Cancer

Question 1

Somatic Mutations

Answer 1

• NON-GERMLINE TISSUES e.g. breast

* NON-HERITABLE

Question 2

Germline Mutations

Answer 2

• INHERITED from SINGLE ALTERATION in EGG/SPERM
• HERITABLE
• Cause CANCER FAMILY SYNDROMES

Question 3

Type of Cancer Inducing Genes

Answer 3

Oncogenes: 1 mutation sufficient for cancer development; leads to accelerated cell division

Tumour Suppressor Genes: requires 2 gene mutations to lead to cancer; allows for unchecked growth

DNA Mismatch Repair Genes: faulty DNA mismatch repair introduces mutation

Question 4

Clinical Genetics Consultation Components

Answer 4

Look through FHx: Accurate risk assessment, Effective genetic counselling, Appropriate medical follow-up

Risk Estimation: all Scottish genetics centres, classify as gene carrier (high, medium, low)

Explanation of basis of risk

Interventions: Increased awareness of symptoms/signs; Lifestyle - diet smoking, exercise; Prevention - oestrogen, aspirin use; Screening; Prophylactic surgery

Genetic Testing

Question 5

Benefits & Disadvantages of Genetic Testing

Answer 5

Benefits:

• IDENTIFIES HIGHEST RISK
• IDENTIFIES NON-CARRIERS in FAMILIES w/ KNOWN MUTATION
• Allows EARLY DETECTION & PREVENTION STRATEGIES
• May RELIEVE ANXIETY

Risk & Limitations:

• DOES NOT DETECT ALL MUTATIONS
• CONTINUED RISK of SPORADIC CANCER
• VARIABLE EFFICACY of INTERVENTIONS
• May result in PSYCHOSOCIAL/ECONOMIC HARM (e.g. insurance rate rise)

Question 6

When to Suspect Hereditary Cancer Syndromes

Answer 6

• CANCER ≥ 2 RELATIVES (on same side of family)
  
  • EARLY AGE at DIAGNOSIS
  • MULTIPLE PRIMARY TUMOURS
  • BILATERAL/MULTIPLE RARE CANCERS
  • CHARACTERISTIC PATTERN of TUMOURS e.g. breast, ovary
  • EVIDENCE of AUTOSOMAL DOMINANT TRANSMISSION

Question 7

Lynch syndrome: mutations

Answer 7

• MUTATION in MISMATCH REPAIR GENES
  
  • EXCESS COLORECTAL, ENDOMETRIAL, URINARY TRACT, OVARIAN, GASTRIC CANCERS
  • ADENOMA - CARCINOMA SEQUENCE for POLYP FORMATION (polyps do form, but much less in FAP)

Question 8

Lynch syndrome: presentation

Answer 8

• EARLY, VARIABLE AGE at CRC DIAGNOSIS (~ 45YRS)

* TUMOUR SITE: predominantly PROXIMAL COLON

Question 9

Lynch syndrome: surveillance

Answer 9

CRC:

• COLONSCOPY

* GENE CARRIER = 2yrly from 25/35
* MODERATE RISK = 55 or 5yrly from 50
* PROPHYLACTIC ASPIRIN

Endometrial cancer:

• SYMPTOM AWARENESS + SURGERY
• DEBATABLE RECOMMENDATIONS - DISCUSS OPTIONS

Question 10

Lynch syndrome: genetic testing

Answer 10

• IMMUNOHISTOCHEMISTRY for mismatch repair gene proteins/microsatellite instability testing (MSI)

* If IHC/MSI HIGH, GENE SCREEN to determine if GENE is IMPLICATED (as 2 somatic hits can mislead otherwise)
* IHC/MSI RECOMMENDED CRC MANAGEMENT - it can be useful for MANAGEMENT TOO (e.g. chemotherapy)

Question 11

BRCA1 + BRCA2: surveillance options

Answer 11

• BREAST AWARENESS
  
  • EARLY CLINICAL SURVEILLANCE 5YR < AGE of 1st CANCER in FAMILY○ ANNUAL/CLINICAL BREAST EXAMS
    ○ MAMMOGRAPHY (moderate/high = 2 yearly from 35 - 40yrs, yearly from 40 - 50yrs)
    ○ HIGH ONLY 18 MONTHLY (50 - 64yrs)
    ○ MRI SCREENING for those at HIGHEST RISK - EARLY DETECTABILITY

Question 12

BRCA1 + BRCA2: prophylactic mastectomy

Answer 12

• REMOVES MOST (but not all) BREAST TISSUE
  
  • SIGNIFICANTLY REDUCES BREAST CANCER RISK in WOMEN w/ FHx
  • TOTAL MASTECTOMY REMOVES MORE BREAST TISSUE than S/C MASTECTOMY
  • BRCA1 +VE WOMEN BREAST CANCER INCIDENCE REDUCED to 5%

Question 13

BRCA1 + BRCA2: prophylactic oophorectomy

Answer 13

• ELIMINATES RISK of PRIMARY OVARIAN CANCER - PERITONEAL CARCINOMATOSIS may still occur
  
  • LAPAROSCOPIC OOPHORECTOMY REDUCES POSTSURGICAL MORBIDITY
  • INDUCES SURGICAL MENOPAUSE but HRT til 50 DOES NOT CHANGE BRCA RISK
  • RISK of SUBSEQUENT BRCA HALVED in MUTATION +VE WOMEN