Genetics of colorectal cancer

Section: Colorectal Sub-section: Colorectal cancer Curriculum:

Family History

Assessment:

• History of personal symptoms, previous large bowel polyps, large bowel cancers, cancers at other sites, other risk factors e.g. IBD, acromegaly.
• Family history

Risk categories

As per: Update on Surveillance Recommendations for Individuals with a Family/Whānau History of Colorectal Cancer July 2023

Slightly increased:

• Criteria
  • One first-degree relative diagnosed at 55 years or older
• Advice
  • Strongly advise these individuals to participate in the NBSP when they become eligible.
  • Individuals should make healthy lifestyle choices and report any bowel symptoms to their health care provider.

Moderately increased:

• Criteria
  • one first-degree relative diagnosed with CRC under the age of 55 years
  • two first-degree relatives on the same side of the family/whānau diagnosed with CRC at any age
• Advice
  • Individuals have a colonoscopy every five years from age 50, or from an age 10 years before the earliest age at which colorectal cancer was diagnosed in the family/whānau, whichever comes first.
  • Provided they have had a high-quality colonoscopy within the previous five years, individuals then participate in the NBSP from the age of 60 years.

Potentially high

• Criteria
  • Family history of inherited syndrome
  • Suggestion of possible inherited syndrome
    • one first-degree relative plus two or more first- or second-degree relatives all on the same side of the family/whānau with a diagnosis of CRC at any age
    • two first-degree relatives, or one first-degree relative plus one or more second-degree relatives, and one such relative:
      • was diagnosed with CRC when aged 54 years or under, or
      • developed two or more bowel cancers, or
      • developed an extracolonic tumour suggestive of Lynch syndrome (ie, endometrial, ovarian, stomach, small bowel, renal pelvis, pancreas or brain)
    • at least one first- or second-degree family/whānau member diagnosed with CRC in association with multiple bowel polyps or a polyposis syndrome
    • a first-degree relative with multiple colonic polyps if the relative is aged 30 years or younger).
• Advice
  • Referred to genetic service or NZ familial GI cancer registry for accurate risk assessment.
  • Will then need surveillance plan.

Molecular pathway

1. Chromosomal instability (CIN)
2. The mutator phenotype/mismatch repair pathway
3. Serrated/Hypermethylation phenotype pathway - Epigenetic pathways e.g. CpG Island Methylator Phenotype (CIMP)

Chromosomal instability (CIN)

• Classic pathway - > Adenoma to carcinoma sequence
• Randomly acquired somatic mutations in several genes affected in hereditary cancers, due to allelic losses, chromosomal amplifications and translocations,
• APC mutation
• K-RAS; 12p12, oncogene, deletion in ~50% CRC, 50% late adenomas, <10% early adenomas
• 18q21 (SMAD4) – suppressor, mediator in TGFB,
  • hereditary defect responsible for Cowden’s, JP,
• P53; 17p12, suppressor, controller of apoptosis,
  • inherited defect = Li-Fraumeni syndrome
  • Deletion in 75% of carcinoma

The mutator phenotype/mismatch repair pathway

• Lynch syndrome/HNPCC
• Germline mutations in one of several different DNA mismatch repair (MMR) genes, most commonly MLH1, MSH2, MSH6 and PMS2, which leads to dysfunction of the DNA MMR enzymes.
• The biologic “footprint” is the accumulation of abnormalities in short sequences of nucleotide bases that are repeated dozens to hundreds of times within the genome; these are called microsatellites, and the tumors are described as having high levels of microsatellite instability (MSI-H).
• High levels of MSI are also found in approximately 15 percent of sporadic CRCs. However, in most of these cases, gene silencing is not due to a specific MMR mutation, but to an epigenetic phenomenon as below

Serrated/Hypermethylation phenotype pathway

• Epigenetic pathways e.g. CpG Island Methylator Phenotype (CIMP)
• Activating mutations in the BRAF gene (most of which are in the V600E codon) occur almost exclusively in MSI-H, CIMP+ cancers that do not carry mutations in KRAS. Lynch-related CRCs present only with KRAS and not BRAF mutations
• Followed by hypermethylation of the gene promoter for a DNA MMR gene

Familial adenomatous polyposis

Autosomal dominant, inherited familial colorectal cancer syndrome due to mutation in APC gene on chromosome 5q.

• ~75% is inherited; which means 25% arise without family history, as first mutation Risk of colorectal cancer is nearly 100%

Characterised by:

• Hundreds of colorectal adenomatous polyps at young age
• Duodenal adenomatous polyps
• Multiple extraintestinal manifestations
  • Ectoderm: epidermoid cyst, pilomatrixoma, CNS tumours, congenital hypertrophy of retinal pigment epithelium (CHRPE)
  • Mesoderm: connective tissue – (desmoid tumour, excessive adhesions), bone – (osteoma, exostosis, sclerosis), dental – dentigerous cyst, odontoma, supernumerary teeth, unerupted teeth)
  • Endoderm: adenomas and carcinomas of duodenum, stomach, small intestine, biliary tract, thyroid, adrenal cortex, fundic gland polyps, hepatoblastoma

Diagnosis

• Clinical/endoscopic – over 100 colorectal adenomas.
  • Chromoendoscopy with dye spray, and random biopsies to look for microadenomas (hallmark of FAP and MAP, not in Lynch)
  • Gastroscopy may show fundic gland polyps or duodenal adenomas
• Genetic – mutation of APC gene (only 80% of polyps affected)
• Family history. However, 20% will be new mutations with no family history.
• Ddx: MAP (MUTYH-associated polyposis)

Genetic testing

• Affected family member tested first. Once mutation identified, at risk family offered simple blood test.
• Genotype-phenotype correlation:
  • Different levels of expression, due to different site of mutation in APC gene, along with modifier genes and environment

Surveillance

• Colonoscopy - from age 10-12 (AFAP 18-20) until colectomy at which point the rectal cuff/J pouch requires annual flexible sigmoidoscopy
• Gastroscopy (including side viewing scope) - from age 25 and then as per the Spigelman stage
• Thyroid USS - age 18 then eery 2-5 years

Treatment

Lower GI

Surgery

• Should be done as early as possible. Depends on social and educational factors.
• Options:
  • Colectomy + ileorectal anastomosis (IRA)
    • Slightly better functional outcome
• Restorative proctocolectomy (RPC) with ileal pouch-anal anastomosis
  • Benefit of no rectum
  • Good option of high polyp burden in rectum
  • Small cuff of rectal mucosa retained at anastomosis – small risk of cancer here
  • Risk of infertility in women and sexual dysfunction in men
• Total proctocolectomy and end ileostomy

Surveillance

• Both procedures need annual PR and flexi sig
• No long term evidence for NSAID or COX-2 inhibitor

Upper GI

• Fundic gland polyps are common with malignant potential
• Duodenal adenomas occur in nearly all patients with FAP, but malignant only in 5%

Spigelman staging

• Severity of duodenal polyposis in FAP

	Points allocated
	1	2	3
Number of polyps	1–4	5–20	> 20
Polyp size (mm)	1–4	5–10	> 10
Histological type	Tubular	Tubulovillous	Villous
Degree of dysplasia	Mild	Moderate	Severe

Total points	Spigelman stage	Recommended follow-up interval
0	0	5 years
1–4	I	5 years
5–6	II	3 years
7–8	III	1 year and consider endoscopic therapy
9–12	IV	Consider prophylactic duodenectomy

Treatment

• Endoscopic removal
• Whipples in stage IV may be required

See: Desmoid tumour

MUTYH-associated polyposis (MAP)

• Genetics: Autosomal recessive, MYH gene on chromosome 1p
• Management: similar to FAP, annual colonoscopy can be started slightly later. Gastroscopy from age 25.
• Phenotype of FAP, half have 100’s of polyps, half have fewer than 100 polyps.
• Other manifestations:
  • Duodenal adenomas – but less of a problem than in FAP
  • Association with breast cancer (18%)
  • Osteomas and dental cysts
  • No desmoid

Lynch syndrome

Autosomal dominant inherited bowel cancer syndrome due to mutations in mismatch repair genes.

• Hereditary non- polyposis colorectal cancer (HNPCC)
• Epidemiology: 3% of colorectal cancers
• Commonest inherited bowel syndromes.

Genetics:

• Due to germline mutation in MMR – majority are MLH1, MSH2, MSH6, PMS2
• MMR are tumour-suppressor genes.
  • When defective, DNA mismatches are no longer repaired, resulting in accumulation of mutations in other genes, leading to tumour formation.
• Microsatellite instability (MSI) (only 15% of sporadic show MSI)

Pathology:

• LAMPS:
  • Lymphocytes/lymphoid
  • Associated cancers
  • Mucinous/metachronous
  • Poorly differentiated/proximal
  • Signet cell/synchronous

Clinical features:

• Average age at diagnosis 45 years, mostly proximal colon.
• Often multiple (synchronous or metachronous).
• Tend to be mucinous, poorly differentiated, signetring appearance, with infiltration by lymphocytes and lymphoid aggregation at margins.
• Cancers associated with Lynch syndrome:
  • Large bowel 30-75%
  • Endometrium 30-70% (of women)
  • Stomach 5-10%
  • Ovary 5-10% (of women)
  • Urothelium 5%
  • Other – small bowel, pancreas, brain < 5%

pedigree/family history

• Amsterdam criteria II (50% who meet criteria)
  • At least 3 relatives with Lynch syndrome associated cancer, one of whom should be a first-degree relative of the other two
  • At least two successive generations affected
  • At least one cancer diagnosed before 50
  • FAP excluded
  • Tumours verified by pathological examination Pathological testing
• Histologically Bethesda criteria (determine whether to test for MSI) was used to determine who to test
• NZ Guidelines now suggest
  • Test all newly diagnosed cases of colorectal cancer for mismatch repair deficiency preferably on initial biopsy
    • Immunohistochemistry for MMR proteins or MSI testing are appropriate methodologies.
    • If performing immunohistochemistry, then use a four-panel test for MLH1, PMS2, MSH2 and MSH6.
      • If MSH2, MSH6 or PMS2 are abnormal (deficient), then the patient will need genetic testing. For this testing, refer them to the New Zealand Familial Gastrointestinal Cancer Service.
      • If MLH1 is abnormal (deficient), then you must perform further testing to differentiate a sporadic cancer from a cancer associated with Lynch syndrome .
        • BRAF V600E mutation analysis → if demonstrates mutant then sporadic
        • If BRAF V600E is wild-type then perform promoter hypermethylation testing and if negative, then refer the patient to the New Zealand Familial Gastrointestinal Cancer Service.
  • Conduct BRAF V600E mutation analysis in all newly diagnosed stage IV colorectal cancers
  • Conduct extended RAS mutation testing before considering treatment with EGFR-targeted monoclonal antibodies

Genetic testing

• Costly.
• Based on patient factors, family history and tumour factors
• Need consent

Surveillance

• Reduces risk of colorectal cancer by 63%
• Chromoendoscopy increases pick up
• Every 2 years from age 25 or 5 years younger than affected relative.
• Gastroscopy every 2 years from age 30
• No evidence for TBUS or CA 125 surveillance - https://www.eviq.org.au/cancer-genetics/adult/risk-management/1410-mmr-genes-lynch-syndrome-risk-management#cancer-tumour-risk-management-guidelines

Surgery

• Prophylactic
  • Prophylactic colectomy should be discussed.
  • Subtotal with ileorectal or proctocolectomy. Risk of rectal cancer about 12% at 12 years. Should have annual flexible sigmoidoscopy if ileorectal.
  • Similar hysterectomy and BSO could be discussed once completed family.
  • No significant advantage of prophylactic surgery over good-quality surveillance
• Treatment
  • Once diagnosed, decision of segmental colectomy (better function but increased risk of metachronous cancer and need for colonoscopy surveillance)
  • vs colectomy + ileorectal anastomosis (reduce metachronous risk, easier surveillance)
  • Risk of metachronous cancer of 16% at 10 years
• Medical
  • MSI reduced when exposed to NSAIDs - give 100-300mg daily Aspirin (exact dosing still being established)
  • Adjuvant therapy – only for stage III not stage II.

Peutz-Jeghers syndrome

Overview

• Autosomal dominant, STK11 (LKB1) gene on chromosome 19p13.
• 25% have denovo mutation (no Fhx)
• Prevalence – 1/50,000 – 1/200,000

Clinical Characteristic

• Characterised by mucocutaneous pigmentation with multiple GI hamartomatous polyps + cancers of GI, breast, lung and genitals.
  • Hamartoma – abnormal benign growth of tissue
• If 2 characteristics, considered to have PJS:
  • At least 2 Peutz-Jeghers type hamartomatous polyps in small intestine
  • Characteristic freckling of mouth, lips, fingers or toes
  • At least 1 relative diagnosed with PJS
• Commonest polyp complication is SBO, often caused by intussusception. Incidence of subsequent SBO reduced by intraoperative small bowel enteroscopy + polypectom.
• Manifestations – BCHOMPT:
  • Beast Ca
  • Colorectal, cervical Ca
  • Hamartomatous
  • Ovarian cancer
  • Mucocutaneous lesions
  • Pancreatic cancer
  • Testicular cancer (sertoli)
• Cancer risk high but not quantified.

Surveillance:

• Annual physical exam, haemoglobin.
• Upper and lower GI endoscopies + capsule endoscopy (from age 8). MRI enerography is an option
• Annual cervical smear from 18 or annual testicular exam
• Annual breast MRI and mamm from age 30

Juvenile polyposis

• Autosomal dominant
• Multiple characteristic juvenile polyps mostly colon, also upper GI.
• Other features sometimes associated are macrocephaly, hereditary haemorrhagic telangiectasia and congenital heart disease.
• Some have SMAD4 or BMPR1A gene mutations
• Risk of colorectal cancer ~40%. Increased risk of gastric cancer.
• Surveillance: regular upper and lower GI scopes + polypectomy.
• Occasionally prophylactic colectomy or gastrectomy required

Serrated polyposis syndrome

• Likely genetic component. Some families display AD pattern.
  • Some associated with SMAD4, PTEN, MUTYH
  • Majority do not have altered genes.
• WHO Criteria – one of the following:
  • At least 5 histologically diagnosed serrated polyps proximal to rectum (two >10 mm)

  • 20 serrated lesions of any size throughout the colon

  • Any number of serrated polyps proximal to sigmoid with 1st degree relative with serrated polyposis
• Surveillance:
  • 1-3 yearly from age 40 (or 10 years earlier than family presentation of SPS)
  • Intervals based on number/size of polyps. High risk of CRC (50%).
• Surgery:
  • Indications:
    • CRC or HGD
    • Severe symptoms related to neoplasia
    • Multiple adenomas > 6 mm
    • Significant increase in polyps since previous scope
    • Patient preference to avoid surveillance
  • If surgery required, likely IRA as opposed to RPC, but determined by polyp distribution and burden, age/comorbidity and functional outcome.

Cowden’s syndrome

• PTEN mutation
• GI Hamartomas and cancers, increased risk of cancer of breast, thyroid, endometrium and cervix, benign fibrocystic breast disease, non-toxic goitre and varied benign mucocutaneous lesions particularly trichilemmomas (benign tumour in outer root sheath of hair follicle)
• Screening: Colonoscopy (age 35), Breast MRI - age 30, Renal USS - age 40, TVUS - Age 35, Thyroid USS - age 7