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
provider).
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
members.
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:
