Tuesday, March 21, 2017

PancNext- A Genetic Test for Hereditary Pancreatic Cancer

PancNext is a next generation sequencing panel that simultaneously analyzes 13 genes associated with increased risk for pancreatic cancer.

Ambry utilizes next generation sequencing (NGS) to offer a comprehensive hereditary pancreatic cancer panel.  Genes on this panel include APC, ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, STK11, and TP53. Full gene sequencing is performed for 12 of the genes (excluding EPCAM). Gross deletion/duplication analysis is performed for all 13 genes. Specific Site Analysis is available for individual gene mutations identified in a family.

Risk assessment by a healthcare provider can help define your chance of developing pancreatic cancer.
- A person with no family history of pancreatic cancer most likely has “sporadic” or average risk. The average risk of developing pancreatic cancer is about 1% over a lifetime. People who have risk factors for pancreatic cancer (described on page 1) may have a higher risk.
- For the person who has a family history of pancreatic cancer, genetic testing may be indicated to help determine if he/she has a moderately increased “familial” risk or a high “hereditary” risk of developing pancreatic cancer. The level of risk depends on the number of family members with pancreatic cancer and whether a genetic cause is identified.
- If someone has had pancreatic cancer, genetic testing may be indicated to help determine if he/she has an increased risk for additional cancers.

PancNext Panel Genes

APC germline mutations are well established as the primary cause of familial adenomatous polyposis (FAP) and attenuated familial adenomatous polyposis (AFAP). FAP and AFAP are autosomal dominant colon cancer predisposition syndromes characterized by hundreds to thousands of adenomatous polyps in the internal lining of the colon and the rectum. They affect 1 in 8,000 to 1 in 10,000 individuals and account for about 1% of all colorectal cancers. In individuals affected with classic FAP, colonic polyps generally begin developing at an average age of 16 years.  In these families, colon cancer is inevitable without surgical intervention like colectomy, and the mean age of colon cancer diagnosis in untreated individuals is 35-40 years.  Individuals with FAP or AFAP may also have increased risks to develop duodenal cancer, pancreatic cancer, papillary thyroid cancer, hepatoblastoma in childhood, and medulloblastoma.  Some individuals may also have non-malignant features such as osteomas, congenital hypertrophy of the retinal pigment epithelium (CHRPE), and/or desmoid tumors.

ATM is a gene classically associated with an autosomal recessive condition called ataxia telangiectasia (AT). AT is characterized by progressive cerebellar ataxia with onset between ages 1 and 4, telangiectases of the conjunctivae, oculomotor apraxia, immune defects, and a predisposition to malignancy, particularly leukemia and lymphoma. Women who carry ATM mutations also have an estimated 2-4-fold increased risk for breast cancer. Cancer risk estimates for male ATM mutation carriers are not currently available. Recent studies have also reported ATM germline mutations in individuals with familial pancreatic cancer. In one of these studies, ATM mutations were identified in 4/87 (4.6%) families with more than three affected members.

BRCA1 and BRCA2 are tumor suppressor genes inherited in an autosomal dominant pattern. Mutations in these two highly penetrant genes increase the chance for cancer of the breast, ovaries (including primary peritoneal and Fallopian tube), pancreas and prostate. Studies suggest female BRCA1 mutation carriers have a 57-87% lifetime risk to develop breast cancer and a 39-40% lifetime risk to develop ovarian cancer by age 70.9-14 Male BRCA1 mutation carriers have a cumulative breast cancer lifetime risk of about 1.2% by age 70.15,16 Similar studies suggest female BRCA2 mutation carriers have a 45-84% lifetime risk to develop breast cancer and an 11-18% risk to develop ovarian cancer by age 70.9-11,17,18 Male BRCA2 mutation carriers have up a 15% lifetime prostate cancer risk and a cumulative lifetime breast cancer risk of 6.8% by ages 65 and 70 respectively.15,16,18,19 BRCA1/2 mutation carriers may also be at an increased risk for melanoma, pancreatic cancer, and potentially other cancers. BRCA2 is also known as FANCD1.  Individuals who inherit a BRCA2/FANCD1 mutation from each parent may have a rare autosomal recessive condition called Fanconi-anemia type D1 (FA-D1), which affects multiple body systems. 

CDKN2A encodes two distinct proteins, p16 and p14ARF, which are both involved in cell cycle regulation. Germline p16/CDKN2A mutations are associated with familial atypical multiple mole melanoma (FAMMM) syndrome. FAMMM is an autosomal dominant disorder characterized by an increased risk for atypical mole malignant melanoma, often associated with dysplastic or atypical nevi. CDKN2A mutation carriers have an approximate 28-67% lifetime risk of developing melanoma, with penetrance estimates varying widely based on study design and geographic region. Individuals carrying CDKN2A mutations also have an approximate 17-25% lifetime risk for pancreatic cancer; however, recent reports suggest this risk may be as high as 58% and elevated further in smokers. Rare mutations that affect the p14ARF mutations have also been reported to predispose to melanoma and possibly pancreatic cancer.

MLH1, MSH2, MSH6, PMS2 and EPCAM germline mutations are associated with Lynch syndrome (previously known as hereditary nonpolyposis colorectal cancer, HNPCC). Lynch syndrome is an autosomal dominant condition estimated to cause 2-5% of all colon cancer. It is associated with a significantly increased risk for colorectal cancer (up to 82% lifetime risk), uterine/endometrial cancer (25-60% lifetime risk in women), stomach cancer (6-13% lifetime risk), and ovarian cancer (4-12% lifetime risk in women). Risk for cancer of the small bowel, hepatobiliary tract, upper urinary tract (including transitional cell carcinoma of the renal pelvis), brain, and sebaceous glands may also be elevated.

PALB2 germline mutations have been associated with an increased lifetime risk for pancreatic cancer, breast cancer, and Fanconi-anemia type N (FA-N). Familial pancreatic and/or breast cancer due to PALB2 mutations is inherited in an autosomal dominant pattern, while FA-N is a rare autosomal recessive condition affecting multiple body systems. Females with a PALB2 mutation have a 2 to 4-fold increase in risk for breast cancer. A 2014 article concluded that in the context of a strong family history, mutations in PALB2 may be associated with up to a 58% risk of female breast cancer.  Without a family history, the risk for female breast cancer was estimated to be 33% (the difference attributed to genetic and/or environmental modifiers). Studies have identified PALB2 mutations in 1-3% of families with pancreatic cancer; however, the exact lifetime pancreatic cancer risk has not yet been established. Additionally, recent studies have shown an increased risk for ovarian cancer.

STK11 germline mutations are associated with Peutz-Jeghers syndrome (PJS), an autosomal dominant disorder characterized by the development of gastrointestinal hamartomatous polyps, along with hyperpigmentation of the skin and mucous membranes. Overall, individuals affected with PJS have up to an 85% lifetime risk of developing cancer by the age of 70, with gastrointestinal and breast cancers being the most common. Individuals with PJS are also at elevated risk for tumors of the pancreas, lung, and, in females, ovarian tumors, specifically, sex cord tumors with annular tubules (SCTATs) and mucinous ovarian tumors.

TP53 is a tumor suppressor gene, and germline mutations within it are associated with Li-Fraumeni syndrome (LFS). An individual carrying a TP53 mutation has a 21-49% lifetime risk of developing cancer by age 30 and a lifetime cancer risk of 68-93%. The most common tumor types observed in LFS families include soft tissue and osteosarcomas, breast cancer, brain tumors (including astrocytomas, glioblastomas, medulloblastomas and choroid plexus carcinomas), and adrenocortical carcinoma (ACC); other cancers, including colorectal, gastric, ovarian, pancreatic, and renal, have also been reported.  Studies have shown that a small percentage of women with early onset breast cancer who do not carry BRCA1 and BRCA2 mutations are identified to have mutations in TP53.

How the test is performed?

The genetic test is done using a blood or saliva sample. Your sample is collected using a special kit which is shipped overnight to Ambry Genetics Laboratory (this is all coordinated by your healthcare

Once your sample arrives at Ambry, 13 known pancreatic cancer genes are analyzed. Everyone has these genes – they each have a specific role in your body. The genetic test is looking for any changes (“mutations”) that make the gene(s) non - functional.

Genetic testing must be ordered by a healthcare provider and should be performed in the context of pre- and post-test education so that you understand the test and its implications for you and your family

Mutation Detection Rate

PancNext can detect >99.9% of described mutations in the included genes listed above, when present (analytic sensitivity).

Sources and Additional Information:

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