Familial cancer Flashcards by sita clark

Angelina Jolie

Bilateral Masectomy
Mother: Marcheline Bertrand Breast cancer age 48 Died ovarian cancer aged 56
Aunt: Debbie Martin Breast cancer age 52 died 2013 age 61
Grandmother:Lois Bertrand Died age 45 Ovarian cancer
Uncle: Raleigh Bertrand Died cancer
Great Grandmother: Died age 52 Ovarian cancer
-Strong family history
-Different sorts of cancer (breast, ovarian, prostate)
-inherited predisposition and risk of cancer

How well did you know this?

Not at all

Perfectly

The Angelina Effect

Strong family history of breast and ovarian cancer
Elected to have genetic testing for familial breast cancer genes
BRCA1 mutation positive (germline mutation)
Elected for prophylactic double mastectomy; reconstruction; bilateral oophorectomy

How well did you know this?

Not at all

Perfectly

Indicators Familial Cancer

Involvement of close relatives – at least one first degree relative
Presence of cancer over successive generations
Young age at onset of cancer (for that type of cancer)
- breast cancer onset rare under 60
Multiple types of cancers – in same individual or within the family
- males inherit BRCA 2 gene for prostate cancer etc

How well did you know this?

Not at all

Perfectly

Cancer Criteria

e.g. Amsterdam Criteria for Familial Colorectal Cancer (CRC)
be aware that number of groups/countries to develop guidelines to help indicate/select for high risk individuals
e.g. breast and bowel cancer
(Features: familial, generation, young onset)

How well did you know this?

Not at all

Perfectly

Molecular basis of inherited cancers

Involves cancer causing genes -Oncogenes

Tumour suppressor genes
Genes involved in apoptosis
DNA repair genes

How well did you know this?

Not at all

Perfectly

Familial Cancers Involving Oncogenes

Rare to have inherited mutation in oncogenes as germ-line mutation
-would have profound effects on embryonic and fetal development
RET Oncogene (REarranged during transfection)
-Receptor tyrosine kinase (signal transduction pathways)
-Germline mutations associated with MEN type 2 (malignancy of multiple endocrine glands) and familial medullary thyroid cancer
Normal RET receptor –> Controlled Growth
Mutant form of RET receptor –> Uncontrolled growth

How well did you know this?

Not at all

Perfectly

What are the majority of genes seen in Familial cancers?

Recessive acting genes
Tumour surpressor or apoptotic acting or DNA repair genes
“two hit hypothesis”
– initial inherited mutation that is germline/present in all the cells (is compatible with normal phenotype)
-second acquired mutation mutation (the second hit transform’s involved cell)

How well did you know this?

Not at all

Perfectly

Molecular basis of inherited cancers Diagram

Familial:
Inherits on mutant copy (compatible with normal fetal/embryonic development) –> Mutation occurs in second copy –> Total loss of gene function
Sporadic:
Inherits two normal copies –> Mutation occurs in one copy –> Mutation occurs in second copy in the same cell –> Total loss of gene function
e.g. Retinoblastoma (inherited mutation in Rb gene on chromosome 13 (cell cycle regulator)

How well did you know this?

Not at all

Perfectly

Examples of Familial cancer

Cancer –> Gene
Retinoblastoma –> Rb gene
Li-Fraumeni breast –> p53
FAP (bowel) –> APC gene
*Breast, ovary –> BRCA1, BRCA2
Neurofibromatosis –> NF1 gene
Melanoma –> p15, p16
*Colorectal cancer –> hMLH1, hMSH2
-familial component becoming increasingly common
-3-5% potential for inherited predisposition
-series of predisposition genes in conjunction with environmental factors, that increase risk of malignancy
-e.g. Leukemia: not inherited predisposition gene like BRAC1 or 2, probably series of polymorphisms that predispose development of those cancers in conjunction with environmental factors

How well did you know this?

Not at all

Perfectly

Familial Bowel Cancer

5% of cases of colorectal cancer in NZ
a) 3-5% of cases are due to hereditary non polyposis colorectal cancer (HNPCC)
-may present same as sporadic cancer
-Lynch syndrome
-more common
b)

How well did you know this?

Not at all

Perfectly

Likelihood with Leukemia example in regards to Familial inheritance

-e.g. Leukemia: not inherited predisposition gene like BRAC1 or 2, probably series of polymorphisms that predispose development of those cancers in conjunction with environmental factors

How well did you know this?

Not at all

Perfectly

Hereditary Non Polyposis Colorectal Cancer (HNPCC)

3-5% of colorectal cancer cases
Autosomal dominant inheritance (present about 50% of each generation. Males and females equally)
Multisystem disorder 
-Colorectal cancer
-Endometrial tumours
-Also cancers small bowel, ovaries, renal pelvis &amp; ureter (transitional epithelium)
-may present same as sporadic cancer
-Lynch syndrome
-more common

How well did you know this?

Not at all

Perfectly

Adenoma to Carcinoma Sequence

Normal colon (benign adenoma)
Mucosa at Risk
Adenomas
Carcinoma
-Tumours progress through adenoma to carcinoma stages i.e. same as sporadic colorectal cancer
-but would be alerted with family history, generational etc.

How well did you know this?

Not at all

Perfectly

Genetics of HNPCC

Heterozygous for germline mutation in DNA mismatch repair gene
6 mismatch repair genes identified
hMSH2, hMLH1
PMS1, PMS2, hMLH3, hMSH6
-second hit
-protein encoded by these mismatch repair genes recognise abnormalities in DNA sequencing/mismatching/additional bases inserted. Will facilitate excision and polymerase repair
-mutated mismatch repair genes will predispose acquisition of additional acquired mutations in multiple genes that could have growth promoting activity –> malignancy

How well did you know this?

Not at all

Perfectly

Genetics of HNPCC Diagram

Lynch Syndrome (HNPSS) –> Germline mutation in MMR gene –2nd hit–> Defective DNA MMR Repair causes MSI-H –> Mutation ingenes with coding microsatellites and non-coding regions –> Tumorigenesis (colorectal cancer)
Sporadic CRC (~15%) –> hMLH1 MMR gene methylation –> Defective DNA MMR Repair causes MSI-H –> BRAf mutation –> Tumorigenesis

How well did you know this?

Not at all

Perfectly

Implications of defective mismatch repair

Inactivation of both alleles increases mutation rate ( 1. germline. 2. acquired hit)
Alters a number of cell regulatory genes – increased risk of cancer
Microsatellite instability seen in the cancer ie useful biomarker of mismatch repair gene defect

Mismatch repair gene mutations and microsatellite instability

Normal DNA repair
Base pair mismatch –> Defective DNA repair (MMR+)
-risk of instability in repeat sequences
-labs look for micro-satellite instability as a marker of DNA mismatch repair gene
-look at repeat sequences, and if there are increased/decreased numbers of micro-satellite regions in tumour in comparison to germ-line
-Micro-satellite instability doesn’t cause the tumour, but is a biological reflection that DNA mismatch repair mechanisms
-would encourage further genetic testing

Genetics of HNPCC

Mismatch repair gene mutation increases risk of cancer
HNPCC mutation carriers vs General Population
-Colorectal cancer by age 70: Upto 80% vs 2%
-Endometrial cancer by age 70: Upto 71% vs 1.5%
-Ovarian cancer by age 70: up to 12% vs 2%
-high penetrance for inherited germ line mutation for mismatch repair genes

Clinical Implications: Diagnosis of HNPCC / Familial Colorectal cancer

Clinical suspicion
-Eg young age at diagnosis, other family members with cancer, Amsterdam Criteria
Further analysis of the cancer tissue (biomarkers)
-Microsatellite instability in the tumour (biomarker)
-Immunohistochemistry to detect expression of mismatch repair gene (antibodies, low levels of expression)
Genetic studies looking for germline mutation of a mismatch repair gene
Overall: (Family history–> Biomarkers –> Sequencing)

Clinical Implications: Management of families with HNPCC (mutation analysis)

Mutation analyses:
Identify those with gene
Penetrance 80 – 85% but variable phenotypes with different mutations
Allows interventions
-Screening strategies (pick up early adenomas before progression into adenocarcinoma)
-Changes of diet (lifestyle changes)
Affected individuals – recommend regular screening by colonoscopy (looking to pick up early tumours)

Why dont you go straight to genetic strudies

6x different genes
whole lot of mutations with those genes
-requires alot of lab work
-if have strong family history like Angelina Jolie, then would be reasonable to go from Family history –> Sequencing (w/o biomarker testing)

Adult with abdominal mass (Abdo 5)
A 52 year old NZ European woman presents to her GP with bloating of her abdomen, worsening over the last few months associated with intermittent diarrhoea and 5kg weight loss. Her brother and father were diagnosed with bowel cancer in their 40’s.

Change in bowel habit and weight loss - raise concerns re. malignancy or inflammatory bowel disease
Brother and father diagnosed with bowel cancer in their 40s
Amsterdam Criteria:
-2 successive generations
-one first degree relative
-under age 50
=high suspicion for familial colorectal cancer

Clinical scenarios

Adult with abdominal mass (Abdo 5) Diagram

Amsterdam I/II criteria

— -ve –> Bethesda guidlines II
a) – +ve –> MSI/IHC testing
i) – +ve –> Genetic testing for MSH2 and MLH1
ii) – -ve –> No genetic testing for MSH2 and MLH1
b) – -ve –> No genetic testing for MSH2 and MLH1
– +ve – (fulfilled all markers) > Genetic testing for MSH2 and MLH1

Familial Adenomatous Polyposis

Autosomal dominant disorder with multiple polyps or adenomas in bowel – transform to carcinomas
Sheet of polyps in bowel
- Polyps begin to develop second decade of life
- Colonoscopy age 12+
- Often need colectomy (resection)

Genetics of FAP

Linkage studies placed gene chromosome 5q – APC gene identified
Tumour suppressor gene
- Inherited germline mutation
- Most mutations frameshift or nonsense – yield truncated protein
-Second hit required – sometimes hypomethylation (epigenetic changes)
-Mutation analysis allows family screening
APC gene mutations (somatic) seen in 85% cases of sporadic colorectal cancer

Familial Breast and Ovarian Cancer

About 5% of breast cancer cases can be
attributed to a known breast cancer gene
- Strong family history – risk 20-30%
- Family history of breast and ovarian cancer 60 – 80% have a BRCA-1 or BRCA-2 mutation
- Rarely other genes may be involved eg p53, ATM, PTEN

BRCA-1 and BRCA-2 mutations (Women)

Women who inherit BRCA1 or BRCA2 mutations lifelong risk of breast cancer of 75 - 85%
BRCA-1 and BRCA-2 also have increased risk of ovarian cancer (40-45%)
-45% for BRCA-1
-30% for BRCA-2

BRCA-1 and BRCA-2 mutations (Male)

Males with BRCA gene mutations also increased risk of cancer
BRCA-1: prostate 6% increase in risk
BRCA-2: prostate 6 - 10% increase risk;
breast cancer 5% risk
relatively less of a risk compared to woman carrying same mutation

BRCA-1 and BRCA-2 mutations general

Not 100% risk ie not fully penetrant

Other risk modifying factors - environmental, hormonal, genetic (influence penetrance and expression of the phenotype)

Function of BRCA 1 and 2

Mutations usually result in truncated proteins
-some mutations occur more commonly than others
-there is a wide spectrum of mutations
-present technical and scientific challenges for lab re testing for families
-therefore important to have index case
Protein products involved in DNA repair
-resulting mutations that give rise to development of malignancy

Clinical issues: familial breast cancer

Clinical suspicion
-Family history, breast and ovarian cancer
Analysis of the tumour
-Similar features to sporadic breast cancer
BRCA gene analysis for germline mutation
-Need index case
-BRAC1 and 2 testing on peripheral blood sample looking for mutation

Genetic testing for familial breast cancer Advnatages

Advantages

Empowers patient – allows to make choices
Early screening programmes can be offered
- Mammography
- Pelvic ultrasound
- Tumour markers eg CA125
Prophylactic surgery (due to 80% change of breast cancer)
-Double mastectomy often with reconstruction (breast c)
-Bilateral oophorectomy (ovarian c)

Genetic testing for cancer Concerns/other issues

Concerns / other issues
-Potential for genetic discrimination – e.g. medical insurance, employment, life insurance etc
-Additional stress with results ( as result was unexpected)
-Guilt feelings in those not affected
-Guilt feelings in those affected e.g. if already have children (already passed gene onto children, maybe potentially not have had children had they known)
Therefore: Pre-Test genetic counselling critical

Familial Cancer Summary

Think about it when you see patient
-Family history important in identifying cases
-Young age at onset
-Multiple cancers
Similar genetic mechanisms to those seen in sporadic cancers
-but now germline mtuation of an allele
Raises important clinical and ethical issues
-counseling critical component of this interaction w families

Brainscape's Knowledge GenomeTM

Familial cancer Flashcards

Brainscape's Knowledge Genome^TM