cancer 7 Flashcards
- bowel cancer affects — system also known as —–
- Incidence: — most common cancer in the world1
- Risk factors: Age, Poor diet, Obesity, Smoking, Excess alcohol, Family history including — conditions
(e.g. FAP, HNPCC)
digestive
colon rectal and colorectal
3rd
heredity
symptoms of colorectal cancer:
* In early stages, often –
* Changes in bowel movement , including persistent constipation or diaherria
* Abdominal discomfort or bloating
* Loss of appetite / weight loss
* Blood in stool (faecal occult blood test (FOB))
* Unexplained anaemia / fatigue
* Long, thin, “pencil stools“ (rectal cancer)
* Pelvic pain, which occurs at later stages of the disease
no symptoms
multi model of colon cancer development :
* Vogelstein’s theory of colonic carcinogenesis
* Different — changes are associated with progression of adenoma of colon (benign neoplasm) to carcinoma of the colon
* More than — — mutation is generally needed to produce a full-fledged cancer cell
* About – DNA changes must occur for a cell to become fully cancerous
* Typically occur over several —
* Usually includes at least one —- and — or — of several — genes
genetic
one somatic
6-7 dna
decades
one active oncogene
mutation
loss
tumour-suppressor
( check slide 6,7)
staging of bowel cancer:
* TNM staging system:
– — of the tumour (T)
– if it has spread to — (N)
– if it has spread to other parts of body as — (M)
- Stage 1: tumour is in — of — or – only.
- Stage 2: tumour is in — of — or –
and may have spread to nearby — . - Stage 3: tumour has spread to nearby —
- Stage 4: tumour has spread to other — e.g. liver or lungs. aka — cancer.
size
lymph nodes
metastases
inner wall of colon or rectum
muscle layer of colon or rectum
nearby tissues
lymph nodes
other parts of body
advanced
- Colonoscopy examines the — of colon.
- Sigmoidoscopy examines only the —
( Sessile - no stalk is present
Pedunculated - attached to the surface by a narrow elongated stalk)
entire length
lower 3rd
colon cancer occurrence :
* 75% – - damage to the genes occurs by — after a person is born (typically at older age), no prior —
* 20% — - — that occurs in >1 family member; may have — or — etiology. A single gene, a combination of genes, or a combination of genetic and environmental/lifestyle factors.
* 5% — - when the exact gene defect that causes the disease in a family is—.
sporadic
by chance
family history
familial
phenotype
genetic or non genetic
heredity
known
APC tumour suppressor gene in colon cancer :
- APC: adenomatosis polyposis coli
- Tumour suppressor gene (TSG)
- Mutated in large % of – & –
colon cancers - Familial adenomatous polyposis (FAP) – inherit – mutated APC allele (— pattern, one copy of the altered gene is sufficient to cause the disorder)
- APC protein involved in many pathways:
- Wild type APC decreases — – loss of – function results in dysregulated expression of — e.g.
- Cyclin D1 – proliferation
- MMPs – matrix degradation + invasion
( basically APC is a tumour supressor which is highly mutated in colorectal cancer )
sporadic n inherited
one
autosomal dominant
b- catenin
APC function
b-catenin-regulated genes
genetic syndrome the increases the risk of colon cancer:
Genes associated with a higher risk of colon cancer are — .
Only ~5 % cases are linked to – genes.
* Familial adenomatous polyposis (FAP), inherited — gene. Near 100% lifetime chance of developing CC.
* Lynch Syndrome/Hereditary nonpolyposis colorectal cancer
(HNPCC),
‘Nonpolyposis’ means that the cancer can occur with only a —
number of polyps present, or even with – at all.
Inherited mutation in one of several DNA — genes, e.g. hMSH2 and hMLH1. 80% lifetime chance of developing CC.
* Peutz-Jeghers syndrome, associated with mutations in — gene (STK11: signal transduction molecule- serine threonine kinase).
rare
inherited genes
mutated APC
small
none
mismatch repair genes
STK11/LKB1
genes associated w predisposition to other cancers :
* Breast/ovarian – mutation in — TSGs (role in — DNA repair)
* Retinoblastoma – mutation in — TSG (Rb protein prevents excessive — by inhibiting — progression until a cell is ready to divide)
* Renal cell carcinoma – mutation in — TSG (von Hippel-Lindau disease - VHL is a ubiquitin ligase that targets
proteins for — e.g. HIF1a)
* Familial melanoma – mutation in — TSG (codes for — , involved in Rb pathway – cell cycle
regulation)
BRCA1/BRCA2
double strand
rb
excessive cell growth
cell cycl;e
VHL
degradation
CDKN2A
p16
personalised medicine in cancer:
* — programmes e.g. BRCA1 mutations
* — – high risk populations, e.g.
colonoscopy/FAP familial cancer
* — diagnostics (e.g. IHC for oestrogen receptor, ER+ tumour treated with anti-oestrogens)
* Monitoring individual response to — , biomarkers e.g. CEA (carcinoembryonic antigen)
* — therapy based on — of the tumour (precision medicine)
screening
monitoring
molecular
treatment
molecylary targeted therapy
molecular features
Select the most appropriate
treatment for each patient
based on the knowledge of
the molecular abnormalities,
such as genetic mutations, in
the patients’ tumour.
this is known as
precision medicine
- — receptor expressed by two-thirds of all human cancer cells
- Upregulated in —
- — of – as therapeutic strategy
Cell surface growth receptor
CRC
inhibitors of EGFR
- Cetuximab (Erbitux) - chimeric (mouse/human) monoclonal antibody, an —-
- Given by — for treatment of mCRC and – & – cancer.
epidermal growth factor
receptor (EGFR) inhibitor
iv infusion
head n neck
- KRAS gene encodes a — with —
activity in the EGFR pathway. - Cetuximab and other EGFR inhibitors only work on tumours that are — (i.e. wildtype KRAS)
- 2009, FDA updated labels of two anti-EGFR MoAbs; panitumumab (human Mab) and cetuximab to include
information about KRAS mutations. - Genetic testing to confirm the absence of — mutations (i.e. presence of the KRAS wild-type gene) now routine before treatment with EGFR inhibitors.
- ~65% of mCRC patients have —
small G protein w gtpase
not mutated
KRAS
KRAS wild-type gene.
—– Is Predictive of Response to Cetuximab Therapy in
Colorectal Cancer
KRAS Mutation Status
