Genetic Predisposition to Cancer Flashcards
What are somatic mutations?
Occur in nongermline tissues
What are germline mutations?
Mutations in germ cells - responsible for producing eggs and sperm. Heritable, cause cancer family syndromes
What is the function pf proto-oncogenes?
Codes for proteins that regulate cell growth and differentiation
What is an oncogene?
Mutated proto-oncogene
what is the effect of oncogenes?
Accelerate cell division
How many mutations of the chromosomes are needed before control of the cell cycle is lost in oncogenes?
1 mutation needs to occur
What is the function of tumour suppressor genes?
Slow down cell division
Repair DNA mistakes
Tell cells when to die (a process known as apoptosis or programmed cell death)
What is the function of DNA damage response genes?
The repair mechanics for DNA
Cancer arises when both genes fail, speeding the accumulation of mutations in other critical genes
What is the function of Mismatch repair genes?
MMR corrects errors that spontaneously occur during DNA replication like single base mismatches or short insertions and deletions
What does Micro satellite instability an indicator of?
Phenotypic evidence that MMR is not functioning normally.
Cells with abnormally functioning MMR tend to accumulate errors, simple sequence repeats are created
Give an example of a cancer syndrome associated with Oncogenes
MEN2 (Multiple endocrine neoplasia)
Familial medullary thyroid cancer
Can be caused by viruses
Give an example of a cancer syndrome associated with Tumour suppressor gene
Breast/ovarian cancer FAP Li-Fraumeni syndrome Retinoblastoma
Give an example of a cancer syndrome associated with DNA repair (mis-match repair)
HNPCC / Lynch Syndrome
(Hereditary non-polyposis colon cancer)
What are other causes of cancer?
Autosomal recessive syndromes
E.g. MYH polyposis
Multiple modifier genes of lower genetic risk
What is a De Novo mutation?
New (de novo) mutation occurs in germ cell of parent
No family history of hereditary cancer syndrome
A new mutation in a germ cell?
Describe cancer susceptibility genes
They are dominant with incomplete penetrance
Is heritable retinoblastoma usually bilateral or unilateral?
Usually bilateral
Does heritable retinoblastoma usually contain a family history?
Yes in 20 percent of cases
What are the risk factors of breast cancer?
Ageing, family history, Early menarche - first period, late menopause, Nulliparity -not having children
Estrogen use, dietary factors, lack of exercise.
What are the common genes responsible for breast cancer?
BRCA1 BRCA2 TP53 PTEN Undiscovered genes
What is the function of BRCA1?
Checkpoint mediatorDNA damage signalling and repairChromatin remodelling (inactive X chromosome)Transcription (not essential for this)
(PROTEIN THAT ACTS AS A TUMOUR SUPPRESSOR)
What is the function of BRCA2?
DNA repair by HR (homologous recombination)
What are the BRCA1 associated cancers?
Breast cancers, second primary breast cancer
Ovarian cancer
What are the BRCA2 associated cancers?
Breast cancer, ovarian cancer, male breast cancer
Increased risk of prostate, laryngeal, and pancreatic cancers (magnitude unknown)
What are risk factors for colorectal cancers?
Ageing Personal history of CRC or adenomas High-fat, low-fibre diet Inflammatory bowel disease Family history of CRC
What is the sequence of events for Adenoma to carcinoma?
Epithelium becomes hyperactive, adenoma forms, carcinoma forms
How many adenomas are present in non-polyposis (Hereditary Colorectal Cancer (CRC) syndromes)
few to no adenomas
HNPCC (hereditary non-polyposis colon cancer / Lynch Syndrome) - CRC &/or endometrial cancer (EC
How many adenomas are present in polyposis (Hereditary Colorectal Cancer (CRC) syndromes)
(multiple adenomas)
FAP – severe colonic polyposis +/- CRC
AFAP - less severe colonic polyposis +/- CRC
MAP – varying degrees of colonic polyposis +/- CRC
FAP – familial adenomatous polyposis
AFAP – attenuated FAP
MAP – MYH associated polyposis
What are the clinical features of HNPCC
Early but variable age at CRC diagnosis (~45 years)
Tumor site throughout colon rather than descending colon
Extracolonic cancers: endometrium, ovary, stomach, urinary tract, small bowel, bile ducts, sebaceous skin tumors
What are clinical features of FAP?
Estimated penetrance for adenomas >90%
Risk of extracolonic tumors (upper GI, desmoid, osteoma, thyroid, brain, other)
CHRPE may be present
Untreated polyposis leads to 100% risk of cancer
Describe the effect of attenuated FAP
Later onset (CRC ~age 50) Few colonic adenomas Not associated with CHRPE Upper GI lesions Associated with mutations at 5' and 3' ends of APC gene
What condition is similar to attenuated FAP?
Recessive MYH polyposis
Common mutations in mut- MYH gene
What can Multiple modifier genes explain?
May explain families with history of cancer and no identified mutation
May explain differences in cancer penetrance in families with same mutation
How can you manage caner risk in Adenomatous Polyposis syndromes?
Surveillance
Surgery
Chemoprevention
What portion of cancers are due to inherited mutations?
Only a small portion
