Flashcards in Lynch Syndrome (Abali) Deck (84):
Individuals with Lynch syndrome are at an increased risk of
Colorectal cancer (CRC), endometrial cancer, and several other malignancies
The majority of lynch syndrome patients are asymptomatic until they present with symptoms of colorectal cancer such as
Gastrointestinal bleeding, abdominal pain, or a change in bowel habits
The lifetime risk of CRC in Lynch syndrome is approximately
The incidence of CRC is moderately higher in men than in women, and although the age of onset varies by genotype, CRC in Lynch syndrome occurs at a
Younger age than other CRC's (44 years vs 69 years)
The mean age at colorectal cancer diagnosis in HNPCC is
The mean age at colorectal cancer diagnosis in HNPCC is 44 years with 70% located
Proximal to the splenic flexure
Individuals with Lynch syndrome suffer from increased incidence of
Synchronous and metachronus CRC
Cancers occuring within 6 months of the first primary cancer
Cancers occuring more than 6 months after the first primary cancer
Is the survival rate in people with CRC from lynch syndrome better or worse than individuals with CRC from a sporadic variant?
In Lynch syndrome, colorectal cancer is somewhat more likely to develop on the
Right (Proximal) side of the colon
For every 100,000 new cases of CRC in the united states, how many individuals will have lynch syndrome (Hereditary nonpolyposis colorectal cancer: HNPCC)?
(0.1% will have Familial Adenomatous Polyposis: FAP)
Lynch syndrome is caused by a germline mutation in
DNA MMR genes
Lynch syndrome is caused by a germline mutation in DNA MMR genes resulting in
Microsatellite instability (MSI)
The recognition of similar kindreds by Lynch et al10 in 1966 led to the description of a cancer-prone syndrome that included aggregation of colon, gastric, and notably, endometrial cancers, which they termed the
"Cancer Family Syndrome"
Lynch syndrome is due to mutations in which MMR genes?
MSH2, MLH1, and MSH6
What type of inheritance pattern is seen in HNPCC (Lynch syndrome)?
Suggests a clustering of cancers that probably occurred by chance. In other words, there may be a combination of genetic and non-genetic (i.e., environmental) factors that contributed to the development of cancers within a family.
Means that an alteration in a single major gene strongly contributes to the development of cancer or cancer-related conditions within the family.
Why is Lynch syndrome favored as the name over HNPCC?
Because it is associated with more cancers than just CRC
Microsatellite instability caused by defects in DNA mismatch-repair genes are either
Inherited as germ-line defects, or somatically acquired
What are the three genetic instability pathways that drive colon neoplasia?
Chromosomal instability, Microsatellite instability, and the CpG island methylator phenotype
Mutations in which genes account for 90% of patients with Lynch Syndrome?
MSH2 and MLH1
Mutations in hMSH2 or hMLH1 usually result in high levels of
Mutations in genes such as hMSH6 result in low levels of
MMR protein that functions in recognition of mismatch
Single base mismatches are bound by
Large insertion/deletion loops are recognized by
When a mismatch is generate, the recognition complex binds the DNA as a
When a mismatch is generated, the recognition complex binds the DNA as a heterotetramer. After binding, the complex recruits an
Excision nuclease (from either 5' or 3' direction)
In bacteria, the complex is able to recognize which strand to correct because the parental strand is
One type of error called "slippage" can occur while DNA polymerase is replicating
Defined as short dinucleotide or mononucleotide repeats
Microsatellite sequences are usually within
Backward slippage causes
Forward slippage causes
Recruited by MSH2/MSH6 binding to complete the tetramer
MLH1 and PMS2
Acts as an endonuclease and cleave the newly synthesized strand on either site of the mismatch
MLH1 and PMS2
Degrades the section of the strand containing the Mismatch
How can we detect MSI?
PCR using MSI markers and immunohistochemistry
Observed by designing PCR primers in sequence flanking the actual repeat and analyzing the PCR products using gel electrophoresis or an automated sequencer that separates the products on the basis of size.
Microstate instability is analyzed by assessing the stability of at least
Five microsatellite loci
MSI can be detected either using
Gel electrophoresis or Capillary Electrophoresis
Absence of staining of one or more of the MMR gene proteins in the tumor is consistent with a mutation in the gene and suggests the presence of
Lynch syndrome shows and autosomal dominant inheritance with a colon cancer penetratance of
Lynch syndrome shows and autosomal dominant inheritance with an endometrial cancer penetratance of
What is Amsterdam Criteria I for determining Lynch Syndrome?
At least one familial cancer case diagnosed before age 50
What is Amsterdam Criteria II for determining Lynch Syndrome?
Cases span at least two generations
Must have Three relatives with an HNPCC associated cancer, one a first degree relative of the other two
Amsterdam Criteria III
Says that the Amsterdam Criteria must be met and that the patient is younger than age 50
Amsterdam and Bethesda criteria are met, and there is a population screening of colon and uterine cancer by MSI/IHC
Clinical Criteria for Lynch Syndrome
95% of HNPCC tumors have
MSI at multiple loci
10-15% of sporadic tumors have
An immunohistochemistry screening for lynch syndrome is abnormal if their are
Specific protein(s) absent in the tumor tissue
Which disease has a Lynch like phenotype?
Polymerase proofreading associated polyposis (PPAP)
Characterized by an increase in childhood cancers, mainly hematological malignancies and/or brain tumors, as well as early onset CRC's
Constitutional mismatch repair deficiency (CMMR-D)
Almost all patients with CMMR-D also show signs reminiscent of
Neurofibromatosis type 1 and coffe-like stains
New class of genes that may cause polyposis (polymerase proofreading-associated polyposis) and/or Lynch syndrome esq phenotype
POLE and POLD1 genes
Characterized by young onset colon adenomas (
POLE and POLD1 mutations
Can be due to either MMR mutations, or APC mutations
Characterized by CNS tumor in addition to colorectal cancer or polyposis
How does Muir Torre differ from classic Lynch Syndrome?
Skin tumors (sebacous or keratocanthomas)
Prospective studies show the males with Lynch Syndrome can have a 5x increased risk for
The highest risk of lynch syndrome patients for prostate cancer was with
Classified as: the majority of markers exhibit microsatellite instability
Classified as: only a minority of the markers exhibit microsatellite instability
Classified as: None of the markers exhibit microsatellite instability
MSS (Microsatellite Stable)
Defined as having instability in two or more markers
Defined as having instability in one marker
Short repetitive sequences consisting of 1-4 base nucleotide of DNA. These repeat sequences can often be read as DNA “fingerprints” for individual human beings.
If a tumor tissue travels less far that normal tissue in gel or capillary electrophoresis, it means that the tumor incurred mutations that
Made the microsatellites larger
Under autosomal recessive inheritance, what percentage of children will get the disease?
Under autosomal dominant inheritance, what percentage of children will get the disease?
Inactivation of MLH1 could be hereditary (as in Lynch syndrome), or it could be due to
Methylation of CpG island (Not lynch syndrome)
Mutations in which two MMR proteins typically result in high MSI?
hMSH2 or hMLH1
Mutations in which MMR protein typically results in low MSI?
Are heterodimers; if one is deleated, the other will likely be deleated as well
MSH2 and MSH6
Transcriptionally silences MSH2 through methylation
Amsterdam criteria only picks up about
50% of cases
Newer criteria for diagnosing lynch syndrome where the patient already has cancer, and you only have to meet one of the criteria
Patients with CMMR-D experience biallelic inheritance of the MMR gene for PMS2, what does this mean?
They receive two defective copies of the gene
If you were to perform immunohistochemistry on a patient with CMMR-D, what would you expect to see?
Lack of PMS2 in both healthy and tumorous cells due to biallelic inheritance
The PPAD related genes POLE and POLD1 are characterized by a
Microsatellite stable tendency