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Flashcards in Genetic Predisposition to Cancer Deck (47):

What are somatic cells?

Cells that do not reproduce


Where do somatic mutations arise from?

Occurs in non-germline tissue and are non-heritable


Where do Germline mutating rise from?

Present in egg or sperm and are inheritable - cause cancer family syndromes


What genes are associated with cancer?

Oncogenes, tumour suppressor genes and DNA damage-response genes


What are proto-oncogenes?

Normal gene that codes for proteins to regulate cell growth and differentiation


What are oncogenes?

Mutated proton-oncogenes that can accelerate cell division


What is you first mutation that leads to cancer development and what are its effects?

Oncogenes - causes uncontrolled cell proliferation


What are tumour suppressor genes?

Control cell cycle - by inhibition or initiating apoptosis but when its action fails cancer arises


What is the two-hit hypothesis?

Two mutations required for cancer to arise
First mutation can be inherited making individual susceptible carrier and then a second mutation or loss of certain gene leads to cancer


Second mutation that can cause cancer?

Loss of tumour suppressor genes


What are DNA damage-response genes?

Repair mechanics for DNA - cancer will arise when both genes fail, speeding the accumulation of mutations in other critical genes


What are mismatch repair (MMR) genes?

Correct error that spontaneously occurs during DNA replication (single base mismatch, short insertions or deletions etc)

If gene is defective, faulty DNA is not repaired and leads to mutated DNA


What does MMR failure lead to?

Microsatellite instability (MSI) - phenotypic evidence that MMR is not functioning properly as MMR failure accumulates error like simple sequence repeats (SSRs)


Describe benign tumours

Cannot metastasise, and rarely becomes cancerous but can still cause negative health effects due to pressure on other organs


Describe dysplastic tumours

They are benign tumours but could progress to malignancy

Cells have abnormal appliance and cell maturation - "pre-mailgnant"


Describe Malignant tumours

Able to metastasise


What gene process is affected in Breast/Ovarian cancer and how?

Mutated BRCA1, BRCA2 genes alter Tumour suppressor genes


What gene process is affected in Li-Fraumeni syndrome and how?

Mutated P53 alters Tumour suppressor gene


What is a De Novo mutation?

New mutation which occurs in germ cell of parent in people with no family history of hereditary cancer syndrome


In what cancers are De Novo mutations common in?

Familial adenomatous polyposis
Multiple endocrine neoplasia 2B
Hereditary retinoblastoma


What kind of genes are cancer susceptibility gene?

Dominant with incomplete penetrance - people with condition which hasn't developed into cancer


In pedigree charts, what does a circle (or square) with a line though the middle indicate?

That person is a susceptible carrier


Features of Retinoblastoma

-1/20 000 children
-Common eye tumour in children
-Can be hereditary or sporadic
-Identify susceptible infants to reduce morbidity and motility


Where is the mutation in Retinoblastoma?

Germline mutation in RB1 gene


Nonheritable vs heritable: Features on the tumour in RB cancer

Non- unilateral
H - bilateral (both eyes)


Nonheritable vs heritable: Features on the risk of second primaries in RB cancer

Only in heritable - osteosarcoma, other sarcomas, melanoma


Risk factors for breast cancer

-Dietary factors (alcohol)
-Lack of exercise
-Late menopause
-Early menarche
-Estrogen use


What genes contribute to breast cancer and how?

BRCA1 and BRCA2 - normal genes code for tumour suppressor genes so a mutation in them leads to faulty TSG


What process is affected in HNPCC (hereditary non-polyposis colon cancer) and by what genes?

MLH1, MSH2, MSH6, PMS1, PMS2 alter MMR gene so that it doesn't repair DNA


What is the function of the BRCA1 gene?

Checkpoint mediator, involved in DNA damage signalling and repair and chromatin remodelling


Function of BRCA2

DNA repair by homologous recombination


What are BRCA1-Associated cancers?

-Breast cancer
-Secondary primary breast cancer
-Ovarian cancer

Increased risk of other cancers - i.e. prostate, colon


What are BRCA2-Associated cancers?

-Breast cancer
-Ovarian cancer
-Male breast cancer

Increased risk of prostate, laryngeal and pancreatic cancers


Risk factors for Colorectal Cancer (CRC)

-History of CRC or adenomas (dysplastic)
-High fat, low-fibre diet
-Inflammatory bowel disease
-Family history of CRC


Adenoma to Carcinoma sequence

1. Normal epithelium
2. APC mut. - Hyperproliferative epithelium
3. k-ras mut. - Adenoma
4. p53 mut. - Carcinoma


What is the nonpolyposis hereditary CRC syndrom?

HNPCC - few to no adenoma


Types of polyposis Hereditary CRC syndromes?

FAP - severe colonic polyposis
AFAP - less severe
MAP - varying degrees


Clinical feature of HNPCC

-Early but variable age at CRC diagnosis (~45yrs)
-Tumour through colon
-Extracolonic cancers: endometrium, ovary, stomach, UT, small bowel, bile ducts, sebaceous skin ducts


Clinical features of FAP

-Penetrance of adenomas >90%
-Risk of extracolonic tumours - upper GI, desmoid, osteoma, thyroid, brain - usually benign but pressure effect)
-CRHPE my be present (spot on retina)
-Untreated leads to 100% risk of cancer


What is attenuated FAP (AFAP)?

Less sever colonic polyposis with a later onset in life.

Few colonic adenoma but still dysplastic so can develop into tumour

Upper GI and associated with mutations as 5' and 3' ends of APC gene


What is recessive MYH polyposis?

-Similar clinical features to AFAP
-Common mutation in mut. MYH gene
-Recessive inheritance


What are modifier genes?

Genes that influence expression of another gene

May explain families with history of cancer and no indemnities mutation and the difference in cancer penetrance in families with same mutation


How to manage cancer risk in adenomatous polyposis syndromes



Predictive gene tests problems

-Not always possible or required
-Problems of gene variant of unknown significance (VUS) - whether it'll develop into cancer
-For adult onset cancers, predictive gene test. not offered until adult hood


What is exome sequencing?

Looking at specific part of gene


What is genome sequencing?

Looking at entire genome (code)


How do most people develop cancers?

Most due to sporadic mutations and only a small number due to inherited mutations