Hereditary Breast, Ovarian and Prostate Cancer

Myo Htet Thu (MTMT/M-5736939)

Thet Su Win (MTMT/D-5736940)

Outline

• Hereditary Breast Cancer

• Hereditary Ovarian Cancer

• Hereditary Prostate Cancer

• Update article

Hereditary Breast CancerMost frequent carcinoma in women.A fimilial history of BC is a significant risk factor.BRCA1/BRCA2 mutations are responsible for 3-8% of all

case and 30-40% of familial case.Prophylatic mastectomy is the only option to reduce the

risk.Heriditary BC has different pathological characteristics

and the BRCA mutation is an independent negative prognostic factor.

Essential to identify and provide genetic consultation for women who are at high risk to assess the individual disease risk, offer genetic analysis.

Carcinoma incidence and Risk for disease

Familial history of BC is important risk factor.

BRCA1/BRCA2 and other hereditary breast cancer syndrome

BRCA mutations are responsible for a large portion of cases of familial BC with autosomal-dominant inheritance.

A number of other genes that are associated with a predisposition to developing BC.

Genetics of Breast Cancer

BRCA1, tumor suppressor gene on chromosome 17 and BRCA2 was on 13q12.

The mechanism involved in BRCA1 and BRCA2 differs from Knudson’s model.

Loss of hetrogenesity can be seen at the BRCA1 and BRCA2 loci in sporadic BC, but the remaining allele almost mutates.

BRCA associated BC different from sporadic BC.This fact that have differences in pathology,

prognosis and therapeutic management.

• BRCA1 or BRCA2 mutation have 35%-80% lifetime risk of breast cancer by age 70

• Higher risk of breast cancer with 300 T > G mutation

Genes involved in HBOC syndrome

Counseling and risk calculation

Interdisciplinary genetic counseling Collaboration between physicians in the different fields

is the appropriate approach to identify who are at familial risk

Determining and calculating risk Lifetime risk for disease and probability of mutation. Different calculation models are available ( eg; Gail

model, Claus model, BRCAPRO, Tyrer-Cuzick model etc.)

The choice of clinical options requires information on the patient’s risk for disease and mutation status.

Early Breast Cancer detection.

Chemoprevention for Breast cancer

Chemoprevention in BC focuses on a variety of endocrine, paracrine and autocrine factors.

Aromatase inhibitors, retinoic acid, isoflavonoids, gonadotropin-releasing hormones, low dose contraceptives and hormone replacement treatment have been tested.

Prophylactic surgery (bilateral prophylactic mastectomy)

Therapy (no specific guidelines are available on the treatment of patients with hereditary BC)

Prognosis

Familial risk is an important risk factor in BC

BRCA1 and BRCA2 linked carcinomas have special pathological characteristics, which can be relevant for treatment and prognosis.

BRCA mutation is a basic prerequisite for discussing the need for and availability of early cancer detection, specific therapy, chemopreventation and prophylactic surgery with the patients concerned.

Ovarian Cancer

• Ovarian cancer is the sixth most frequent cancer in women.

• It accounts for about 3% of cancers among women, but it causes more deaths than any other cancer of the female reproductive system.

• It is the most lethal gynecological malignancy• Incidence has increased by 30% over the past

decade • The overall survival rate is 38% at 5 years

http://www.cancer.org/cancer/ovariancancer/

http://www.mountsinai.org/patient-care/service-areas/obgyn-and-reproductive-services/areas-of-care/gynecologic-oncology/ovarian-cancer/infographic/ovariancancerinfo

http://www.mountsinai.org/patient-care/service-areas/obgyn-and-reproductive-services/areas-of-care/gynecologic-oncology/ovarian-cancer/infographic/ovariancancerinfo

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• Mutations in BRCA1/2 do not account for all cases of HBOC.

• Involvement of other susceptibility genes

– Fanconi Anemia (FA) cluster (FANCD2, FANCA, FANCC)

– MMR cluster (MLH1, MSH2, PMS1, PMS2, MSH6)

– DNA checkpoint cluster (ATM, ATR, CHK1/2)

– Tumor suppressor cluster (TP53, SKT11, PTEN)

Kobayashi et al. Oncology Reports. 2013;30:1019-1029

DNA checkpoint cluster

(ATM, ATR, CHK1/2)

• ATM and ATR kinases signal DNA stress during S phase

• to CHK1/2 protein kinases.

• CHK2 targets the CDC25 phosphatase for destruction or inhibition of its nuclear import.

http://www.nature.com/nature/journal/v432/n7015/fig_tab/nature03097_F3.html

Tumor suppressor cluster (PTEN)

• PTEN mutations are associated with Breast, Thyroid and endometrial cancers.

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Tumor suppressor cluster (TP53)

• Germline mutations are associated with hereditary cancers.

• Mutations

• LOH

• Overexpression

• Loss of function

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Prostate Cancer

• It is the most commonly diagnosed cancer in men

• The second leading cause of cancer deaths in men after lung cancer.

• The risk of Pca is 1 in 6

• Risk of death is 1 in 30.

• It is estimated to be found in 50% of all men over 70 and in almost all men over the age of 90 Risk Factors to Prostate Cancer

It is estimated to be found in •Up to 29% of men (30-40yrs)•64% of men (60-70yrs)•in almost all men over the age of 90

Racial difference and risk for Prostate Cancer

• African-American men and Jamaican men of African ancestry have the highest risk and are likely to be diagnosed at an advanced stage.

http://www.prostatecancerprevention.net/index.php?p=prostate-cancer-world-map

Family history and Genetic background

• Genetic background may contribute to prostate cancer risk by association with race, family and specific gene variants.

• Having a father or brother with prostate cancer more than doubles a man’s risk of developing this disease.

• But most men diagnosed with prostate cancer do not have a family history of the disease.

Inherited genes and PCa

• Some inherited genes seem to raise risk.

• But this accounts for only a very small number of cases.

• No single gene is responsible for prostate cancer.

• Many different genes have been implicated.

BRCA1BRCA2

HPC1 MSR1

AR, CYP17, SRD5A2

RNASEL

RNASEL and HPC1

• RNASEL gene encodes latent endoribonuclease• Interferon-inducible RNA-decay pathway

(degrade the viral and cellular RNA)• RNASEL has been linked to HPC1.

• In one family, 4 brothers with PCa carried RNASEL mutation.

• In another family, 4 out of 6 brothers with Pca carried RNASEL base substitution.

Nelson et al. N Engl J Med. 2003;349(4):366-381

http://www.provenge.com/treatment-and-me.aspx

To determine the prevalence of PALB2 mutations for diagnostic testing for hereditary breast cancer.

Update Article

HBOC genes (BRCA1/2) deleterious mutations increased the risk of cancer.

Identification of disease associated mutation genes has important implications for the clinical management .

Mutation of BRCA1 and BRCA2 – 84% of familial hereditary predisposition to breast cancer.

BRCA 1/2 and Breast Cancer

P53 (Li-Fraumeni syndrome) and PTEN(Cowden syndrome) has small portion of hereditary predisposition to breast cancer.

Small to moderate risk of predisposing gene are recently identified that are CHEK2, ATM, NBS1, RAD51, BRIP1 and PALB2.

Binding partner BRCA2 (PABL2) is novel component of endogenous BRCA2 containing complex.

Other genetic involvement to Breast Cancer

PABL2• 13 exons and maps on chromosome 16p 12.2, that region

shows loss of heterogenesity in 12% of BC,DNA repair gene.

• Bridge between BRCA1 and BRCA2 complex.

• Critical for homologous recombination (HR) and double-strand break (DSB) repair.

• Biallelic mutation of PABL2 – Fanconi Anaemia that clinical phenotype similar to Biallelic mutation BRCA2 mutation carrier.

• Heterozygous or monoallelic germ line mutations of PALB2 have been found in BC families.

• Indicated that PABL2/BRCA1/BRCA2 is a tumor suppressor for familial breast cancers.

Comprehensive SequencingDNA sample from breast cancer patients.Previously tested negative for mutation of BRCA1

and BRCA2 genes.

Three categories for Mutation

deleterious and suspected deleterious

Variant of uncertain significance

Polymorphism

Result

Disease associated mutation – 12 of 1479 patientsPABL2 mutation – 10 of 955 (High Risk) (9 Female/ 1 Male)PABL2 mutation – 2 of 524 (Low Risk) (2 Female)

>50 years old with family history

<50 years old without family history

8 – Nonsense Mutation3 – Frame shift Mutation1 – Splice Site Mutation

4 mutations were Novel

Discussion

PABL2 mutations in 1% of sample from patients with breast cancer who are negative for BRCA1/2 deleterious mutations.

Suggest that PABL2 mutations occur in low frequencies in hereditary BC.

Even the prevalence of the mutation of PABL2, suggests that there are found in the negative mutation of BRCA1/2 of the BC.