Familial cancer Flashcards
(34 cards)
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
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
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
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)
Molecular basis of inherited cancers
Involves cancer causing genes -Oncogenes
- Tumour suppressor genes
- Genes involved in apoptosis
- DNA repair genes
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
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)
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)
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
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)
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
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 & ureter (transitional epithelium) -may present same as sporadic cancer -Lynch syndrome -more common
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.
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
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
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)
