1. NGS panel - Genetic testing for pancreatic cancer

Pancreatic cancer

November 15, 2017

Clinical features

Pancreatic cancer is one of the world’s most lethal malignant neoplasms, with a 5-year survival rate of about 5-7%1, 2, 6.

Pancreatic cancer now represents the fourth to fifth most frequent cause of cancer mortality in North America, Europe, and Japan3, 4. The incidence of pancreatic cancer varies greatly across regions and populations. Incidence rates for pancreatic cancer are highest in Northern America (7.4 per 100000 people) and Western Europe (7.3 per 100000), followed by other regions in Europe and Australia/New Zealand (~ 6.5 per 100000)6.

Approximately 75% of all pancreatic carcinomas occur within the head or neck of the pancreas, 15-20% occur in the body of the pancreas, and 5-10% occur in the tail7. The two main tumor types of pancreatic cancer are adenocarcinoma (which accounts for about 85% of cases), and pancreatic endocrine tumors (which comprise fewer than 5% of all cases)8.

Typical presenting symptoms of pancreatic cancer include abdominal or mid-back pain, obstructive jaundice, and weight loss. Pancreatic-duct obstruction could result in attacks of pancreatitis. Gastric-outlet obstruction with nausea and vomiting sometimes happens with more advanced disease. Deep and superficial venous thrombosis is not unusual and might be a presenting sign of malignant disease. About 25% of patients with pancreatic cancer have diabetes mellitus at diagnosis and roughly another 40% have impaired glucose tolerance. Less common manifestations include panniculitis and depression.

Early-stage pancreatic cancer is usually clinically silent, and the disease only becomes apparent after the tumor invades the surrounding tissues. Most people who present with symptoms attributable to pancreatic cancer already have the advanced disease.

Risk factors for pancreatic cancer include smoking, a family history of chronic pancreatitis, advancing age, male sex, diabetes mellitus, obesity, non-O blood group, occupational exposures, African-American ethnic origin, a high-fat diet, diets high in meat and low in vegetables and folate, and possibly Helicobacter pylori infection and periodontal disease3, 6.

Approximately 20% of hereditary cases of PC are currently attributed to a known genetic syndrome4, 9. The term familial pancreatic cancer (FPC) applies to the remaining 80% of patients with an inherited predisposition: families in which at least two first-degree relatives (FDRs) have been diagnosed with PC but that do not meet the diagnostic criteria for the previous settings4.

Numerous hereditary cancer syndromes are known to be associated with an increased risk of pancreatic cancer, including Peutz-Jeghers syndrome (PJS), melanoma pancreatic-cancer syndrome (MPCS) or familial atypical multiple mole melanoma (FAMMM)-PC, hereditary breast-ovarian cancer (HBOC), Lynch syndrome (LS) and familial adenomatous polyposis (FAP). In addition, an increased risk of PC is present in patients with hereditary pancreatitis or cystic fibrosis4, 9, 6.

Several pancreatic cancer genes have been established, including high-penetrance genes such as BRCA2, STK11, CDKN2A, PALB2 and others (see table).


Overview genes included in CENTOGENE´s pancreatic cancer panel

Gene
(OMIM)
Locus Protein Allelic disorders (OMIM)
APC
611731
5q22.2 APC protein phosphatase Adenomatous polyposis coli (175100); Colorectal cancer, somatic (114500); Desmoid disease, hereditary (135290); Gastric cancer, somatic (613659); Hepatoblastoma, somatic (114550)
ATM
607585
11q22.3 Ataxia-telangiectasia mutated gene Ataxia-telangiectasia (208900); Breast cancer susceptibility to (114480); Lymphoma, B-cell non-Hodgkin, Lymphoma, mantle cell, T-cell prolymphocytic leukemia (unknown OMIM)
BMPR1A
601299
10q23.2 Bone morphogenetic protein receptor 1A Juvenile polyposis syndrome (174900); Polyposis syndrome, hereditary mixed, 2 (610069)
CDKN2A
600160
9p21.3 Cyclin-dependent kinase inhibitor 2A Pancreatic cancer/melanoma syndrome (606719); Melanoma and neural system tumor syndrome (155755); Melanoma, cutaneous malignant 2 (155601)
EPCAM
185535
2p21 Epithelial cellular adhesion molecule HNPCC8 (613244); Diarrhea 5, with tufting enteropathy, congenital (613217)
MLH1
120436
3p22.2 MutL, homolog of E. coli 1 HNPCC2 (609310); Mismatch repair cancer syndrome (276300); Muir-Torre syndrome (158320)
MSH2
609309
2p21-p16 MutS homolog of E. coli 2 HNPCC1 (120435); Mismatch repair cancer syndrome (276300); Muir-Torre syndrome (158320)
MSH6
600678
2p16.3 MutS homolog of E. coli 6 HNPCC5 (614350); Mismatch repair cancer syndrome (276300); Endometrial cancer, familial (608089)
PALB2
610355
16p12.2 Partner and localizer of BRCA2 Pancreatic cancer, susceptibility to, 3 (613348); Fanconi anemia, complementation group N (610832); Breast cancer, susceptibility to (114480)
PMS1
600258
2q32.2 Postmeiotic segregation increased S. Cerevisiae 1 Pancreatic cancer (unknown OMIM); Mismatch repair cancer syndrome (276300)
PMS2
600259
7p22.1 Postmeiotic segregation increased S. Cervisiae 2 Colorectal cancer, hereditary nonpolyposis, type 4 (614337); Mismatch repair cancer syndrome (276300)
PRSS1
276000
7q34 Protease serine 1 Pancreatitis, hereditary (167800); Trypsinogen deficiency (614044)
SMAD4
600993
18q21.2 Homolog of mothers against decapentaplegic 4 Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome (175050); Myhre syndrome (139210); Pancreatic cancer, somatic (260350); Polyposis, juvenile intestinal (174900)
STK11
602216
19p13.3 Serine/Threonine protein kinase 11 Melanoma, malignant, somatic (no OMIM); Pancreatic cancer (260350); Peutz-Jeghers syndrome (175200); Testicular tumor, somatic (273300)

With genetic testing, we are able today to analysis pancreatic cancer susceptibility for better planning of preventive cancer screening in at risk individuals and thereby able to detect cancer at early stage and to reduce cancer mortality. Genetic testing for pancreatic cancer is the most accurate means of determining the genetic risk of pancreatic cancer.

The only potentially curative treatment for pancreatic cancer is surgical resection. Early detection of disease with curative resection has been shown to improve 5-year survival rates up to 60% 5. In addition, an important role exists for chemotherapy and/or radiation therapy.

CENTOGENE experts have designed the Pancreatic cancer panel which includes these genes: APC, ATM, BMPR1A, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS1, PMS2, PRSS1, SMAD4, STK11.


Differential diagnosis

The differential diagnosis of pancreatic cancer-related disorders – depending on the major symptoms in the initial case – includes the following diseases1:

  • Acute pancreatitis
  • Chronic pancreatitis
  • Cholangitis and/or cholecystitis, cholelithiasis
  • Choledochal cysts
  • Gastric cancer/peptic ulcer disease

Testing strategy

CENTOGENE offers an advanced, fast and cost-effective strategy to test large NGS panels and diagnose complex phenotypes based on PCR-free whole genome sequencing and NGS technology. This approach offers an unparalleled advantage by reducing amplification/capture biases and providing sequencing of the entire gene with more uniform coverage.

To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for pancreatic cancer using NGS Panel Genomic targeted towards this specific phenotype:

Step 1: Whole genome sequencing from a single filter card. The sequencing covers the entire gene (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the pancreatic cancer panel. Copy Number Variants analysis derived from NGS data is also included.

Step 2: If no pathogenic variants is identified after analysis of the Pancreatic cancer panel, we further recommend continuing the bioinformatics analysis of the data using whole genome sequencing to cover those genes which are either implicated in an overlapping phenotype or could be involved in a similar pathway but are not strongly clinically implicated based on the current information in literature.


Referral reasons

Genetic testing for pancreatic cancer is recommended for people who show one or more of the following features:

  • History of colon or any gastrointestinal cancer
  • Positive family history of pancreatic cancer and premalignant gastrointestinal conditions
  • Present endocrinological and/or gastrointestinal conditions and family history of cancer
  • History of chronic and complex gastrointestinal condition.

Test utility

Sequencing, deletion/duplication of pancreatic cancer related genes should be performed in all individuals suspected of having pancreatic cancer. In parallel, other genes reported to be related with this clinical phenotype should also be analyzed for the presence of pathogenic variants, due to the overlap in many clinical features caused by those particular genes.

Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management. Genetic counseling can provide a patient and/or family with the natural history of pancreatic cancer, identify at-risk family members, provide information about reproductive risks as well as preconception/prenatal options, and allow for appropriate referral for patient support and/or resources.


More information on CENTOGENE´s Pancreatic cancer panel can be found in our genetic test catalogue.