Cancer Genetics

Front 1

MSH2 and BRCA1 are _______ genes that maintain genomic integrity.

APC, VHL, and PTEN are _________ genes that regulate cell growth.

RAS, c-MYC, and HER2/NEU are _______, and their activation leads to carcinogenesis.

Back 1

Caretaker (tumor suppressor)
Gatekeeper (tumor suppressor)
Oncogenes

Front 2

In the “two hit” paradigm for inherited cancer (discussed in another lecture), what is the second hit and how does it come about?

Back 2

The first hit is the inheritance of a bad allele. The second hit is the loss of the remaining good allele. This second hit DOES NOT usually come about via a separate mutation, but is rather the result of a mistake made during cell division in which one of the daughter cells only gets the mutated copy of the gene.

Front 3

Almost all inherited cancers are inherited in an autosomal _____dominant or recessive_____ manner with ______complete or incomplete______ penetrance.

Back 3

Dominant
Incomplete

(Note: it’s passed down in an autosomal dominant manner, but on the cellular level, it behaves in a recessive manner → both genes must be knocked out for there to be an effect.)

Front 4

How can you distinguish inherited from sporadic retinoblastomas?

Back 4

Inherited (one germline mutation + one somatic mutation):
• Multiple tumors
• Bilateral (note: not a metastasis, but a completely separate tumor)
• Early-onset
• Mendelian inheritance pattern

Sporadic (two separate somatic mutations):
• Single tumor
• Unilateral
• Later-onset
• “out of the blue” inheritance

Front 5

The _______ gene is ubiquitously expressed. It is implicated particularly in retinoblastoma, but also in other cancers, such as pinealomas, osteosarcomas, soft tissue sarcomas, and melanomas. _______ can induce second hits for people with a mutation in this gene.

Back 5

RB1
radiotherapy

Front 6

Besides retinoblastoma, what other cancers may result from loss of heterozygosity? What are the associated genes? What TYPE of genes are (nearly) always involved in loss of heterozygosity cancers?

Back 6

Familial polyposis coli; colorectal carcinoma → APC
Colorectal carcinoma; breast carcinoma → Tp53
Colorectal carcinoma → DCC

These always involve tumor suppressor genes

Front 7

What is multiple endocrine neoplasia (MEN2)? What is unusual about this particular cancer syndrome? What type of mutation causes MEN2, and how does that bear on genetic testing decisions?

Back 7

MEN2 is due to mutations in RET proto-oncogene, inherited in an autosomal dominant manner (though lower penetrance may result in “skipping” generations). Associated with three types of endocrine cancers: thyroid, parathyroid, pheochromocytoma. This is an unusual case because it is an INHERITED cancer that is actually the result of an ONCOGENE (normally inherited cancers result from tumor suppressor genes). So this is a Gain of Function mutation, (in this case the RET → receptor tyrosine kinase complex).

Hyperactivity mutations are always MISSENSE mutations. Therefore, for a genetic test, you’re not going to be doing FISH or looking for deletions or frameshift mutations. And since the mutation involves different phosphorylation of particular molecules, it is possible to create a very specific assay to diagnose this type of syndrome.

Front 8

Describe Li Fraumeni syndrome. What is the mutation? What types of cancers are associated with the syndrome?

Back 8

Li Faumeni syndrome is the most rare, but also the worst type of inherited cancer syndromes, usually due to p53 mutations. Autosomally dominantly inherited.

Most commonly: Early onset breast cancer, sarcomas (also early onset, often pediatric).

But you’ll also see pretty much ANY kind of cancer: specifically – brain tumors, lymphoma, leukemia, adrenocortical carcinoma, prostate cancer.

Note: unlike MEN2, this is 100% penetrant. If you live long enough, you WILL end up with a cancer.

Front 9

________ mutations are the most common mutation in sporadic cancers.

Back 9

p53

(note: also true for inherited cancers)

Front 10

ALL cancers are genetic in that it is the genes responsible for cell division that cause the cancer, but only ______% of breast and ovarian cancers are INHERITED. The majority (______%) of inherited breast cancers are the result of the inheritance of a mutated BRCA-1 or BRCA-2 gene. These genes are also implicated in the inheritance of _________ cancer. This is inherited in a ___(dominant or recessive)_____ fashion. The mutation in these genes are ____loss or gain____ of function mutations. The penetrance for BRCA-1 and BRCA-2 is higher for ____(ovarian or breast)____ cancer. The prognosis for someone with breast or ovarian cancer who is positive for a BRCA-1 or 2 mutation is _____(better or worse)______ than someone with a sporadic cancer.

Back 10

7-10 (respectively)
84 (52 for BRCA-1; 32 for BRCA-2)
ovarian
dominant
loss
breast
better (or the same) (especially with chemotherapy)

Front 11

What is PARP therapy and how does it work?

Back 11

PARP therapy: Poly ADP-ribose polymerase inhibitors.

The BRCA-1and 2 proteins are involved in single stranded break repair, so mutations lead to defective, non-homologous end joining, which leads to instability across the genome. The PARP protein is involved in DNA base excision repair. PARP therapy actually induces a SECOND mutation in a different DNA repair protein (i.e. INHIBITS PARP), which will cause the cell to have a SECOND replicating error. Twice the errors means that these cells will be more likely to be arrested at the G2/M checkpoint and sent for cell death.

NOTE: the key here is that BRCA 1 & 2 mutated cells are much more sensitive to PARP inhibition than other cells (PARP inhibitors seem to have no effect on cells with functional homologous recombination). So this is a TARGETED way to kill these cells → much more refined than massive, non-specific cytotoxic therapies.

Front 12

What happens when you inherited BOTH BRCA-1 and BRCA-2? What happens when you inherit two copies (homozygous) of either BRCA-1 or BRCA-2? What happens if you have two separate mutations on BRCA-2?

Back 12

Inherit both BRCA-1 and 2 → similar to if you just inherited one or the other (does not result in infantile cancers)

Homozygous → no known cases; probably lethal in utero

Two mutations on BRCA-2 → results in completely different phenotype. Instead of early onset breast cancer, you’ll get “Fanconi Anemia” (aplastic anemia). Also birth defects and infantile cancer (esp leukemia and brain cancers).

Front 13

What is HNPCC? How is it inherited? What genes are commonly mutatated and what are they responsible for?

Back 13

Hereditary Non-Polyposis Colon Cancer → inherited autosomal dominantly.

Mutations in MLH1, MSH2, MSH6 are the most common genes involved → these are DNA mismatch repair genes. Mutations in these genes lead to accumulation of point mutations and microsatellite instability.

Front 14

What is Microsatellite Instability (MSI)?

Back 14

This is a hallmark feature of HNPCC that can be used in diagnosis. (This feature is found in >90% of HNPCC-associated colorectal cancers, compared to 15% of sporadic cancers.)

Microsatellites are repeating DNA sequences (di-, tri-, or tetra-) of unknown function found through out the genome. “Instability” refers to when the length of the DNA sequence in a tumor differs from that in nontumor tissue. This happens because a defective mismatch repair gene is not able to keep the fidelity of the repeat sequences from cell division to cell division (“slippage”).

Since MSI is also seen in sporadic cancers, it is not a definitive diagnostic test, but it can be used as a “prescreen” colorectal patients to see if they are candidates for genetic mutation analysis. The genetic testing can be done on paraffin-embedded tumor, which means that it can be done years after diagnosis and resection.

Front 15

What other cancers are associated with HNPCC?

Back 15

Colorectal, Endometrial, Gastric, Ovarian

And to a lesser degree …
Small Bowel, Bladder, Brain, Kidney, Biliary tract

Front 16

What is FAP? What is the phenotype? How is it different from HNPCC? What gene is responsible for this?

Back 16

Familial Adenomatous Polyposis → due to mutations in the APC gene (Remember: APC is the gatekeeper that regulates beta catenin, which controls gene expression).

Unlike HNPCC, which increases your susceptibility to polyps and cancer, the classical phenotype of FAP is TONS (100,000 +) of polyps in colon and rectum, progressing to colorectal cancer, as well as in the upper GI tract progressing to duodenal cancer. This requires complete resection of the colon, not just “nipped in the bud” removal of polyps, as in HNPCC. Also unlike HNPCC, in FAP the polyps begin to appear in children.

Also → as you would expect with a young age of onset, 25% of FAP cases are DE NOVO mutations. 75% are autosomal dominant.

Front 17

Besides colorectal and duodenal cancer, what other phenotypes are seen in FAP?

Back 17

Other phenotypes:
• Mandibular osteomas
• Congenital hypertrophy of the retinal pigment epithelium
• Desmoids (benign fibrous tumors on musculoaponeurotic structures)
• Epidermoid cysts
• Supernumary teeth

Front 18

What is Von Hippel-Lindau syndrome?

Back 18

A rare inherited disorder characterized by abnormal growth of blood vessels (esp eyes, brain, kidneys, adrenal glands). Not malignant, but causes problems.

Autosomal dominantly inherited.