Breast Cancer Genetics:An Overview

Kevin Sweet, MS, CGCCertified Genetic CounselorClinical Associate ProfessorDivision of Human Genetics

Kevin Sweet discloses no significant financial interests or other relationships with commercial interests. Presentation will not include discussion of commercial products or services and will not include unapproved or off-label usage of a commercial product or device.

The following planning committee members have no significant financial interests or relationships with commercial interests to disclose, their educational unit does not have a financial interest or affiliation with an organization that may receive direct benefit from the subject of the proposed CME activity, and they will not be personally compensated for their role in the planning or execution of this proposed CME activity by an organization other than The Ohio State University: Amy Ehrlich, MA and Henry Zheng, PhD, MBA

What is Cancer?

• Cancer is a term that encompasses a complex group of more than 100 different diseases that all share the primary characteristic of uncontrolled cell growth.

• Each individual type of cancer arises from a

single cell that requires varying numbers of gene mutations for progression to the invasive state.

• Cancer is a term that encompasses a complex group of more than 100 different diseases that all share the primary characteristic of uncontrolled cell growth.

• Each individual type of cancer arises from a

single cell that requires varying numbers of gene mutations for progression to the invasive state.

All Cancer is Genetic, but NOT All Cancer is Hereditary (Inherited)

• 10-25% of all cancers are caused by inherited (germline) gene mutations

• More often the cumulative effect of genetic damage (somatic mutations) acquired over the individual’s lifetime leads to malignancy.

• Genes involved with cell signaling and proliferation pathways, repair of normal DNA damage, the mitotic cycle and apoptosis all contribute to the cancer phenotype.

• Numerous nongenetic factors, such as environmental radiation exposure, carcinogens from cigarette smoke, and even age are contributing factors.

All Cancer is Genetic; Not All Cancer is Inherited

Normal cell

First mutation

Second mutation

Third mutation

Malignant cell

First mutation

Second mutation

Third mutation

Malignant cell

Common cancer pathway due to somatic mutation

Hereditary cancer pathway, where initial gene mutation is inherited

Breast Cancer is Common

1 in every 8 American women will be diagnosed with breast cancer in her lifetime

Risk Factors for Breast Cancer

• Age

• Nulliparity

• Early menarche and late menopause

• Personal history• Atypical hyperplasia • Female hormone

replacement therapy• Family

history/genetics

Goal: ClassificationWho Needs What?

Family History

Assessment

Personalized detection/prevention recommendations

Referral for genetic evaluationwith personalized screening recommendations

Standard screening recommendations

Intervention

Average (70%)

Moderate (15-20%)

High (5-10%)

Risk Classification

Average Risk for Breast Cancer• Little or no family history of cancer and no

other known risk factors• Examples of average risk:

– One 1st degree relative (parent, sibling, child) diagnosed with breast cancer >50 yrs

– One or two 2nd degree relatives (aunts, uncles, grandparents) diagnosed >60 yrs

• Follow American Cancer Society screening recommendations

Moderate Risk for Breast Cancer

• Clustering of cancer cases seen in a family

• Ages of onset not strikingly young (average age breast cancer dx is 62)

• However, risk for all first degree relatives increased– Risk depends on number of family members affected, how

closely related, ages of onset

• Multiple low-penetrance genes may play a role and interact with environmental triggers

Case 1: Moderate Risk Family

Dx 5865 yr

Dx 6571 yr

Dx 79d.81

Caucasian mix

Swedish / Finnish

Key:

Breast CAAlison40 yr

15 yr

Case 1: Risk Assessment Modeling

• Gail Model: National Cancer Institute's website (http://nci.nih.gov )– 5 year risk of 1.2% / lifetime risk of 20.4%

• Claus Model: (BreastCa for Palm, version 1.0, copyright 2001) http://www.palmgear.com/index.cfm?fuseaction=software.showsoftware&prodID=29820 – Lifetime risk of 18.8%

The Gail model is limited because it does not incorporate second-degree relatives (e.g. aunts, grandmothers) or the age of onset of breast cancer in the family.

The Claus model incorporates up to two relatives with breast cancer, taking into account their ages of onset, but does not include relatives with ovarian cancer or take into account nongenetic risk factors such as age at menarche.

Case 1: Risk Based Management

• Gail or Claus lifetime risk for breast cancer of

18-20%

• Low risk (2-3%) of BRCA1/2 gene mutation

• Ovarian (or other cancer) risk not increased

• Screening recommendations: – Monthly breast self exam monthly

– Clinical breast exam every six months

– Mammogram once a year by age 40 (or 10 yrs prior to earliest diagnosis)

Case 1: Take Home Messages• Number of cancers in family is not as

important as the ages at diagnosis– which side of the family matters– all on one side or some on each – not convergent!

• Perceived risk does not always equal actual risk– genetic counseling/risk assessment may help

• Some low penetrant gene variants (SNPs) may account for moderate risk families with breast cancer

Breast Cancer Gene SNP Variants With Low Penetrance

• Genome-wide association studies have identified at least 17 gene variants which constitute risk-increasing alleles for breast cancer

• Drawbacks to currently available SNP based tests:– Many of these breast cancer risk-increasing SNPs are

either rare enough in the population that they do not contribute to many cases, or of low enough penetrance that possessing the risk-increasing allele does not significantly increase the individual's risk

– For example, the D allele of the D302N SNP in the caspase 8 (CASP8) gene has a frequency of 0.86, and conveys a rather low RR of 1.13

Frequencies Of And Relative Risks Associated With Commercially Available SNPs For Breast Cancer

dbSNP No. Gene Chromosome Risk-IncreasingAllele Frequency

Relative Risk Per Allele

rs2981582 FGFR2 10q 0.38 1.26

rs3803662 TNCR9 16Q 0.25 1.20

rs889312 MAP3K1 5q 0.28 1.13

rs3817198 LSP1 11p 0.30 1.07

rs1053485 CASP8 2q 0.86 1.13

rs13281615 Unknown 8q 0.40 1.08

rs13387042 Unknown 2q 0.50 1.20

rs4415084 MRP530 5p Unknown 1.03

rs1219648 FGFR2 10q Unknown Unknown

Commercial GWA Offerings

• Some commercial GWA companies provide breast cancer risk estimates based on the number of these low penetrance alleles the individual possesses.

• Each company uses a different specific algorithm to combine the genotype data and produce their risk estimate.

Breast Cancer Risk and SNPs• RR associated with a risk-increasing SNP allele is

often dose–dependent and complex; possessing two copies of the risk-increasing SNP allele often conveys more than twice the risk that possessing one copy of the risk-increasing allele does– For example, for the rs2981582 SNP in the FGFR2 gene, the

genotype specific RR of breast cancer (individual's risk compared to the risk in the general population) is 0.83 for carriers of two risk-reducing alleles (common allele homozygotes), 1.05 for carriers of one risk-increasing and one risk-reducing allele (heterozygotes) and 1.38 for carriers of two risk-increasing alleles (rare allele homozygotes). This projects a lifetime risk of 10% for women who carry one risk-increasing allele and 13% for women who carry two risk-increasing alleles.

Breast, dx 44d. 48

Breast Cancer and Ovary, 42, 55

d. 58

High (hereditary) Risk Family

Breast, dx 49

Breast, dx 40d. 40

50-70% lifetimerisk for breast cancer

Increased risk for other cancers

Breast Cancer Gene VariantsWith High Penetrance

• 5-10% of all breast cancer are strongly hereditary, with high penetrance and an autosomal dominant single gene determinant – Always co-segregated with the disease in families– See multiple generations of affected family members– Gene mutation found equally in males and females– Mutation carriers will have a heterozygous genotype,

which means they will have a 50% risk of passing on the gene mutation to each of their offspring

Highly Penetrant Genes For Breast Cancer Gene Syndrome Inheritance Protein Function Penetrance

BRCA1 HBOC Autosomal dominant Tumor suppressor 60-85%

BRCA2 HBOC Autosomal dominant Tumor suppressor 60-85%

PTEN Cowden (part of the PTEN hamartoma tumor syndrome which also includes Bannayan-Riley-Ruvalcaba syndrome and Proteus-like syndrome

Autosomal dominant Tumor suppressor 70-80%

P53 Li-Fraumeni Autosomal dominant Tumor suppressor >90%

Hereditary Breast and Ovarian Cancer Syndrome (HBOC)

• ~50 to 75% of hereditary breast cancer caused by mutations in either the BRCA1 or BRCA2 gene

• Dominant deleterious mutations in either gene increase cancer risk dramatically

• Genetic testing for BRCA1 and BRCA2 gene mutations is available to women with personal or family cancer history meeting criteria

Features That Indicate Increased Likelihood of Having BRCA Mutations

• Multiple cases of early onset breast cancer in a family

• Ovarian cancer (with family history of breast or ovarian cancer)

• Breast and ovarian cancer in the same woman• Bilateral breast cancer• Ashkenazi Jewish heritage • Male breast cancer along with female breast

cancer in a family

Misconceptions• Cancer on the father’s side of the family doesn’t

count– Half of all women with hereditary breast cancer risk

inherited it from their father

• Ovarian cancer is not a factor in breast cancer risk– Ovarian cancer is an important indicator of hereditary

risk, although it is not always present

• The most important thing in the family history is the number of women with breast cancer– Age of onset of breast cancer is more important than the

number of women with the disease

BRCA1-Associated Cancers:Risk by Age 70

Possible increased risk of other cancers (e.g., prostate)

Breast cancer 50-85% (often early age at onset)

Second primary breast cancer 20%-60%

Ovarian cancer 15-45%

BRCA2-Associated Cancers: Risk by Age 70

Increased risk of prostate, laryngeal, and pancreatic cancers

(magnitude unknown)

breast cancer (50-85%)

ovarian cancer (10-20%)

male breast cancer (6%)

BRCA1/2 Mutation Incidence

• 1 in 800 women in the general population

• 5-8% of all women with breast cancer

• 18% of women with breast cancer <50 and one close relative with breast cancer <50

• 2% of all women of Ashkenazi Jewish ancestry

• 25% of all Ashkenazi Jewish women with ovarian cancer

Who to Test for BRCA?

• Determine family’s risk – Individual’s cancer status– History of breast and ovarian cancer in 1st and

2nd degree relatives• Person affected with cancer

– Early onset breast preferably– Ovarian at any age– Assistance with surgical decision making

• Any Ashkenazi Jewish or Icelandic person• Any person in family with known mutation

Interpreting Test Results: Positive for a BRCA Deleterious Mutation

• Mostly frameshift and nonsense mutations • Any mutation that prevents a functioning

protein from being made is assumed to be deleterious, even if it has not been seen before

• Hundreds of deleterious mutations have been described in BRCA1 and BRCA2

Interpreting Test Results: No Mutation Detected

• If there is a known BRCA mutation in the family:• The risk of cancer is the same as that of the

general population, despite a strong family history

• If there is not a known BRCA mutation in the family:

• A negative result rules out most, but not all, causes of hereditary breast and ovarian cancer

• Some unusual types of abnormalities in the BRCA genes, such as very large deletions, are not detected on standard analysis

Interpreting Test Results: Variants of Uncertain Significance (VUS)• Result seen in 5-10% of all BRCA test

reports• Mostly amino acid substitutions, also some

variants in non-coding introns• VUS have uncertain clinical significance

so associated cancer risk unknown• VUS may be further characterized by

additional studies

Case 2: BRCA Mutation Positive Family

Ruth is a 45 year old woman recently diagnosed with breast cancer.

• Maternal family history is negative for cancer

Paternal family history is significant for:• Paternal aunt with ovarian cancer age at 55• Paternal grandmother with breast cancer age 42

Case 2: High RiskKey

-Breast CA

-Ovarian CA

Dx 55d. 56

Dx 42d. 49

Ruth45

English/Irish German

37 28

60 58

1822

• 36-44% risk of BRCA mutation in proband

• 50% risk for each of her daughters

Case 2: After Testing, Ruth has a Deleterious Mutation in the BRCA1 Gene

Key

-Breast CA

-Ovarian CA

Dx 55d. 56

Dx 42d. 49

Ruth45

English/Irish German

60 58

1822

BRCA1(+)

37 28

BRCA(-) BRCA1(-)

BRCA1(+)

Surveillance-BRCA1 and BRCA2 Mutation Carriers

• Mammograms are not completely sensitive -MRI may be more sensitive, but less specific -Begin use of imaging at 25• Breast physical examination is recommended -Encourage monthly breast self-exams (begin at 18) -Clinician performed exams 2-4 times per year (begin at 25)• Frequency of interval cancers suggests that six-month

screening intervals may be preferable

Modified from Burke W et al. JAMA. 1997; 277:997-1003. Scheuer L et al. J Clin Oncol. 2002; 20: 1260-1268.Warner E et al. J Clin Oncol. 2001; 19:3524-3531.

Ovarian Cancer: Chemoprevention

• Limited data available for BRCA-mutation carriers; preliminary study showed a 60% risk reduction with ≥6 years use

• May increase breast cancer risk

Oral Contraceptives

CASH study NEJM 316:650, 1987; Ursin Cancer Res 57:3678, 1997; Narod NEJM 339:424, 1998

40% to 50% risk reduction in general populationafter 3 years cumulative use

Prophylactic Oophorectomy• Decreases risk of ovarian cancer by as much as

80% (primary peritoneal carcinoma may still occur)• Reduces risk of breast cancer by 60% if done prior

to age 40 and by 50% if done prior to age 50• Induces surgical menopause • Laparoscopic procedure reduces postsurgical

morbidity • Consider complete hysterectomy for management

of menopause – unopposed, low-dose estrogen

Rebbeck NEJM 346(21):1660, 2002; Kauf NEJM 346(21):1660, 2002; Rebbeck et al JNCI 101(2):80-7, 2009

Case 2: Impact of Results Medical Management

• Ruth (mutation positive)– may want to consider oophorectomy

• Ruth’s daughters are negative for their mother’s BRCA mutation– general population risk for breast and ovarian cancer– follow American Cancer Society screening guidelines– cannot pass the family’s BRCA mutation to their children

• Ruth’s sister (mutation positive)– consider increased breast cancer screening +/-

chemoprevention OR mastectomy and ovarian cancer screening OR oophorectomy (after child-bearing, <40)

Case 2: Take Home Messages

• Risk assessment and genetic testing gives information to patient AND family members– Some family members may want this information and some

may not• Genetic testing, when informative, can help individuals

– make decisions about early detection and risk-reduction– relieve anxiety about cancer risk (if negative)

• Informed decision-making imperative• Follow-up support and/or counseling sometimes

necessary

Li-Fraumeni Syndrome (LFS)

• Germline mutations in the TP53 tumor suppressor gene cause Li-Fraumeni syndrome.

• These mutations are relatively rare, but they have almost complete penetrance.

• The lifetime risk for a primary cancer in someone with one mutant copy of the TP53 gene is close to 90%.

Li-Fraumeni Syndrome

• As the TP53 gene is one of the key gatekeepers for cell cycle maintenance and regulation, germline mutation leads to very high risk for single and multiple primary cancers in mutation carriers.

• Osteosarcomas and soft tissue sarcomas are the signature cancers of LFS, although early onset breast cancer (20-30s), brain tumors, leukemias, lymphoma and adrenal tumors are also seen regularly.

Cowden Syndrome• Caused by germline mutations in the PTEN gene• Mutation carriers are at increased risk for breast and

thyroid cancer (30% and 10% increase in risk, respectively).

• As a tumor suppressor gene, PTEN is a key regulator of cell signaling pathways; disruption leads to both benign and malignant cellular overgrowth.

• Cowden syndrome is part of the more comprehensive PTEN hamartoma tumor syndrome which also includes Bannayan-Riley-Ruvalcaba syndrome and Proteus-like syndrome.