doi.org/10.1007/s10897-005-9014-3

Rizzo, J., & Buck, M. (2012). Key Principles and Clinical Applications of "Next-Generation" DNA

Sequencing. Cancer Prevention Research, 5(7), 887-900. http://dx.doi.org/10.1158/1940-6207.capr-11-0432

Schneider, K., Zelley, K., Nichols, K., & Garber, J. (2013). Li-Fraumeni Syndrome. University Of Washington,

Seattle. Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK1311/

Slater, E., Langer, P., Niemczyk, E., Strauch, K., Butler, J., & Habbe, N. et al. (2010). PALB2 mutations in

European familial pancreatic cancer families. Clinical Genetics, 78(5), 490-494.

http://dx.doi.org/10.1111/j.1399-0004.2010.01425.x

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http://dx.doi.org/10.1038/ng1959

http://dx.doi.org/10.1111/j.1399-0004.2010.01425.x

The Evolution of Genetic Testing for Hereditary Cancer Susceptibility

Meagan Farmer, MS, CGC, MBA

Certified Genetic Counselor

Department of Genetics

University of Alabama at Birmingham

the evolution of genetic testing for hereditary cancer ......the evolution of genetic testing for...

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