Hereditary predisposition to colorectal cancer
 
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Oncology – Hereditary predisposition to colorectal cancer (HNPCC)

a-    Background

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.

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. 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.

b-   How does it work ?

  • Stage 1: Patient identification
    Discussion of personnal and family history
    Eplanation of genetic testing options
  • Stage 2: Sample submission
    The patient’s sample and necessary paperwork are sent to the laboratory
  • Stage 3: Genetic testing
    At the laboratory, genetic testing for most genes includes next-generation sequencing and/or exon aray analysis
  • Stage 4: Genetic test results
    Contains information on the results of the genetic test and available medical management options.
    The final report is sent to the ordering Incorpore specialist
  • Stage 5: Post-test discussion
    Incorpore specialist discusses the test resutls, medical management options, and implication for family members with the patient

c-   To whom it is recommended?

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 :

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

d-    Why choose this assay?

Test benefit

  • Targeted risk management & treatment guidance
  • The subsequent identification of affected relatives in families where a disease causing mutation has already been found. This would allow an earlier management of at-risk family members.

Risk Management

Management options include:

 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

 

 e–   What is investigated?

Panel composition

Gene MIM Gene Related disease / Phenotype MIM Phenotype
APC 611731 Familial Adenomatous Polyposis 1 (FAP1) / Attenuated FAP 175100
BMPR1A 601299 Juvenile polyposis syndrome 174900
MLH1 120436 Lynch syndrome (HNPCC), Muir-Torre syndrome 609310, 158320
MSH2 609309 Lynch syndrome (HNPCC), Muir-Torre syndrome 120435, 158320
MSH6 600678 Lynch syndrome (HNPCC), Endometrial cancer, familial 614350, 608089
MUTYH 604933 Adenomas, multiple colorectal (FAP2) 608456
PMS2 600259 Lynch syndrome (HNPCC) 614337
PTEN 601728 Cowden syndrome 158350
SMAD4 600993 Juvenile polyposis syndrome 174900
STK11 602216 Peutz Jeghers 175200
TP53 191170 Colorectal cancer 114500

 

Technical Details

Methodology

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

 

TAT

5-6 weeks in average. Urgent testing is available upon request.

 

Cost CHF 5’000—

 

 

 

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