Pancreatic cancer – panel testing

• 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.

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 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

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:

• RCPA catalogue of genetic tests and laboratories  
• GeneReviews^® 
• Genetic Testing Registry 
• NHS National Genomic Testing Registry

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 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.

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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.

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