abcs of cancer genetics for the general ob-gyn · 2017-05-17 · 1/19/2016 1 abcs of cancer...

1/19/2016

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ABCs of Cancer Genetics for the General OB-GYN

ABCs of Cancer Genetics for the General OB-GYN

Jessica Ordonez, M.S., CGC.Certified Genetic Counselor

01/29/2016

DisclosuresI have no relevant commercial relationships to disclose.

Outline� General concepts

� Hereditary cancer syndromes associated with gynecological cancers� Common Syndromes

� Hereditary Breast and Ovarian Cancer Syndrome (HBOC)

� Lynch Syndrome

� Rare Syndromes

� Cowden Syndrome

� Peutz-Jeghers Syndrome

� New Genes

� Assessment for a hereditary cancer syndrome

� Changing landscape of genetic testing

� Case vignette

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GENERAL CONCEPTS

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Cancer

Sporadic (80%)

Familial (10%)

Hereditary (10%)

Cancer prevalence in 2012 (SEER):

~622,000 (Endometrial ca)~192,000 (Ovarian ca)

Approximate prevalence of Hereditary Endometrial/Ovarian

Ca cases:~81,000

Flags for Hereditary Cancers

� Ovarian, fallopian tube, peritoneal cancer at any age

� Uterine cancer diagnosed at age 50 or under

� Multiple primary cancers in one person

� Multiple close family members with ovarian/uterine & other cancer types in the same side of the family

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Common Features of Hereditary Cancer Genes

� NOT sex-linked

� Normal functions: tumor suppression, DNA mismatch repair,cell division checkpoint

� Heterozygous mutation status (only one gene copy, or allele,bears a mutation) usually results in increased lifetime risksfor cancer

� Homozygous mutation status (both gene copies, or alleles,bear a mutation) usually results in rare clinical features

� Inheritance is usually autosomal dominant

� High penetrance and variable expressivity

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HEREDITARY CANCER SYNDROMES

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Common Syndromes:

Hereditary Breast and Ovarian Cancer Syndrome (HBOC)

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HBOC� Caused by germline mutations in BRCA1 and BRCA2

� Accounts for as much as 20% of all invasive ovarian cancercases and the majority of hereditary breast cancer(Castera 2014, Zhang 2011)

� Associated with increased lifetime risks for breast, ovarian,prostate, pancreatic cancer (Mono-allelic mutations)

� BRCA2 bi-allelic mutations: Fanconi anemia

� Penetrance: Incomplete

� Prevalence: 1/300-1/800

� Founder mutations in specific populations (AshkenaziJewish (Unselected carrier rate 1/40; Breast ca carrier rate:~1/10), Bahamian (Unselected carrier rate: 1/1000; Breastca cases carrier rate: ~1/5)

(Akbari et al 2013, Rubinstein et al 2004, Trottier 2015)

� Genotype-phenotype correlations are complex but present

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Lifetime Cancer Risks Through Age 70 for HBOC vs.

General Population(Adapted from NCCN 2015)

Cancer

General Population

Risk BRCA1+ Risk BRCA2+ Risk

Breast 12%50-80% 40-70%

Second Primary Breast

11% Up to 64% Up to 64%

Ovarian <2% 24-40% 11-18%

Pancreatic 1% 1-3% 2-7%

Male Breast <1% 1-2% 5-10%

Prostate ~15% <30% <40%

HBOC Breast/Ovarian Management NCCN,2015

WOMEN

Breast

� Breast awareness starting at age 18

� Clinical breast exam every 6-12 mo and breast MRI annually starting at age 25

� Breast MRI and mammogram annually between ages 30-75

� For women s/p treatment, screening of the remaining breast tissue with breast MRI and mammogram annually

� Discuss risk-reducing mastectomy

� Discuss chemoprevention options

Ovarian

� Risk-reducing BSO between ages 35-40 or after completion of childbearing

� Consider screening with transvaginal US and CA-125 after age 30

� Discuss chemoprevention options

MEN

� Breast self-exam training at age 35

� Clinical breast exam every 6-12 mo starting at age 35

� Consider mammogram at age 40, then annually based on findings

HBOC Other

Management NCCN,2015

MEN

� Prostate screening starting at age 40 with annual digital rectal exams and PSA

MEN and WOMEN

� No specific guidelines for pancreatic cancer and melanoma. Personalized recommendations may exist based on family history.

� Education regarding signs and symptoms of cancers

� Patients of reproductive age:

� Discussion about options for prenatal diagnosis and assisted reproduction (Pre-Implantation Genetic Diagnosis -PGD)

� Discussion of reproductive risks related to Fanconianemia for BRCA2 positive individuals

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HBOC Genotype-Phenotype Correlations

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BRCA1

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BRCA2

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Genetic testing for BRCA1/2 genes is common practice among general

practitioners, breast/GYN specialists, and cancer genetics centers.

When to offer BRCA testing? (NCCN 2015) (1/2)

� Ovarian cancer diagnosis at any age

� Breast cancer diagnosis and any of the following:� Age at diagnosis ≤ 45� Age at diagnosis ≤ 50 AND any of the following:

� An additional breast ca primary � ≥ 1 close relative with BC at any age, pancreatic or

prostate ca (Gleason score ≥7)� Limited family history

� Any age at diagnosis AND any of the following:� ≥ 2 individuals with BC, pancreatic or prostate ca in the

same side of the family� ≥1 close relative with BC diagnosed ≤50 or ovarian ca at

any age� Ashkenazi Jewish ancestry� Prior history of ovarian/fallopian tube cancer

� Triple negative histopathology diagnosed at ≤ age 60� Male breast ca

When to offer BRCA testing? (NCCN 2015) (2/2)

� Prostate cancer diagnosis (Gleason score ≥7) AND ≥ 1 close blood relative with any of the following:� Breast cancer ≤ age 50� Invasive ovarian cancer

� Pancreatic cancer� Prostate cancer (Gleason score ≥7)

� Pancreatic cancer diagnosis AND any of the following:� Ashkenazi Jewish ancestry

� ≥ 1 close blood relative with any of the following:

� Breast cancer ≤ age 50� Invasive ovarian cancer

� Pancreatic cancer

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Common Syndromes:

Lynch Syndrome

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Lynch Syndrome� Generally caused by mutations in DNA-mismatch-repair genes

(MLH1, MSH2, MSH6, PMS2) and EPCAM gene deletions

� Accounts for ~1% of all endometrial cancer cases and 1-3% of all colorectal cancer cases

� Associated with increased lifetime risks for endometrial, ovarian, colorectal, stomach cancer (Mono-allelic mutations)

� Bi-allelic mutations: Constitutional Mismatch Repair Deficiency -CMMRD

� Gene-dependent lifetime cancer risks and surveillance recommendations


� Prevalence: ~1/400

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Cancer

General Population

Risk

MLH1/MSH2 MSH6 PMS2

RiskMean Age of Onset

Risk

Mean Age of

onset

RiskMean Age of onset

Colorectal ~6% 40-80%44-61

yr10-22% 54 yr 15-20%

61-66 yr

Endometrial ~3% 25-60%48-62

yr16-26%* 55 yr 15% 49 yr

Ovarian ~2% 4-24% 43 yr 1-11% 46 yr * 42 yr

Stomach <1% 1-13% 56 yr <4% 63 yr *70-78

yr

Other cancers with increased lifetime risks <10% primarily associated with MLH1/MSH2 mutations:

Hepatobilliary and urinary tract, small bowel, brain/CNS, sebaceous neoplasms,

pancreatic.

Lifetime Cancer Risks Through Age 70 for Lynch Syndrome

vs. General Population(Adapted from NCCN 2015)

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� Prophylactic hysterectomy and bilateral salpingo-oophorectomy(TAH/BSO) should be considered by women who have completed child-bearing

� Patient awareness about dysfunctional bleeding (evaluation needed)

� Annual office endometrial sampling and/or ultrasound is optional

� Annual or semi-annual routine ovarian screening with transvaginal US and CA-125 is optional

� Increased breast cancer risk? Currently, average-risk breast cancer screening recommendations are supported

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Lynch

SyndromeEndometrial/

Ovarian Management NCCN,2015

� GI/GU/CNS:

� Colonoscopies every 1-2 yr starting at age ~20 (MLH1/MSH2/EPCAM) or ~25 (MSH6/PMS2)

� Consider annual urinalysis starting at ages 25-30

� Consider annual endoscopy with extended duodenoscopy every 3-5 yr starting at ages 25-30

� Annual physical/neurological exam starting at ages 25-30


� Discussion about options for prenatal diagnosis and assisted reproduction (Pre-Implantation Genetic Diagnosis -PGD)

� Discussion of reproductive risks for CMMRD

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Lynch

SyndromeOther


Lynch Syndrome� Germline diagnostic molecular testing

� Sequencing and deletion/duplication analysis of MMR genes associated with LS

� Screening tests (colon and endometrial tissue):

� IHC: staining tumor tissue for protein expression of the 4 MMR genes associated with Lynch Syndrome.

� Normal IHC result: All 4 MMR proteins are normally expressed (LS unlikely)

� MSI: PCR analysis of microsatellite markers to assess for MMR function

� MSI-H (microsatellite instability-high) tumors: Changes in 2 or more of the 5 microsatellite markers are detected (LS likely)

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Many centers perform IHC and sometimes MSI in all newly diagnosed CRC and endometrial cancer cases regardless of family history

(Universal Tumor Screening)

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Rare Syndromes:

Cowden Syndrome

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Cowden Syndrome� Caused by germline mutations in the PTEN tumor suppressor

gene (New gene: KILLIN)

� Nomenclature: Cowden Syndrome is part of a clinicalspectrum associated with PTEN mutations

(PTEN Hemartomatous Tumor Syndrome -PHTS)

� Highly variable presentation associated with benign findingsand increased risk for malignancy (Relevant clinical scenarios:GYN, pediatrics, neurology, GI, oncology, breast surgery,dermatology…)


� Prevalence: ~1/200,000 (underestimate)

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Clinical Dx: Major Criteria

� Breast cancer

� Endometrial cancer

� Thyroid cancer

� Multiple GI hemartomas or ganglioneuromas

� Macrocephaly

� Skin lesions (macular pigmentation of glans penis, trichilemmomas, etc.)

Clinical Dx: Minor Criteria

� Autism spectrum disorder

� Colon cancer

� Intellectual disability

� Lipomas

� Renal cell carcinoma

� Vascular anomalies

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CancerGeneral Population

Risk PTEN Risk

Breast ~12% 25-50%*

Endometrial ~3% 5-10%*

Thyroid (Non-medullary)

~1% 3-10%*

Colorectal ~6% 9-16%

Lifetime Cancer Risks Through Age 70 for Cowden

Syndrome vs. General Population

(Adapted from NCCN 2015v.2)

*Risks from other studies are higher• Breast cancer: 75-85%

• Thyroid: 35-38%• Endometrial: up to 28%

• Renal: up to 34%

Tan et al 2012; Riegert-Johnson DL1 et al 2010; Buvien V1 et al 2013 (Ascertainment bias)

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Cowden

SyndromeBreast/

Endometrial Management NCCN,2015

WOMEN

Breast

� Breast awareness starting at age 18

� Clinical breast exam every 6-12 mo starting at age 25

� Breast MRI and mammogram annually between ages 30 or 35-75

� For women s/p treatment, screening of the remaining breast tissue with breast MRI and mammogram annually

� Discuss risk-reducing mastectomy

Endometrial

� Consider annual endometrial sampling and/or ultrasound starting at age 30-35

� Patient awareness about dysfunctional bleeding

� Discuss risk-reducing hysterectomy

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Cowden

SyndromeOther


MEN and WOMEN

� Annual comprehensive physical exam starting at age 18 with particular attention to thyroid exam

� Annual thyroid ultrasound starting at the time of diagnosis

� Colonoscopies every 5 yr starting at age 35 unless symptoms or a personal history of polyps are present

� Consider renal ultrasound every 1-2 yr starting at age 40

� Consider dermatology management

� Consider psychomotor assessment in children at diagnosis and brain MRI if there are symptoms

� Education regarding the signs and symptoms of cancers


� Discussion about options for prenatal diagnosis and assisted reproduction (Pre-Implantation Genetic Diagnosis –PGD)

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Rare Syndromes:

Peutz-Jeghers Syndrome

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Peutz-Jeghers Syndrome � Caused by germline mutations in

STK11

� Variable clinical presentation associated with benign features and increased risk for malignancy (Possible clinical scenarios: GYN, GI, oncology, breast surgery….). Clinical diagnostic criteria are available.

� Penetrance: Complete

� Prevalence:

1/25,000- 1/280,000

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CancerGeneral Population

Risk STK11 Risk

Breast ~12% 45-50%*

Colorectal ~6% 39%

Stomach ~1% 29%

Small intestine <1% 13%

Pancreas ~1% 11-36%

Ovarian (Non-epithelial)

~2% 18-21%

Cervical ~1% 10%

Endometrial ~3% 9%

Lung ~7% 17-17%

Lifetime Cancer Risks Through Age 70 for Peutz-Jeghers

Syndrome vs. General Population

(Adapted from NCCN 2015)

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� Mammogram and breast MRI annually starting at age 25

� Clinical breast exams every 6-12 mo starting at age 25

� Pelvic exam and PAP-smear annually starting at age 18-20

� Consider annual transvaginal US starting at age 18-20

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Peutz-

JeghersBreast/GYN Management NCCN,2015

MEN and WOMEN

� Colonoscopy and upper endoscopy every 2-3 yr starting in the late teens

� Magnetic resonance cholangiopancreatography or endoscopic US every 1-2 yr starting at age 30-35

� Small bowel visualization starting at age 8-10 (CT/MRI enterography baseline at age 8-10 with follow up interval based on findings but at least by age 18, then every 2-3 yr)

� Smoking cessation

� Education regarding signs and symptoms of cancers


� Discussion about options for prenatal diagnosis and assisted reproduction (Pre-Implantation Genetic Diagnosis –PGD)

Peutz-

JeghersOther



New genes

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New Genes

� BRIP1, RAD51C, RAD51D: 10-15% lifetime risk for ovarian cancer

� SMARCA4 (Small cell ovarian carcinoma, hypercalcemictype- No lifetime risk estimates yet available)

� DICER1 (Sex-cord and stromal ovarian tumors- No lifetime risk estimates yet available)

� POLD1 (Endometrial cancer and clinical presentation similar to Lynch Syndrome- No lifetime risk estimates are yet available)

� PALB2? CHEK2?

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ASSESSMENT FOR A HEREDITARY CANCER SYNDROME

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Assessment for a Hereditary Cancer Syndrome

� Ideally performed by professionals with expertise in cancer genetics (genetic counselors, physicians, advanced practice nurses)

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Pre- and Post-Test Counseling

� Targeted medical history intake� Detailed family history intake� Education� Informed consent and decision-making/Counseling� Test facilitation � Results disclosure and follow-up� Identification of available support resources

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Targeted medical history intake

� Cancer history (Pathology, age at diagnosis, laterality, treatment)

� Screening and relevant findings (Breast/GYN/GI)

� Carcinogen exposure (i.e. mantle radiation)

� Reproductive history

� Hormone and oral contraceptive use

� Dermatological features commonly associated with hereditary cancer syndromes

� Ethnicity

� Genetic testing history (Year performed, name of the test, name of the laboratory, copy of the report!)

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Detailed family history intake

� Three generation pedigree to include first-, second-, and third-degree relatives (FDR, SDR, TDR, respectively)

� FDR: parents, siblings, children

� SDR: grandparents, uncles, aunts, nieces, nephews, grandchildren, half-siblings

� TDR: first cousins, great-grandparents, great-aunts, great-uncles, great-grandchildren

� Types of cancer, laterality, age at diagnosis

� Pay attention to risk assessment confounders!

(Adoption, early death, TAH/BSO for reasons

unrelated to cancer)

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Education

� Basic genetics (Genes, inheritance, penetrace, variable expressivity)

� Risk factors for a hereditary cancer susceptibility

� Hereditary cancer syndromes of interest

� Testing strategies

� Genetics Information and Non-Discrimination Act (GINA)

Informed consent and decision-making/Counseling

� Possible results and plan to manage them

� Timing

� Coping strategies and support system

� Impact of results on personal health and relationships

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Test facilitation

� Choosing a laboratory

� Clinical appropriateness of the test

� Cost effectiveness

� Turn-around time

� Completing appropriate documentation

� Communicating regularly with testing laboratory and insurance company about documentation and authorizations


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Results disclosure and follow-up

� In-person/telephone disclosure

� Referral to genetic specialists for complex results should be considered if a genetic specialist is unavailable during pre-test counseling

� Referral to research/national registries available for patients with positive results or variants of unknown significance


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Identifying support resources

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CHANGING LANDSCAPE OF GENETIC TESTING

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Changing Landscape of Genetic Testing

� Multi-gene panel testing was introduced in 2012 in clinical practice (Technological advancements parallel to ethical/legal changes)

� Syndrome-driven and multi-gene panel testing options are currently widely used

� General indications to consider panel testing:� Personal and family history strongly

suggestive of a hereditary component� The personal/family history could be

explained by 2 or more hereditary cancer syndromes

� Multi-gene panels, though popular, are not currently the standard of care

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Multi-gene Panel Testing

Benefits

• Increased diagnostic yield

• Minimized testing fatigue

• May open unforeseen opportunities for prevention

• Cost effectiveness (*)

Challenges

• Increased likelihood of variants of unknown significance

• Limited clinical utility for moderate-risk genes

• Incidental results

• Wide variation among testing laboratories

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Professional Statements on Multi-gene Panel Testing

National Comprehensive Cancer Consortium Network

(NCCN) (2015)“Multi-gene testing is ideally offered in the context of

professional genetic expertise for pre- and post-test counseling”

Society of Gynecologic Oncology (SGO) (2014)

“Advantages of cancer gene panels include decreased cost and improved efficiency of cancer genetic testing by reducing the time involved, number of patient visits, and number of tests sent… Involvement of a cancer genetics professional is

important to help order the most appropriate genetic test and to interpret the results.”

CLINICAL VIGNETTES

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Case #1� 26 yo G1P1 premenopausal Hispanic female

� Referred by GYO for consideration of multi-gene panel testing due to a personal and family history of cancer

� Personal history of an endometroid adenocarcinoma of the right ovary diagnosed at 23

� The patient is s/p unilateral salpingo-oophorectomy and omentectomy.

� Followed with CT scan, transvaginal US, and CA-125 every 3 mo

� BRCA1/2 sequencing and deletion analysis done in early 2015 with negative results

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Case #1� Topics of discussion during pre-test counseling session:

� Flags for a hereditary cancer susceptibility syndrome (targeted assessment)

� Availability of multi-gene panel testing

� Differences between high- and moderate-risk gene mutations

� Potential impact of positive, negative results, or variants of unknown significance

� Increased lifetime risk for breast cancer (23-30%)

(Tyrer-Cuzick v6, v7)

� Test of choice:

� 22-gene breast and GYN cancers panel

� Results?

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“Negative result. No Pathogenic sequence variants or

deletions/duplications identified.”

CONSIDERATIONS FOR POST-TEST COUNSELING

• What does a negative result mean in this context?• Should genetic testing be considered in other family

members?• What does risk-management entail for unaffected family

members?

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Case#2

� 54 yo G2P2 postmenopausal Middle Eastern female

� Referred by her breast surgeon due to a family history of ovarian cancer

� Followed by GYN with yearly mammograms, transvaginalUS and CA-125 screening every 6 mo

� Menarche at 12; menopause at 52

� No history of OCP use

� No history of hormonal therapy

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Case #2

� Topics of discussion during pre-test counseling session:

� Limitations of genetic testing in unaffected individuals

� Availability of syndrome-driven and multi-gene panel testing

� Differences between high- and moderate-risk gene mutations

� Potential impact of positive, negative results, or variants of unknown significance

� GINA

� Test of choice:

� 25-gene cross-cancer panel

� Results?

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“Positive- Clinically significant mutation identified.

BRIP1, dup exon 17 (Heterozygous)This patient has BRIP1-associated

Cancer Risk.”


• What does a positive result mean in this context?• Should genetic testing be considered in other family

members?• What does risk-management entail for unaffected family

members?• Discuss importance of testing affected sister

Case #2

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“Negative- No clinical significant mutation identified”

• Affected sister presents for genetics evaluation• 25-gene cross cancer panel ordered• Result?...


• Is there room for confirmatory testing?• New samples sent to original laboratory• Blind samples sent to second laboratory

• Should genetic testing for the BRIP1 mutation be considered in other family members?

• What does risk-management entail for unaffected family members who test negative for the BRIP1 mutation?

Clinical Pearls

� GYN/GYO MDs and allied health professionals have a major role in identifying patients at increased risk of inherited cancer syndromes

� New genetic testing strategies may bring about complex test results

� Genetic testing availability is continuously changing

� Genetics follow-up is important in some cases

� The hereditary bases of GYN cancers is an unfinished story

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Thank you!

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Baptist Children’s HospitalBaptist Hospital Doctors Hospital

Miami Cardiac &Vascular Institute

Homestead Hospital Mariners Hospital

West KendallBaptist Hospital

Baptist Outpatient Services

South Miami Hospital

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South Miami Hospital West Kendall Baptist Hospital Baptist Outpatient Services Baptist Health Medical Group

Doctors Hospital Baptist Hospital of Miami Homestead Hospital

Miami Cardiac & Vascular Institute Miami Cancer Institute

Mariners Hospital

Baptist Children’s Hospital

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References� Akbari M, Donenberg T, Lunn J, Curling D, Turnquest T, Krill-Jackson E,

Zhang S, Narod S, Hurley J."The spectrum of BRCA1 and BRCA2 mutations in breast cancer patients in the Bahamas." Clin Genet. 2013 Mar 4.

� Ballinger, L. L. Hereditary gynecologic cancers. Obstetrics and Gynecology Clinics of North America 39, 165–181 (2012).

� Bellcross, C. A. "The changing landscape of genetic testing for hereditary

breast and ovarian cancer." Current problems in cancer. 2013; 38(6): 209-15.

� Bubien, V. et al. High cumulative risks of cancer in patients with PTEN hamartoma tumour syndrome. Journal of Medical Genetics 50, 255–263 (2013).

� Castéra, L. et al. Next-generation sequencing for the diagnosis of hereditary breast and ovarian cancer using genomic capture targeting multiple candidate genes. European Journal of Human Genetics 22, 1305–1313 (2014).

� Donenberg T, Lunn J, Curling D, Turnquest T, Krill-Jackson E, Royer R, NarodSA, Hurley J. A high prevalence of BRCA1 mutations among breast cancer patients from the Bahamas. Breast Cancer Res Treat. 2011 Jan;125(2):591-6

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� Eng C. PTEN Hamartoma Tumor Syndrome (PHTS) 2001 Nov 29 [Updated2014 Jan 23]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors.GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle;1993-2016. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1488/

� Kapoor, N. S. et al. Multigene Panel Testing Detects Equal Rates ofPathogenic BRCA1/2 Mutations and has a Higher Diagnostic Yield Comparedto Limited BRCA1/2 Analysis Alone in Patients at Risk for Hereditary BreastCancer. Annals of Surgical Oncology 22, 3282–3288 (2015).

� Kohlmann W, Gruber SB. Lynch Syndrome. 2004 Feb 5 [Updated 2014 May22]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews®[Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016.Available from: http://www.ncbi.nlm.nih.gov/books/NBK1211/

� LaDuca, H. et al. Utilization of Multigene Panels in Hereditary CancerPredisposition Testing. Next Generation Sequencing in Cancer Research,Volume 2 459–482 (2015). doi:10.1007/978-3-319-15811-2_26

� Lancaster, J. M., Powell, C. B., Chen, L. & Richardson, D. L. Society ofgynecologic oncology statement on risk assessment for inheritedgynecologic cancer predispositions. Gynecologic Oncology 136, 3–7(2015).

� McGarrity TJ, Amos CI, Frazier ML, et al. Peutz-Jeghers Syndrome. 2001Feb 23 [Updated 2013 Jul 25]. In: Pagon RA, Adam MP, Ardinger HH, et al.,editors. GeneReviews® [Internet]. Seattle (WA): University of Washington,Seattle; 1993-2016. Available from:

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� Miesfeldt, S., Lamb, A. & Duarte, C. Management of genetic Syndromespredisposing to gynecologic cancers. Current Treatment Options inOncology 14, 34–50 (2013).

� National Comprehensive Cancer Network. NCCN Clinical PracticeGuidelines in Oncology: Genetic/Familial High-Risk Assessment: Breastand Ovarian. V.2.2015. Accessed at www.nccn.org on 01/19/2016.

� National Comprehensive Cancer Network. NCCN Clinical PracticeGuidelines in Oncology: Genetic/Familial High-Risk Assessment:Colorectal. V.2.2015. Accessed at www.nccn.org on 01/19/2016.

� Rebbeck TR, Mitra N, Wan F, et al. Association of Type and Location ofBRCA1 and BRCA2 Mutations With Risk of Breast and Ovarian Cancer.JAMA. 2015;313(13):1347-1361. doi:10.1001/jama.2014.5985.

� Riley BD, Culver JO, Skrzynia C et al. (2011) Essential elements of geneticcancer risk assessment, counseling, and testing: Updatedrecommendations of the National Society of Genetic Counselors. Journal ofGenetic Counseling [epub ahead of print]. Available atwww.springerlink.com/content/ax33415046874623/.

� Rubinstein WS (2004) Hereditary breast cancer in Jews. Fam Cancer3:249–257. doi:10.1007/s10689-004-9550-2

� Tan, M.-H. et al. Lifetime cancer risks in individuals with Germline PTENmutations. Clinical Cancer Research 18, 400–407 (2012).

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� Trottier, M., Lunn, J., Butler, R., Curling, D., Turnquest, T., Francis, W.,Halliday, D., Royer, R., Zhang, S., Li, S., Thompson, I., Donenberg, T.,Hurley, J., Akbari, M. R. and Narod, S. A. (2015), Prevalence of foundermutations in the BRCA1 and BRCA2 genes among unaffected womenfrom the Bahamas. Clinical Genetics. doi: 10.1111/cge.12602

� Walsh, T. et al. Mutations in 12 genes for inherited ovarian, fallopiantube, and peritoneal carcinoma identified by massively parallelsequencing. Proceedings of the National Academy of Sciences 108,18032–18037 (2011).

� Walsh, T. et al. Detection of inherited mutations for breast and ovariancancer using genomic capture and massively parallel sequencing.Proceedings of the National Academy of Sciences 107, 12629–12633(2010).

� Zhang, S. et al. Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. GynecologicOncology 121, 353–357 (2011).

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