Introductory Overview

Colorectal cancer (CRC) affects 1 in 20 people during their lifetime. An estimated 25% of all CRC cases present a familial clustering of the disease suggesting a contribution of genetic factors among other risk factors, while approximately 5% of all CRC cases are purely hereditary [1].

Hereditary non-polyposis colorectal cancer, also known as Lynch syndrome (LS) accounts for the majority of these hereditary CRC cases (2-3% of overall CRC cases).

But diagnostic criteria are complex and several studies have reported a lack of sensitivity and specificity for the Amsterdam criteria and the revised Bethesda guidelines, which are typically used for the identification of LS patients [2]. In addition, heterogeneous and overlapping phenotypes make it difficult to distinguish from other type of hereditary CRCs and decide which genes should be analyzed first.

Our next generation sequencing panel for CRC therefore aims at facilitating patient referral for molecular screening, while keeping costs at a reasonable level [3].

Incidence of types of CRC cancer:

Prescription Guidance

Clinical Indication

The CRC gene panel is recommended for patient whose diagnosis and/or family history is indicative of a suspicion of hereditary CRC. Such indications include [1, 5-7]:

Early age of cancer onset:

• Patient diagnosed with CRC or endometrial cancer at an age < 50
• Patient diagnosed with CRC at an age < 60 and MSI-H histology

Patient presenting multiple cumulative polyps:

• >10 colorectal adenomatous polyps
• Multiple gastrointestinal hamartomatous polyps

Patient with multiple related primary CRCs or other associated LS cancers

Patient fulfilling the revised Bethesda guidelines or from a family meeting the Amsterdam II criteria

Family history:

• Patient with a family history of hereditary CRC, with or without a known mutation
• Multiple close family members with CRC or other associated LS cancers

Test Benefits & Risk Management

The finding of a pathogenic variant will help to relate the clinical phenotype to a precise type of hereditary CRC or related syndrome for which management strategies might be available. Management options include [1,6,7]:

For Lynch Syndrome

Surveillance

• Colon & rectum: Colonoscopy every 1-2 year(s), starting at age 20-25
• Endometrium & ovary: Gynecologic cancer screening
• Others:
  › Esophagogastroduodenoscopy (EGD) including side-viewing examination every 1-2 year(s), starting at age 30-35
  › Annual urinalysis starting at age 30-35
  › Annual physical exam including screening for skin cancers

Prophylactic Surgical Options

• Prophylactic colectomy in young CRC patients
• Prophylactic hysterectomy and/or bilateral salpingo-oophorectomy, after childbearing is completed

For Familial Adenomatous Polyposis (FAP)

Surveillance

• Colon & rectum: Colonoscopy every 1-2 year(s), starting at age 10-12
• Others:
  › EGD including side-viewing examination every 1-3 years, starting when colorectal polyposis is diagnosed or at age 20-25
  › Annual physical exam including cervical ultrasonography, starting at age 25-30

Prophylactic Surgical Options

• Prophylactic colectomy when polyps become unmanageable

For attenuated Familial Adenomatous Polyposis (aFAP)

Surveillance

• Colon & rectum: Colonoscopy every 2 years, starting at age 18-20
• Others:
  › EGD including side-viewing examination every 1-3 years, starting when colorectal polyposis is diagnosed or at age 20-25
  › Annual physical exam including cervical ultrasonography, starting at age 25-30

Prophylactic Surgical Options

• Prophylactic colectomy when polyps become unmanageable

For MUTYH-Associated Polyposis

Surveillance

• Colon & rectum: Colonoscopy every 2 years, starting at age 18-20
• Others:
  › EGD including side-viewing examination every 1-3 year(s), starting at age 20-25

Prophylactic Surgical Options

• Prophylactic colectomy when polyps become unmanageable

For Peutz-Jeghers syndrome

Surveillance

• Colon & rectum: Colonoscopy every 2-3 years, starting with symptoms or in late teens
• Others:
  › EGD including side-viewing examination every 2-3 years, starting at age 10
  › Magnetic resonance cholangiopancreatography and/or endoscopic ultrasound of the pancreas every 1–2 years starting at age 30
  › Annual mammogram and breast MRI starting at age 25
  › Clinical breast exam starting at age 25
  › Annual pelvic examination, Pap smear and transvaginal ultrasound starting at age 18 years
  › Annual testicular exam starting at age 10

For Juvenile Polyposis syndrome

Surveillance

• Colon & rectum: Colonoscopy every 2-3 years, starting with symptoms or in late teens
• Others:
  › Esophagogastroduodenoscopy every 1-3 years

Test Characteristics

Panel Composition

Technical Details

Methodology

• Targeted capture of all coding exons and exon-intron boundaries followed by NGS.
• Confirmatory Sanger sequencing of potentially pathogenic variants.
• Deletion and duplication assessed by MLPA (Multiplex ligation-dependent probe amplification)

TAT

4-5 weeks in average. Urgent testing is available upon request.