Hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome is an
autosomal dominant genetic condition that is associated with a high risk of
colon cancer as well as other cancers including
endometrial cancer (second most common),
ovary,
stomach
The stomach is a muscular, hollow organ in the gastrointestinal tract of humans and many other animals, including several invertebrates. The stomach has a dilated structure and functions as a vital organ in the digestive system. The stomach i ...
,
small intestine,
hepatobiliary tract, upper
urinary tract
The urinary system, also known as the urinary tract or renal system, consists of the kidneys, ureters, bladder, and the urethra. The purpose of the urinary system is to eliminate waste from the body, regulate blood volume and blood pressure, c ...
,
brain
A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a ve ...
, and
skin
Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation.
Other animal coverings, such as the arthropod exoskeleton, have different de ...
. The increased risk for these cancers is due to inherited mutations that impair
DNA mismatch repair
DNA mismatch repair (MMR) is a system for recognizing and repairing erroneous insertion, deletion, and mis-incorporation of bases that can arise during DNA replication and recombination, as well as repairing some forms of DNA damage.
Mismatch ...
. It is a type of
cancer syndrome
A cancer syndrome, or family cancer syndrome, is a genetic disorder in which inherited genetic mutations in one or more genes predispose the affected individuals to the development of cancers and may also cause the early onset of these cancers. Ca ...
. Because patients with Lynch syndrome can have polyps, the term HNPCC has fallen out of favor.
Signs and symptoms
Risk of cancer
''Lifetime risk and mean age at diagnosis for Lynch syndrome associated cancers
''
In addition to the types of cancer found in the chart above, it is understood that Lynch syndrome also contributes to an increased risk of small bowel cancer,
pancreatic cancer, ureter/renal pelvis cancer, biliary tract cancer, brain cancer, and
sebaceous neoplasms.
Increased risk of
prostate cancer and
breast cancer
Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a r ...
has also been associated with Lynch syndrome, although this relationship is not entirely understood.
Two-thirds of colon cancers occur in the
proximal colon and common signs and symptoms include blood in the stool,
diarrhea
Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin w ...
or
constipation
Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the bowel movement ...
, and unintended
weight loss
Weight loss, in the context of medicine, health, or physical fitness, refers to a reduction of the total body mass, by a mean loss of fluid, body fat ( adipose tissue), or lean mass (namely bone mineral deposits, muscle, tendon, and other co ...
. The mean age of
colorectal cancer diagnosis is 44 for members of families that meet the Amsterdam criteria. The average age of diagnosis of endometrial cancer is about 46 years. Among women with HNPCC who have both colon and endometrial cancer, about half present first with
endometrial cancer, making endometrial cancer the most common sentinel cancer in Lynch syndrome. The most common symptom of endometrial cancer is abnormal vaginal bleeding. In HNPCC, the mean age of diagnosis of
gastric cancer
Stomach cancer, also known as gastric cancer, is a cancer that develops from the lining of the stomach. Most cases of stomach cancers are gastric carcinomas, which can be divided into a number of subtypes, including gastric adenocarcinomas. Lymph ...
is 56 years of age with intestinal-type adenocarcinoma being the most commonly reported pathology. HNPCC-associated ovarian cancers have an average age of diagnosis of 42.5 years-old; approximately 30% are diagnosed before age 40.
Significant variation in the rate of cancer has been found depending on the mutation involved. Up to the age of 75 years the risks of different cancers by the mutations are in the table below.
Genetics
HNPCC is inherited in an
autosomal dominant fashion. The hallmark of HNPCC is defective
DNA mismatch repair
DNA mismatch repair (MMR) is a system for recognizing and repairing erroneous insertion, deletion, and mis-incorporation of bases that can arise during DNA replication and recombination, as well as repairing some forms of DNA damage.
Mismatch ...
, which causes an elevated rate of single nucleotide changes and
microsatellite instability, also known as MSI-H (the H is "high"). MSI is identifiable in
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
specimens in the
pathology
Pathology is the study of the causes and effects of disease or injury. The word ''pathology'' also refers to the study of disease in general, incorporating a wide range of biology research fields and medical practices. However, when used in ...
laboratory. Most cases result in changes in the lengths of
dinucleotide repeats of the
nucleobase
Nucleobases, also known as ''nitrogenous bases'' or often simply ''bases'', are nitrogen-containing biological compounds that form nucleosides, which, in turn, are components of nucleotides, with all of these monomers constituting the basic b ...
s cytosine and adenine (sequence: CACACACACA...).
The 4 main genes involved in HNPCC normally encode for proteins that form
dimers to function:
# MLH1 protein dimerizes with PMS2 protein to form MutLα, which coordinates the binding of other proteins involved with mismatch repair like
DNA helicase
Helicases are a class of enzymes thought to be vital to all organisms. Their main function is to unpack an organism's genetic material. Helicases are motor proteins that move directionally along a nucleic acid phosphodiester backbone, separatin ...
,
single-stranded-DNA binding-protein (RPA), and
DNA polymerase
A DNA polymerase is a member of a family of enzymes that catalyze the synthesis of DNA molecules from nucleoside triphosphates, the molecular precursors of DNA. These enzymes are essential for DNA replication and usually work in groups to create ...
s.
# MSH2 protein dimerizes with MSH6 protein, which identifies mismatches via a
sliding clamp model, a protein for scanning for errors.
The impairment of either gene for the protein dimer impairs the protein function. These 4 genes are involved in error correction (mismatch repair), so dysfunction of the genes can lead to the inability to fix DNA replication errors and cause HNPCC. HNPCC is known to be associated with other mutations in
gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
s involved in the
DNA mismatch repair
DNA mismatch repair (MMR) is a system for recognizing and repairing erroneous insertion, deletion, and mis-incorporation of bases that can arise during DNA replication and recombination, as well as repairing some forms of DNA damage.
Mismatch ...
pathway:
People with MSH6 mutations are more likely to be Amsterdam criteria II-negative.
The presentation with MSH6 is slightly different from with MLH1 and MSH2, and the term "MSH6 syndrome" has been used to describe this condition.
In one study, the Bethesda guidelines were more sensitive than the Amsterdam Criteria in detecting it.
Up to 39% of families with mutations in an HNPCC gene do not meet the
Amsterdam criteria. Therefore, families found to have a deleterious mutation in an HNPCC gene should be considered to have HNPCC regardless of the extent of the family history. This also means that the Amsterdam criteria fail to identify many people who are at risk for Lynch syndrome. Improving the criteria for screening is an active area of research, as detailed in the Screening Strategies section of this article.
Most people with HNPCC inherit the condition from a parent. However, due to incomplete penetrance, variable age of cancer diagnosis, cancer risk reduction, or early death, not all people with an HNPCC gene mutation have a parent who had cancer. Some people develop HNPCC de-novo in a new generation, without inheriting the gene. These people are often only identified after developing an early-life colon cancer. Parents with HNPCC have a 50% chance of passing the genetic mutation on to each child. It is also important to note, that deleterious mutation in one of MMR genes alone is not sufficient to cause cancer, but that rather further mutations in other tumour suppressor genes need to occur.
Diagnosis
A diagnosis of Lynch syndrome is applied to people with a
germline DNA mutation in one of the
MMR genes (MLH1, MSH2, MSH6, and PMS2) or the
EPCAM
Epithelial cell adhesion molecule (EpCAM), also known as CD326 among other names, is a transmembrane glycoprotein mediating Ca2+-independent homotypic cell–cell adhesion in epithelia. EpCAM is also involved in cell signaling, migration, prol ...
gene, identified by genetic testing.
Candidates for germline genetic testing can be identified by clinical criteria such as the
Amsterdam Clinical Criteria and Bethesda Guidelines, or through tumor analysis by
immunohistochemistry(IHC), or
microsatellite instability (MSI) testing.
In the US, professional societies recommend testing every colon cancer for MSI or IHC as screening for Lynch syndrome, but this is not always performed because of cost and resource limitations.
Genetic testing is commercially available and consists of a blood test.
Immunohistochemistry
Immunohistochemistry (IHC) is a method that can be used to detect abnormal
mismatch repair
DNA mismatch repair (MMR) is a system for recognizing and repairing erroneous insertion, deletion, and mis-incorporation of bases that can arise during DNA replication and recombination, as well as repairing some forms of DNA damage.
Mismatch ...
(MMR) protein expression in tumours that are associated with Lynch syndrome. While it is not diagnostic of a Lynch syndrome, it can play a role in identifying people who should have germline testing. Two methods of implementation of IHC testing includes age-based testing and universal testing for all people.
Currently, there is no widespread agreement regarding which screening method should be used.
Age-based testing for IHC has been suggested in part due to cost-benefit analyses, whereas universal testing for all people with colorectal cancer ensures people with Lynch Syndrome are not missed.
To address the costs, researchers are trying to predict MSI or IHC directly from the way the tumor looks under the microscope, without doing any molecular testing.
Microsatellite Instability
Mutations in DNA mismatch repair systems can lead to difficulty transmitting regions within the DNA which contain repeating patterns of two or three nucleotides (
microsatellites), otherwise known as microsatellite instability (
MSI).
MSI is associated with alternate sized repetitive DNA sequences that are not present in the correlated germ line DNA resulting in 15-20% of colorectal cancers. MSI is identified through
DNA extraction
The first isolation of deoxyribonucleic acid (DNA) was done in 1869 by Friedrich Miescher. Currently, it is a routine procedure in molecular biology or forensic analyses. For the chemical method, many different kits are used for extraction, and s ...
from both a tumor tissue sample and a normal tissue sample followed by
PCR analysis of microsatellite regions.
MSI analysis can be used to identify people who may have Lynch syndrome and direct them for further testing.
One study noted that one third of MSI colorectal cancers showed a low immunoscore, suggesting that tumor-infiltrating lymphocytes might be a good option for therapy for these patients. High numbers of tumor-infiltrating lymphocytes were related with better survival rates and treatment responses.
Classification
Three major groups of MSI-H (
microsatellite instability – MSI) cancers can be recognized by histopathological criteria:
* right-sided poorly differentiated cancers
* right-sided mucinous cancers
*
adenocarcinomas
Adenocarcinoma (; plural adenocarcinomas or adenocarcinomata ) (AC) is a type of cancerous tumor that can occur in several parts of the body. It is defined as neoplasia of epithelial tissue that has glandular origin, glandular characteristics, or ...
in any location showing any measurable level of
intraepithelial lymphocyte Intraepithelial lymphocytes (IEL) are lymphocytes found in the epithelial layer of mammalian mucosal linings, such as the gastrointestinal (GI) tract and reproductive tract. However, unlike other T cells, IELs do not need priming. Upon encounteri ...
(TIL)
The histopathological criteria are not sensitive enough to detect MSI from
histology
Histology,
also known as microscopic anatomy or microanatomy, is the branch of biology which studies the microscopic anatomy of biological tissues. Histology is the microscopic counterpart to gross anatomy, which looks at larger structures vi ...
but researchers are trying to use artificial intelligence to predict MSI from histology.
In addition, HNPCC can be divided into ''Lynch syndrome I'' (familial colon cancer) and ''Lynch syndrome II'' (HNPCC associated with other cancers of the gastrointestinal tract or
reproductive system
The reproductive system of an organism, also known as the genital system, is the biological system made up of all the anatomical organs involved in sexual reproduction. Many non-living substances such as fluids, hormones, and pheromones are als ...
).
Prevention
After reporting a null finding from their randomized controlled trial of
aspirin
Aspirin, also known as acetylsalicylic acid (ASA), is a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and/or inflammation, and as an antithrombotic. Specific inflammatory conditions which aspirin is used to treat inc ...
(acetylsalicylic acid – ASA) to prevent the colorectal neoplasia of Lynch syndrome,
Burn and colleagues have reported new data, representing a longer follow-up period than reported in the initial ''NEJM'' paper. These new data demonstrate a reduced incidence in people with Lynch syndrome who were exposed to at least four years of high-dose aspirin, with a satisfactory risk profile. These results have been widely covered in the media; future studies will look at modifying (lowering) the dose (to reduce risk associated with the high dosage of ASA).
Screening
Genetic counseling and genetic testing are recommended for families that meet the Amsterdam criteria, preferably before the onset of colon cancer.
Colon cancer
Colonoscopies
Colonoscopy () or coloscopy () is the endoscopic examination of the large bowel and the distal part of the small bowel with a CCD camera or a fiber optic camera on a flexible tube passed through the anus. It can provide a visual diagnosis (''e.g ...
are recommended as a preventative method of surveillance for individuals who have Lynch syndrome, or LS-associated genes. Specifically, it is recommended that colonoscopies begin at ages 20–25 for MLH1 and MSH2 mutation carriers and 35 years for MSH6 and PMS2 mutation carriers.
Colonoscopic surveillance should then be performed at a 1-2 year interval for Lynch Syndrome patients.
Endometrial/Ovarian cancer
A
transvaginal ultrasound
Vaginal ultrasonography is a medical ultrasonography that applies an ultrasound transducer (or "probe") in the vagina to visualize organs within the pelvic cavity. It is also called transvaginal ultrasonography because the ultrasound waves go ''a ...
with or without
endometrial biopsy
The endometrial biopsy is a medical procedure that involves taking a tissue sample of the lining of the uterus. The tissue subsequently undergoes a histologic evaluation which aids the physician in forming a diagnosis.
Medical uses
There are a ...
is recommended annually for ovarian and endometrial cancer screening.
For women with Lynch syndrome, a yearly CA-125 blood test can be used to screen for ovarian cancer, however there is limited data on the efficacy of this test in reducing mortality.
Other cancers
There are also strategies for detecting other cancers early or reducing the chances of developing them that people with Lynch syndrome can discuss with their doctor, however their effectiveness is not clear.
These options include:
* Upper endoscopies to detect
stomach
The stomach is a muscular, hollow organ in the gastrointestinal tract of humans and many other animals, including several invertebrates. The stomach has a dilated structure and functions as a vital organ in the digestive system. The stomach i ...
and
small bowel
The small intestine or small bowel is an organ in the gastrointestinal tract where most of the absorption of nutrients from food takes place. It lies between the stomach and large intestine, and receives bile and pancreatic juice through the pa ...
cancer every 3–5 years, starting at age 30 at the earliest (preferably in a research setting)
* Annual urinalysis to detect
bladder cancer
Bladder cancer is any of several types of cancer arising from the tissues of the urinary bladder. Symptoms include blood in the urine, pain with urination, and low back pain. It is caused when epithelial cells that line the bladder become ma ...
, starting at age 30 at the earliest (preferably in a research setting)
* Annual physical and neurological exams to detect
cancer in the central nervous system (
brain
A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a ve ...
or spinal cord), starting at age 25 at the earliest
Amsterdam criteria
The following are the Amsterdam criteria in identifying high-risk candidates for molecular genetic testing:
''Amsterdam I Criteria (all bullet points must be fulfilled): The Amsterdam I criteria were published in 1990; however, were felt to be insufficiently sensitive.
''
* Three or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first degree (parent, child, sibling) relative of the other two
* Two successive affected generations
* One or more colon cancers diagnosed under age 50 years
*
Familial adenomatous polyposis
Familial adenomatous polyposis (FAP) is an autosomal dominant inherited condition in which numerous adenomatous polyps form mainly in the epithelium of the large intestine. While these polyps start out benign, malignant transformation into colon ...
(FAP) has been excluded
The Amsterdam II criteria were developed in 1999 and improved the diagnostic sensitivity for Lynch syndrome by including cancers of the
endometrium, small bowel, ureter and renal pelvis.
''Amsterdam Criteria II (all bullet points must be fulfilled):
''
* Three or more family members with HNPCC-related cancers, one of whom is a first-degree relative of the other two
* Two successive affected generations
* One or more of the HNPCC-related cancers diagnosed under age 50 years
*
Familial adenomatous polyposis
Familial adenomatous polyposis (FAP) is an autosomal dominant inherited condition in which numerous adenomatous polyps form mainly in the epithelium of the large intestine. While these polyps start out benign, malignant transformation into colon ...
(FAP) has been excluded
The Bethesda criteria were developed in 1997 and later updated in 2004 by the National Cancer Institute to identify persons requiring further testing for Lynch syndrome through MSI. In contrast to the Amsterdam Criteria, the Revised Bethesda Guidelines use pathological data in addition to clinical information to help health care providers identify persons at high risk.
Revised Bethesda Guidelines
If a person meets any 1 of 5 criteria the tumour(s) from the person should be tested for MSI:
1. Colorectal cancer diagnosed before age 50
2. Presence of synchronous or metachronous colorectal or other Lynch syndrome associated cancers (e.g. cancers of endometrium, ovary, stomach, small bowel, pancreas, biliary tract, ureter, renal pelvis, brain, sebaceous glands,
keratoacanthoma
Keratoacanthoma (KA) is a common low-grade (unlikely to metastasize or invade) rapidly-growing skin tumour that is believed to originate from the hair follicle (pilosebaceous unit) and can resemble squamous cell carcinoma.
The defining characteris ...
s)
3. Colorectal cancer with MSI-high pathology in a person who is younger than 60 years of age
4. Colorectal cancer diagnosed in a person with one or more first-degree relative with colorectal cancer or Lynch syndrome associated tumour diagnosed under age 50
5. Person with colorectal cancer and two or more first- or second-degree relatives with colorectal cancer or Lynch syndrome associated cancer diagnosed at any age.
It is important to note that these clinical criteria can be difficult to use in practice and clinical criteria used alone misses between 12 and 68 percent of Lynch syndrome cases.
Surgery
Prophylactic
hysterectomy and
salpingo-oophorectomy
In medicine, salpingo-oophorectomy is the removal of an ovary and its Fallopian tube. This procedure is most frequently associated with prophylactic surgery in response to the discovery of a BRCA mutation, particularly those of the normally tumo ...
(removal of the
uterus
The uterus (from Latin ''uterus'', plural ''uteri'') or womb () is the organ in the reproductive system of most female mammals, including humans that accommodates the embryonic and fetal development of one or more embryos until birth. The ...
,
Fallopian tubes, and
ovaries
The ovary is an organ in the female reproductive system that produces an ovum. When released, this travels down the fallopian tube into the uterus, where it may become fertilized by a sperm. There is an ovary () found on each side of the body. T ...
to prevent cancer from developing) can be performed before ovarian or endometrial cancer develops.
Treatment
Surgery remains the front-line therapy for HNPCC. Patients with Lynch syndrome who develop colorectal cancer may be treated with either a partial
colectomy
Colectomy ('' col-'' + '' -ectomy'') is bowel resection of the large bowel ( colon). It consists of the surgical removal of any extent of the colon, usually segmental resection (partial colectomy). In extreme cases where the entire large intest ...
or total colectomy with ileorectal anastomosis. Due to increased risk of colorectal cancer following partial colectomy and similar quality of life after both surgeries, a total colectomy may be a preferred treatment for HNPCC, especially in younger patients.
There is an ongoing controversy over the benefit of
5-fluorouracil
Fluorouracil (5-FU), sold under the brand name Adrucil among others, is a cytotoxic chemotherapy medication used to treat cancer. By intravenous injection it is used for treatment of colorectal cancer, oesophageal cancer, stomach cancer, pan ...
-based adjuvant therapies for HNPCC-related colorectal tumours, particularly those in stages I and II.
* Anti-PD-1 antibody therapy can be effective.
Checkpoint blockade with anti-PD-1 therapy is now preferred first line therapy for advanced Microsatellite-Instability–High colorectal cancer.
Epidemiology
Though the exact prevalence of Lynch syndrome-causing mutations in the general population remain unknown, recent studies estimate the prevalence to be 1 in 279 individuals, or 0.35%.
Certain populations are known to have a higher prevalence of founder mutations, including, but not limited to,
French Canadians,
Icelanders,
African Americans, and
Ashkenazi Jews
Ashkenazi Jews ( ; he, יְהוּדֵי אַשְׁכְּנַז, translit=Yehudei Ashkenaz, ; yi, אַשכּנזישע ייִדן, Ashkenazishe Yidn), also known as Ashkenazic Jews or ''Ashkenazim'',, Ashkenazi Hebrew pronunciation: , singu ...
.
Lynch syndrome-causing mutations are found in approximately 3% of all diagnosed colorectal cancers, and 1.8% of all diagnosed endometrial cancers.
The average age of diagnosis of cancer in patients with this syndrome is 44 years old, as compared to 64 years old in people without the syndrome.
Terminology
Henry T. Lynch, Professor of Medicine at
Creighton University Medical Center
Creighton University Medical Center - Bergan Mercy (formerly known as Creighton University Medical Center-Saint Joseph Hospital) is a hospital located in Central Omaha, Nebraska in the United States. On April 24, 2012, CUMC signed an agreement to ...
, characterized the syndrome in 1966.
In his earlier work, he described the disease entity as "cancer family syndrome." The term "Lynch syndrome" was coined in 1984 by other authors; Lynch named the condition HNPCC in 1985. Since then the two terms have been used interchangeably, until later advances in the understanding of the genetics of the disease led to the term HNPCC falling out of favor.
Other sources reserve the term "Lynch syndrome" when there is a known
DNA mismatch repair
DNA mismatch repair (MMR) is a system for recognizing and repairing erroneous insertion, deletion, and mis-incorporation of bases that can arise during DNA replication and recombination, as well as repairing some forms of DNA damage.
Mismatch ...
defect, and use the term "familial colorectal cancer type X" when the
Amsterdam criteria are met but there is no known DNA mismatch repair defect.
The putative "type X" families appear to have a lower overall incidence of cancer and lower risk for non-colorectal cancers than families with documented DNA mismatch repair deficiency.
About 35% of people who meet Amsterdam criteria do not have a DNA-mismatch-repair gene mutation.
Complicating matters is the presence of an alternative set of criteria, known as the "Bethesda Guidelines."
Society
There are a number of non-profit organisations providing information and support, including
Lynch Syndrome International
Lynch Syndrome International is a not for profit, tax exempt charity helping those with Lynch syndrome. It is recognized by the Internal Revenue Service as a 501(c)(3) not for profit charitable organization and contributions to the organization ...
AliveAndKickn Lynch Syndrome UK and Bowel Cancer UK. In the US, National Lynch Syndrome Awareness Day is March 22.
References
Further reading
Books
* Paperback version retitled Before My Time.
External links
FAQs on HNPCC from the
National Institute of Health
The National Institutes of Health, commonly referred to as NIH (with each letter pronounced individually), is the primary agency of the United States government responsible for biomedical and public health research. It was founded in the late ...
GeneReviews/NCBI/NIH/UW entry on Lynch syndrome*
National Cancer Institute: Genetics of Colorectal Cancer information summary
{{DEFAULTSORT:Hereditary Nonpolyposis Colorectal Cancer
DNA replication and repair-deficiency disorders
Colorectal cancer
Hereditary cancers
Syndromes with tumors
Syndromes affecting the gastrointestinal tract