Clinical Cancer Genetics

Lisen Axell, MS, CGC University of Colorado Cancer Center

•  Individuals with cancer – Making surgical decisions (lump vs. mast) – Making treatment decisions (XRT) – Concerns for additional cancers

•  Individuals with no cancer – Assessing risk for cancer(s) – Making screening/surgical decisions – Making lifestyle decisions

•  Likelihood: –  Developing cancer based on family history –  Inherited cancer syndrome –  Detectable mutation

•  Medical management recommendations •  Recommendations for at risk family members •  Discussion of genetic testing and if patient wants

to pursue testing

Family History

•  BOTH SIDES OF THE FAMILY

•  At least 3 generations •  Establish age at diagnosis •  Clarify the exact diagnosis

(pathology reports can be invaluable)

•  Determine the number of family members without cancer

Hereditary Cancer Patterns •  Breast, ovary, prostate cancer, pancreas •  Colon/GI, uterine and ovarian cancer

•  Melanoma and pancreatic cancer •  Gastrointestinal polyposis •  Brain tumors and kidney cancer •  Breast, thyroid and uterine cancer •  Different endocrine gland tumors •  Breast and childhood cancers

Cancer Risk Based on Family History

Sporadic 70%

Familial 25%

Hereditary 5%

“Sporadic” Cancer

Sporadic 70%

Familial 25%

Hereditary 5%

Dx 73

Dx 78

43

“Sporadic” Cancer

•  Onset later in life •  No clear pattern on one side of family •  No inherited gene •  Family members have a small if any increase in

cancer risk

“Familial” Cancer

Sporadic 70%

Familial 25%

Hereditary 5%

Dx 60

Dx 78

43

Dx 70

“Familial” Cancer

•  Clustering of cancer but no clear pattern •  Typically later in life •  May be due to:

–  inherited unknown genes (less penetrant) –  environment –  combination of the two

All cancer is genetic but only a small portion is inherited

Inherited Cancer

Sporadic 70%

Familial 25%

Hereditary 5%

Dx 35

43 Dx 45

Dx 55

Dx 65

Inherited Cancer

•  Cancer in young individuals (less than age 50) •  Many generations affected with the same type or

related cancer on the same side of the family •  Two primary cancers or two related cancers in same

individual

•  “Cancer on the father’s side of the family doesn’t count.”

•  “Even if I have the genetic mutation, I can’t do anything about it”

•  “Cancer runs in my family, so I already know that I have the genetic mutation”

•  “I‘ve already had cancer, so knowing whether or not I have the genetic mutation isn’t important for me”

Myths about Inherited Cancer

• Half of all women with hereditary risk inherited it from their father. • Early detection and risk reduction

• Only a 50% risk to inherit a family mutation

• There may be risk for other cancers. There may be targeted treatment options. is the best family member to test.

Family History

Personalized screening recommendations

genetic evaluation/testing personalized screening and risk reduction recommendations

General population screening recommendations

Sporadic Risk: Average

Familial Risk: Moderate

Inherited Risk: High

Classification: Who Needs What?

&

In Cancer Risk Assessment

Buy One, Get a Dozen ……

Hereditary Cancer Risk and NextGen Sequencing

Next Generation Sequencing

•  Traditional Sanger sequencing can be cumbersome and expensive.

•  NGS allows for rapid analysis of multiple genes at a lower cost compared to traditional sequencing techniques

Panels: •  CancerNext (44 genes) •  ColoNext (colon 14 genes) •  BreastNext (breast 18 genes) •  OvaNext (ovarian 23 genes) •  PancNext (pancreas 13 genes) •  PGLNext (paraganglioma 10 genes) •  RenalNext (kidney 18 genes) •  GynPlus (gynecologic 9 genes) •  MyRisk (25 genes) •  BRCAplus (6 clinically actionable

genes only)

25%

15%

4% 1% 4% 2%

49%

BRCA1 BRCA2 PTEN

p53

Distribution of pathogenetic mutation in BRCAplus

BRCA1 48%

BRCA2 37%

PTEN 2% CDH1 1% STK11 1%

TP53 11%

PLOS ONE, May 2014

Gene   Syndrome   Characteristics  

BRCA1/2   Hereditary Breast and Ovarian Cancer Syndrome (HBOC)  

•  Breast Cancer •  Ovarian Cancer  

PTEN   Cowden Syndrome   •  Skin findings •  Breast Cancer •  Thyroid Cancer •  Endometrial Cancer •  Kidney cancer •  Large Head •  Colon polyps (hamartomas)  

TP53   LiFraumeni Syndrome   •  Childhood cancers (sarcomas) •  Brain tumors •  Breast Cancer •  Adrenal Cortical Cancers  

STK11   Peutz Jeghers Syndrome  

•  Lip, hand and foot freckling •  Colon Polyps (Peutz Jeghers Polyps) •  Colon Cancer •  Breast Cancer •  Pancreatic Cancer

CDH1   Diffuse Hereditary Gastric Syndrome  

•  Diffuse Gastric Cancer •  Lobular Breast Cancer  

BRCAPlus  –  Ambry  Gene2cs  NextGen  Sequencing

Result Interpretation

No Mutation (Negative)

VUS- Likely Benign

Uncertain Significance

(VUS)

VUS- Likely Pathogenic

Pathogenic Mutation (Positive)

Medical management based on personal and family history. Uncertain results do not influence recommendations for care.

Medical management based on cancer risks linked with

gene where mutation found.

10%

34% 56%

Breast Next Results

Mutation

Variant of uncertain significance Negative

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.

Prior to July 2013 all BRCA testing was done at Myriad Genetics •  Testing was done in two parts:

– Sequencing – Deletion/duplication (BART) (6-10% of BRCA

mutations) (started in 2006, included in Integrated BRACAnalysis in Jan 2013)

•  Now all labs include both parts ** IMPORTANT: if testing was done in a family, must look at

test results to be sure what testing was completed**

Multigene Panels •  Benefits

–  Ability to look at several genes at one time –  Clarify risk (but how much do we know?) –  Offer medical management guidance (but how

much do we know?) •  Challenges

–  How much do we know? Risks? Management? –  How to interpret results for family members? –  Variant results –  How to consent? –  Follow up for reclassifications

Indications for Genetic Testing

•  Test to confirm the diagnosis of hereditary cancer in an affected individual

•  Test to establish risk in relatives of affected

•  Test if knowing would alter management

Whom Do We Test?

•  Informed patients •  Reasonable likelihood of positive test •  Youngest affected individual •  ?Minors •  ?Prenatal

Fear of Genetic Discrimination

•  Creates barriers to – Health care providers referring their patients

for hereditary cancer risk assessment – Patients seeking hereditary cancer risk

assessment – Patients’ willingness to have genetic testing or

participate in research

GINA – Prohibits: Genetic Information Non-Discrimination Act (2008)

•  Use of genetic information in setting eligibility or premiums

•  Health insurers from requesting a genetic test

•  Use of genetic information in employment decisions

•  Employers from requesting genetic information

Hereditary Breast Cancer Syndrome Gene

HBOC BRCA1 and BRCA2 Li Fraumeni TP53 Cowden PTEN Hereditary Diffuse Gastric Cancer (lobular pathology)

CDH1

Peutz-Jeghers STK11 CHEK2 CHEK2 HNPCC (Lynch) MMR genes Ataxia Telangiectasia ATM Bloom’s syndrome BLM

Male Breast Cancer

Syndrome Gene Risk

HBOC BRCA1 and BRCA2

6-10% (less with BRCA1)

Klinefelter 46, XXY 3%

Cowden PTEN Case reports

Hereditary Ovarian Cancer

Syndrome Gene Pathology

HBOC BRCA1 and BRCA2

Adenocarcinoma (non-mucinous)

HNPCC (Lynch) MMR genes Adenocarcinoma Peutz-Jeghers STK11 Sex cord tumors

Hereditary Uterine Cancer

Syndrome Gene

Cowden PTEN Lynch MMR genes Peutz-Jeghers STK11

Hereditary Colon Cancers

Syndrome Gene

HNPCC (Lynch) MMR genes

FAP APC

MYH polyposis (MAP) MYH

Li-Fraumeni TP53

Peutz-Jeghers STK11/LKB1

Juvenile Polyposis BMPR1A and SMAD4

Birt-Hogg-Dube FLCN

Hereditary Gastric Cancers

Syndrome Gene

HNPCC (Lynch) MMR genes

Familial Adenomatous Polyposis (FAP)

APC

Li-Fraumeni TP53

Peutz-Jeghers STK11/LKB1

HDGC CDH1

Juvenile Polyposis BMPR1A and SMAD4

Hereditary Pancreatic Cancer

Syndrome (adenocarcinomas) Gene

Familial Pancreatic Ca ? FAMMM CDKN2A (p16) HBOC BRCA1 / BRCA2 Lynch MMR genes PALB2 PALB2 Peutz-Jeghers STK11 Syndrome (neuroendocrine) Gene

VHL VHL MEN1 MEN1

Hereditary Renal Cell Cancer

Syndrome Gene Pathology

Von Hippel Lindau (VHL)

VHL Clear Cell

Birt-Hogg-Dube FLCN (aka BHD)

Oncocytic chromophobe

Hereditary papillary RCC (HPRCC)

C-MET Papillary RCC type 1

Hereditary leiomyomatosis and RCC (HLRCC)

FH Papillary RCC Type 2

Cowden PTEN Papillary RCC Tuberous Sclerosis TSC1 and TSC2 Angiomyolipoma,

oncoytoma, and RCC

Hereditary Pheochromocytoma

Syndrome Gene

Hereditary paraganglioma/ pheochromocytoma

SDH gene family

Von Hippel-Lindau VHL MEN2A and 2B RET Neurofibromatosis Type 1 NF1

Questions?

Lisen  Axell,  MS,  CGC  Lisen.Axell@ucdenver.edu