Colorectal cancer genetics diagnosis and management

Question 1

First of all what is an adenocarcinoma?

Answer 1

A cancer that develops in the mucus secreting glands (adenoids)

Question 2

What two genes are mutated in cancer?

Answer 2

tumour suppressor genes downregualted oncogenes upregulated

Question 3

What is the divide in % of sporadic somatic mutations: familial susceptibility to mutations for CRC?

Answer 3

Somatic: 70% familial: 30%

Question 4

what are some of the pathways that become deregulated in CRC?

Answer 4

Wnt/APc/β-catenin phosphoinositide 3-kinase (Pi3K)/AKt/glycogen synthase kinase-3β (GSK-3β) transforming growth factor-β (TGF)-β/Smad, NF-κb mismatch repair genes (MMr)

Question 5

What is the Wnt->frizzled->dishevelled->‘b-catenin’ pathway?

Answer 5

there are 3 wnt pathways, in cancer cells it is the canonical pathway

frizzled is a GPCR

it is bound to protein dishevelled

when Wnt binds, conformational changes activate dishevelled

this leads to the accumulation of b-catenin.

normally b-catenin is bound to a destruction complex that marks it for ubiquitation. However binding of Wnt to frizzled disrupts this and allows it to accumulate and transcribe to the nucleus where it acts as a transcriptional coactivator of transcription factors that belong to the TCF/LEF family.

Question 6

how is the PI3K, AKT, PTEN pathway involved in cancer cells?

Answer 6

there may be loss of negative feedback phosphatase PTEN which causes chronic stimulation of the growth factor stimulated PI3K pathway.

PI3K results in antiapopotosis, inhibition of autophagy and has growth promoting effects by increasing genetic transcription and release of extracellular growth factors, cytokines, etc. to stimulate stromal growth with the cancer cells. It may work by inhibiting inhibitors, such as GSK3 allowing b-catenin to progress to transcription of multiple genes.

Question 7

what is PTEN?

Answer 7

a tumour suppressor gene

carries out its rule by dephosphorylating and downregulating PIP3 levels

Question 8

what is the Ras/raf pathway?

Answer 8

Extracellular growth factors i.e. Fibroblast growth factor (FGF) bind to RTKs, activate Ras by swapping its bound GDP for GTP

Ras then activates Raf which activates a catatonic stream of MAPK (MAPKKK, MAPKK, MAPK) or MEKs which eventually activates downstream transcription factors: EKR and promote growth and survival.

Question 9

What is the role of E-cadherin in inhibiting cell growth intracellularly.

Answer 9

E-cadherin binds to NF-κB and B-catenin which INHIBITS them from entering the nucleus and transcribing multiple genes.

Question 10

clinical manifestation of CRC?

Answer 10

• Right and left colon lesions cause hematochezia (bloody stools)
• but more often bleeding is occult (not visible) and leads to symptoms of tiredness and anaemia
• rectal cancer gives haematochezia and tenesmus (rectal cramping)
• feeling of not having emptied bowels
• lung metastases
• obstruction present

Question 11

how is CRC clinically diagnosed?

Answer 11

COMPLETE COLONOSCOPY UP TO THE CECUM COUPLED WITH BIOPSY and endoscopic excision of polyps

• imaging
• NGS (new genomic sequencing to characterise the type of cancer and acquired mutations and inherited SNPs so that targetted genomic medicine can be implemented, or practioners can determine the most efficient and specific drug treatment)

Question 12

how are colon and rectal tumours distinguished?

Answer 12

rectal (15cm from anus)

colon (the remainding tract)

DRE can identify up to 8cm from anus

Question 13

how are colorectal cancers classified?

Answer 13

TNM classification

• T stage: local invasion depth
• N stage: lymph node involvement
• M: metastases sites?

Duke’s classificaiton (5 year survival based on invasion of tumour into mucousal layers)

• stage 0: nothing, benign tumour
• stage 1: 90% survival
• stage 2: 70% survival
• stage 3: 30% survival
• stage 4: 5% survival

Question 14

what imaging is used to detect CRC?

Answer 14

CT and MRI (size, heterogenity, and morphology, and N staging - detects involvement of lymph nodes and M-staging: metastases) and sometimes endorectal ultrasound (to determine intactness of the wall (T stage))

Question 15

how is CRC treated?

Answer 15

• complete mesocolic excision (cme) with arteries and veins ligated as close as possible to the main vascular trunk to have lower local recurrence rate and improved survival
• laparoscopic surgery (CLS) with CME
  
  • (right or left colonectomy, high anterior resection or APER (abdo-peroneal resection)
• lymphadectomy and metastatic removal
• temporary or permanent colostomy bag
• chemotherapy (using 5 fluorurosil)- intermittently (12 weeks then break 12 weeks then break) or continuosuly (no difference in survival rates)
• radiotherapy

SURGERY IS THE MAIN DRIVING FACTOR OF INCREASED SURVIVAL RATES

Question 16

what is a SEMS? Why is it used in CRC?

Answer 16

The vast majority of SEMS are used to alleviate symptoms caused by cancers of the gastrointestinal tract that obstruct the interior of the tube-like (or luminal) structures of the bowel — namely the esophagus, duodenum, common bile duct and colon

Question 17

what drugs are used to treat CRC?

Answer 17

• Oxaliplatin (5 FU and fluoronic acid)
• cetuximab or panitumumab (mAb against EGFR)