PoD - Genetic Predisposition to Cancer

Question 1

what is cancer genetics?

Answer 1

• cancer is a genetic disease of somatic cells
• most cancers happen by chance or due to environmental factors
• small proportion of cancers happen because of an increased inherited predisposition

Question 2

what type of mutations are associated with cancer?

Answer 2

• somatic mutation (occur in non-germline tissue and are non-inheritable)
• gremlin mutations (present in egg/sperm, can be inherited and can cause cancer family syndromes)

Question 3

what are tumours?

Answer 3

• tumours are clonal expansions
• develop over time
• every tumour is unique, tend to be grouped together in relation to the genes that are mutated

Question 4

what are oncogenes?

Answer 4

• proto-oncogenes - normal gene that codes for proteins to regulate cell growth and differentiation
• mutations can change a proto-oncogene into an oncogene
• oncogenes accelerate cell division
• 1 mutation is sufficient for cancer development
• cancer arises when stuck in “on” mode

Question 5

what are tumour suppressor genes?

Answer 5

• they are the cell’s brakes for growth
• genes inhibit cell cycle or promote apoptosis or both
• cancer arises when 2 mutations occur
• 1st mutation means individual is susceptible to develop cancer, 2nd mutation leads to cancer

Question 6

what are DNA damage-response genes?

Answer 6

• try to repair mutated DNA

- cancer arises when both genes fail, speeds the accumulation of mutations in other critical genes

Question 7

what does benign mean?

Answer 7

• tissues that rarely or never become cancerous
• lacks ability to metastasise
• can still cause health problems due to pressure on other organs

Question 8

what does dysplastic mean?

Answer 8

• benign but could progress to malignancy
• cells show abnormality go appearance and cell maturation
• pre-malignant

Question 9

what does malignant mean?

Answer 9

• cancerous

- able to metastasise

Question 10

describe what happens in retinoblastoma?

Answer 10

• most common eye tumour in children
• occurs in heritable and non-heritable forms
• identifying at-risk infants reduces morbidity and mortality - early detection means tumours can be treated with laser rather than eye removal
• occurs in germline mutations in the RB1 gene
• non-heritable = unilateral, no family history, diagnosis at 2 years
• heritable = usually bilateral, family history in 20% of cases, diagnosis less than 1 year, likelihood of developing second cancers

Question 11

what increases risk of breast cancer?

Answer 11

• ageing, family history, menopause, oestrogen use, lack of exercise
• genes contributing to familial breast cancer - BRCA1/2
• BRCA1 - 50-85% likelihood of developing breast cancer (early age). increases risk of ovarian cancer
• BRCA2 - 50-85% risk of breast cancer, 6% of male breast cancer, 10-20% ovarian cancer, increased risk of prostate/pancreatic cancers

Question 12

what increases risk of colorectal cancer?

Answer 12

• ageing, history of CRC or adenomas, high-fat/low-fibre diet, inflammatory bowel disease
• genetic changes

Question 13

list types of CRCs

Answer 13

• hereditary non-polyposis colorectal cancer (HNPCC) results from failure of mismatch repair genes
• hereditary polyposis CRC can have varying degrees of adenomas (FAP=severe polyps/AFAP=less severe/MAP=varying degrees of polyps)

Question 14

what are the clinical features of HNPCC?

Answer 14

• early but variable age at diagnosis
• tumour site throughout colon (not descending colon)
• high likelihood of extracolonic cancers (endometrium, ovary, stomach, UT, bowel)

Question 15

what are the clinical features of FAP

Answer 15

• Estimated penetrance for adenomas >90%
• Risk of extracolonic tumors (upper GI, desmoid, osteoma, thyroid, brain, other)
• CHRPE (congenital hypertrophy of the retinal pigment epithelium) may be present
• Untreated polyposis leads to 100% risk of cancer

Question 16

what are the clinical features of attenuated FAP?

Answer 16

• later onset (CRC ~50)
• Few colonic adenomas
• Not associated with CHRPE
• Upper GI lesions
• Associated with mutations at 5’ and 3’ ends of APC gene

Question 17

what are the new advances in breast cancer diagnosis?

Answer 17

• tests to check if people are triple negative for oestrogen, progesterone and HER2 receptors
• sporadic under age of 50
• check for gremlin mutations for family
• therapy = platinum based meds, immunotherapies

Question 18

what are the new advances in ovarian cancer diagnosis?

Answer 18

• will be germline screened
• need to identify germline mutations for family
• therapy = platinum based meds, immunotherapies