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Pancreatic cancer – panel testing

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  • Individual diagnosed with pancreatic ductal adenocarcinoma aged 60 years and under regardless of other personal or family history factors.
  • Individual diagnosed with pancreatic ductal adenocarcinoma at any age with personal or family history suggestive of a familial cancer syndrome* or other phenotypic features suggestive of a known cancer syndrome.
  • Individual diagnosed with pancreatic ductal adenocarcinoma at any age from a population where a founder pathogenic variant of high prevalence exists (e.g. Ashkenazi Jewish).
  • Individual diagnosed with pancreatic ductal adenocarcinoma at any age and evidence of DNA mismatch repair (MMR) deficiency by immunohistochemical staining or microsatellite instability studies in the tumour tissue.

Genetic testing is important for good clinical care of individuals who are suspected of having a familial cancer/tumour predisposition.**

*Hereditary pancreatitis, Peutz-Jeghers syndrome, CDKN2A, BRCA1, BRCA2, Lynch syndrome
**Limited gene testing may be more appropriate in the setting of a specific phenotype

The results of the following investigations may significantly influence the likelihood of detecting a heritable pathogenic variant: 

  • verification of pancreatic ductal adenocarcinoma histology
  • immunohistochemistry for the MMR proteins (MLH1, MSH2, MSH6 and PMS2)
  • results of tumour sequencing for genes included in the panel
  • clinical examination of skin and mucous membranes for features of Peutz-Jeghers syndrome
  • verification of histology of colorectal polyps.
Factor Gene Probability of detecting a heritable pathogenic variant
Pancreatic adenocarcinoma

Panel#

BRCA1

BRCA2

PALB2

ATM##

MMR genes (MLH1, MSH2, MSH6, PMS2, EPCAM^)

CDKN2A

TP53

2.4-14.1%rrr

1.0%r

4.2%r

1.6%r

3.9%r

1.7%r

1.3%r

0.6%r
Hereditary pancreatitis

PRSS1

SPINK1

Unknown

Unknown
Patient has a first or second degree relative with documented pathogenic variant   Up to 50%

#Genes included in the panel varied in each study. The clinical significance with respect to pancreatic cancer risk is unknown for some of the genes included in these panels and this should be considered when deciding which genes to order
##No specific data available on ATM c.7271T>G pathogenic variant
^ “EPCAM” refers to a deletion in EPCAM affecting MSH2 function

When choosing genes to include in a gene panel, care should be taken to select genes which have both clinical validity and clinical utility for the phenotype of concern.

The likelihood of identifying a variant of uncertain significance increases as the number of genes included in a panel increases.

Genes associated with pancreatic cancer
Gene*** Comments
APC

Can usually identify by clinical phenotype

APC (Familial adenomatous polyposis) – risk management
ATM

Lack of data re penetrance and surveillance; if pathogenic variant identified need to make a careful assessment of residual risk for relatives who are non-carriers

ATM (monoallelic pathogenic variants) – risk management
BMPR1A

Can usually identify by clinical phenotype

SMAD4 or BMPR1A (Juvenile polyposis) – risk management
BRCA1

International and eviQ guidelines for risk management have been developed^^

BRCA1 or BRCA2 – risk management (female), BRCA1 or BRCA2 – risk management (male)

Potential treatment implications for cancer affected individuals
BRCA2

International and eviQ guidelines for risk management have been developed^^ 

BRCA1 or BRCA2 – risk management (female), BRCA1 or BRCA2 – risk management (male)

Potential treatment implications for cancer affected individuals
CDKN2A

International and eviQ guidelines for risk management have been developed^^

CDKN2A – risk management
Mismatch repair genes (MLH1, MSH2, MSH6, PMS2, EPCAM^)

International and eviQ guidelines for risk management have been developed^^ 

MMR (Lynch syndrome) – risk management

Potential treatment implications for cancer affected individuals
PALB2 truncating pathogenic variants

International and eviQ guidelines for risk management have been developed^^

PALB2 – risk management

Potential treatment implications for cancer affected individuals
STK11

Can usually identify by clinical phenotype

STK11 (Peutz-Jeghers) – risk management
TP53

International and eviQ guidelines for risk management have been developed^^

TP53 (Li-Fraumeni) – risk management (adult)

***Genes are listed alphabetically; the order of listing does not give any indication of the clinical validity/utility of testing the gene
^“EPCAM” refers to a deletion in EPCAM affecting MSH2 function
^^International guidelines for risk management have been developed for this gene, but may not include pancreatic cancer risk management

Genes associated with hereditary pancreatitis
Gene*** Comment
PRSS1

Can usually identify by clinical phenotype
SPINK1

Can usually identify by clinical phenotype

A variant specific test (rather than a panel test) may be more cost effective and appropriate than a panel test where: 

  • a known pathogenic variant has been identified in a relative
  • a specific pathogenic variant has been identified on somatic tumour testing.

In addition to sequencing using genomic sequencing (“next generation sequencing” or NGS), a range of other testing methodologies may be needed to identify pathogenic changes in the genes in the panel including:

  • Sanger sequencing
  • long range PCR
  • copy number analysis (e.g. MLPA)
  • methylation analysis
  • analysis for structural rearrangements (e.g. chromosome rearrangement).

Information about DNA tests and testing laboratories is available from:

If these genes are tested using genomic sequencing (“next generation sequencing” or NGS), and testing has not identified a pathogenic variant, the value of testing using another methodology (e.g. MLPA, Sanger sequencing) should be considered.

If genetic testing in DNA from peripheral blood is uninformative, testing of two or more different tumour samples may be indicated to assess for mosaicism.

Result Reference databases Considerations and advice
Pathogenic variant search
Pathogenic variant

ClinVar

LOVD

InSiGHT

HGMD

DMuDB
Variant of uncertain significance

Review pathogenicity of variants periodically

Identify other genes for which a pathogenic variant search could be considered 
No reportable variant  

Identify other genes for which a pathogenic variant search could be considered

If a pathogenic variant is identified refer to a clinical genetics service or familial cancer centre for review, family risk notification and predictive testing.

If a mosaic pathogenic variant is identified refer to a clinical genetics service or familial cancer centre for review and guidance about the penetrance of phenotypic features (including cancer risk).

For additional information about the management of genetic test results when ordered by a non-genetic healthcare professional refer to eviQ’s Guide for health professionals ordering genetic testing.

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Bibliography

Goldstein, J. B., L. Zhao, X. Wang, et al. 2020. "Germline DNA Sequencing Reveals Novel Mutations Predictive of Overall Survival in a Cohort of Patients with Pancreatic Cancer." Clin Cancer Res 26(6): 1385-1394.

PURPOSE: Family history of BRCA-related tumors may correlate with response to chemotherapy and overall survival (OS) in pancreatic cancer. The frequency of germline mutations has been reported in patients predominantly under the age of 60 or with strong family history. We examine the incidence of deleterious germline mutations and compare the chemotherapy responses and OS in an unselected group of patients with metastatic pancreatic cancer. EXPERIMENTAL DESIGN: Patients with metastatic pancreatic cancer, who were seen at a single cancer center between 2010 and 2016, were included. Germline DNA was sequenced using a 263-gene panel to identify novel mutations (N = 133 MD Anderson cohort, N = 127 TCGA cohort). Chemotherapy response and OS were determined by review of medical records. RESULTS: Deleterious germline mutations were identified in 26 of 133 patients (19.5%). Patients with DNA damage repair (DDR) gene mutations (ATM, BRCA1/2, CDKN2A, CHEK2, ERCC4, PALB2, n = 15) had an improved OS as compared with patients without (16.8 vs. 9.1 months, P = 0.03). Conversely, patients with other deleterious mutations had a trend toward worse OS. However, survival in the latter group was longer (P = NS) in those mutants initially treated with gemcitabine/nab-paclitaxel. A family history of multiple breast, ovarian, and pancreatic cancers was associated with DDR gene mutations and better survival. CONCLUSIONS: We have identified novel germline mutations that are prognostic for survival in patients with pancreatic cancer. We observe improved survival in patients with DDR gene mutations and worsened survival in patients with deleterious mutations in non-DDR genes.

Version 2

Date Summary of changes
23/11/2021

The following changes were made to the protocol and approved by the RC Chairs: 

  • Target population 
    • Bullet 3: 'diagnosed with pancreatic ductal adenocarcinoma at any age' added into sentence
    • Bullet 4: 'at any age' added into sentence

Protocol version increased to V.2.
06/05/2022

Following updates to the ATM risk management document (ID 1610), the following minor changes were made to the Pancreatic cancer – panel testing document:

  • Genes that might be included in a pancreatic cancer panel: link in the Comments column changed to 'ATM (monoallelic pathogenic variants) – risk management
  • Result interpretation table: link in the Considerations and advice column changed to 'ATM (monoallelic pathogenic variants) – risk management'.

Version 1

Date Summary of changes
09/04/2021 New protocol developed and discussed at October 2020 cancer genetics reference committee meeting. Approved for publication as V.1. Review in 1 year.
13/10/2021 Protocol title changed from 'Pancreatic cancer panel testing' to 'Pancreatic cancer – panel testing'.
10/11/2021 Removed link to "European Directory of DNA Diagnostic Laboratories"

The information contained in this document is based on the highest level of available evidence and consensus of the eviQ reference committee regarding their views of currently accepted approaches to care or treatment. Any clinician seeking to apply or consult this document is expected to use independent clinical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. While eviQ endeavours to link to reliable sources that provide accurate information, eviQ and the Cancer Institute NSW do not endorse or accept responsibility for the accuracy, currency, reliability or correctness of the content of linked external information sources. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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https://www.eviq.org.au/p/3906

27 Nov 2022