Colorectal cancer genetics and signalling transduction

Question 1

Cancer

Answer 1

Second leading cause of death
1 in 2 diagnosed
1 in 4 will die
Importance of understanding mechanism
Develop therapeutic strategies for those in need

Question 2

Oncogenes

Answer 2

Cancer is a genetic disease
Oncogenes and tumour suppressor genes
Mutated
Unrestricted cell growth
Ras, raf, TP53
Guardian of genome
Proliferation

Question 3

Colorectal cancer

Answer 3

10% cancer deaths
Genetic mechanism of cancer
Colon - digest waste for excretion
Highly efficient
Self renewal 3-5 days
10 billions cells into lumen - apoptosis

Question 4

Colon physiology

Answer 4

Cancer progression differs between segments
Leucine rich G protein containing repeats 5 (Lgr5+) ISC
Transit amplifying cells (TA)
Differentiation into secretory and absorptive lineages
WNT and BMP signalling regulation

Question 5

Genetics in colorectal cancer

Answer 5

Step by step tumour progression
APC - polyp
KRAS - early adenoma
DCC - late adenoma
TP53 - malignancy

Age risk
Obesity, diabetes, microbiome, diet etc.

Question 6

Hallmarks

Answer 6

Resisting cell death
Sustained proliferation
Angiogenesis
Invasion and metastasis
Evade growth suppression

Newer:
Avoiding immune suppression
Tumour-promoting inflammation
Unlocking phenotypic plasticity
Differentiate and adapt morphology to environment

Question 7

Signalling transduction

Answer 7

EGFR-RAS-MAPK/ERK
WNTB-CATENIN - MYC/CYCLIND1

Pro-proliferative pathways

50% mutations in KRAS, NRAS or BRAF in CRC
APC loss - b catenin accumulation

Cell survival and proliferation

Question 8

EGFR monoclonal antibodies

Answer 8

Cetuxuniab
Patinunumab
First generation of personalised cancer treatments
Metastatic CRC (approved)
EGFR bind and inhibit
Not working as effectively as hoped
Non-EGFR cells also respond - limitation