Clinical Cancer Genetics and Syndromes Flashcards
What are the three types of cancer in families?
- Sporadic
- Familial
- Hereditary
What represents moderately increased risk for cancer in the consultant? What is the normal age of onset?
Familial cancers, where two close relatives had a specific type of cancer, with a normal age of onset of a primary tumor
What defines a hereditary cancer?
- Two or more relatives in same lineage with same or related cancer
- Early age of onset
- Multifocal / bilateral tumors
- Autosomal dominant inheritance of gene
What is the primary difference between sporadic and hereditary retinoblastoma, particularly as it relates to etiology and outcome?
Hereditary - 40% of cases, will be bilateral since only one hit is needed in RB1 gene (one is germline)
Sporadic - 60%, will be unilateral since two hits (two somatic) mutations are needed.
How does the two-hit theory of cancer explain reduced penetrance and age of onset in hereditary cancers?
- Reduced penetrance - additional somatic mutation is required for development of cancer, which is random
- Age of onset - younger in hereditary since only one mutation is needed
What are three causes of familial cancer patterns?
- Multifactorial
- Low penetrance, single-gene
- Shared environmental risk factors
What are two causes of a misdiagnosis of a familial cancer pattern?
- Masking of true hereditary -> Underreporting of cancer history or small family size
- Masking of true sporadic -> random chance clustering of sporadic cases
What is the clinical difference between treating patients with well characterized cancer syndromes vs less well characterized genes?
Well characterized: Gene specific management guidelines are published
Less well-characterized: Management is typically guided by family history, and there are no gene-specific guidelines published
What are the functions of the BRCA1 and BRCA2 genes? What cancers will this mutation put you at risk for?
Tumor suppressor genes - autosomal dominant
Mutations = increased risk of breast, ovarian, and prostate cancer
What is HBOC and why is it important to identify it early?
Hereditary Breast and Ovarian Cancer syndrome - Caused by BRCA1/2.
Important because breast cancer happens at earlier age, screening for breast cancer normally starts at age 40 in general population.
What ethnic group has the highest prevalence of BRCA1/2? How are they screened?
Ashkenazi Jewish - 1/40 versus 1/400 for general population
Screened for one of three common founder mutations
How is the general population screened for hereditary cancers, and specifically BRCA1/2?
Most commonly a point mutation, but sometimes indels. Use a gene panel to look for all hereditary cancer causes -> once mutation is found, single site analysis can be performed which is specific to the family and much cheaper
What is the screening protocol for breast cancer in HBOC?
Mammograms starting at age 25 rather than 40
Breast MRI’s yearly
Option for bilateral masectomy for risk reduction
What is the recommendation for ovarian cancer prevention in HBOC and why?
Bilateral salpingo-oophorectomy (tubes, ovaries) since screening modalities are ineffective at picking up the cancer at an early, treatable stage
What is the gene implicated in Li Fraumeni Syndrome and what cancers are associated? How does this differ from HBOC?
TP53 gene
-Breast, osteo and soft tissue carcomas
Difference: Risk of childhood cancer in up to 42% of patients -> screen very early, annual MRI by age 20
In all hereditary breast cancer syndromes other than HBOC, what is special about their ovarian cancer risk?
There is no increased risk above baseline, for all
What is the gene implicated in Cowden Syndrome / Hamaratoma Tumor Syndrome and what cancers are associated? How does this differ from HBOC?
PTEN gene
Breast, thyroid, and endometrial cancers.
Difference: Increased risk for GI polyps and skin lesions so colonoscopy is needed earlier (age 35), as well as thyroid + endometrial cancers
What is the gene implicated in Hereditary Diffuse Gastric Cancer and what cancers are associated? How does this differ from HBOC?
CDH1 gene
-Lobular breast cancer, diffuse gastric cancer
Differences: Prophylactic gastrectomy needs to be done, lobular breast cancer (vs typically ductal)
Why are multigene panels increasing in use?
You can cover many genes at once, takes less time than gene-by-gene strategy, less expensive, and identifies a mutation not suspected by family history
What are some of the shortcoming of multigene panels?
There are high rates of variants of unknown significance, and some mutations when found will have much environmental interplay with little clear guidance in how to address them
What percentage of colon cancer is hereditary, and what percent of this is caused by Lynch syndrome?
5%, 80% are caused by Lynch syndrome.
What puts a person at increased risk of colon cancer relative to the general population?
History of polyp, colorectal cancer, or inflammatory bowel disease
Positive family history
What is APC? How often are familial forms de novo?
Adenomatous polyposis coli gene, autosomal dominant tumor suppressor but de novo in 30% of cases. Causes FAP or attenuated FAP
How do FAP and attenuated FAP differ with regards to polyp burden? Age of cancer diagnosis?
FAP: 100-1000, near 100% risk of cancer without colectomy, age of diagnosis of cancer is 39
Attenuated FAP: 10 to 100 adenomas, average of 30 polyps, cancers occur on right side of colon, average age >50
How do FAP and attenuated FAP differ with regards to extracolonic manifestations?
FAP: dental anamolies, desmoids, benign cutaneous lesions, hypertrophy of RPE
Attenuated: Much rarer to have extracolonic
What is FAP + extracolonic lesions called?
Gardner syndrome
Why is sigmoidoscopy acceptable for screening in FAP but not attenuated FAP?
attenuated FAP is more likely to have cancer in ascending colon -> need colonoscopy.
FAP needs screen annually
Attenuated FAP needs screen every 2-3 years
What is MAP and what causes it? Why is this special
MUTYH Associated Polyposis - symptoms very similar to attenuated FAP
-> autosomal RECESSIVE inheritance
What causes Lynch syndrome? Where does it cause cancer?
DNA mismatch repair gene defect, autosomal dominant.
Causes cancer in early age of onset in proximal colon
What other cancers are associated with Lynch syndrome?
- Endometrial cancer
- Ovarian cancer
- Stomach cancer
What are the screening guidelines for colorectal cancer in Lynch syndrome?
Colonoscopy at 20-25 years of age, repeating every 1-2 years.
What genes are involved in Lynch syndrome? Why is EPCAM included?
MLH1, MSH2 (these two make up 90%), PMS2, MSH6
EPCAM is included in this because EPCAM can inactivate MSH2 if part of a germline deletion
When is tumor tissue testing for colon cancer indicated, and what are the two types?
Always indicated, should check for Lynch syndrome everytime there’s cancer (only other time you diagnosis is when you’re screening a high risk individual)
- Microsatellite instability
- Immunohistochemical staining
How does microsatellite instability work?
Marker of deficient DNA mismatch repair, cancers with poor DNA mismatch will have more fragments than just the two alleles at any given locus. Is not DIAGNOSTIC but rather suggestive of Lynch syndrome
How does immunohistochemical staining (IHC) work? How does this relate to Lynch syndrome?
Test for expression of four mismatch repair proteins. Loss of one of these can occur in 10-15% of colon cancers, so this is not diagnostic. Need to verify mutation in germline cells for definitive Lynch syndrome diagnosis.
