Hereditary nonpolyposis colorectal cancer | |
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Micrograph showing tumor-infiltrating lymphocytes (in a colorectal cancer), a finding associated with MSI-H tumours, as may be seen in Lynch syndrome. H&E stain. | |
Specialty | Oncology |
Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary predisposition to colon cancer.
HNPCC includes (and was once synonymous with) [1] Lynch syndrome, an autosomal dominant genetic condition that is associated with a high risk of colon cancer, endometrial cancer (second most common), ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. [2] The increased risk for these cancers is due to inherited genetic mutations that impair DNA mismatch repair. It is a type of cancer syndrome.
Other HNPCC conditions include Lynch-like syndrome, polymerase proofreading-associated polyposis and familial colorectal cancer type X. [1]
Lifetime risk and mean age at diagnosis for Lynch syndrome–associated cancers [3]
Type of cancer | Lifetime risk (%) | Mean age at diagnosis (years) |
---|---|---|
Colorectal | 52-58 | 44-61 |
Endometrial | 25-60 | 48-62 |
Gastric | 6-13 | 56 |
Ovarian | 4-12 | 42.5 |
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. [3] Increased risk of prostate cancer and breast cancer has also been associated with Lynch syndrome, although this relationship is not entirely understood. [3]
Two-thirds of colon cancers occur in the proximal colon and common signs and symptoms include blood in the stool, diarrhea or constipation, and unintended weight loss. [4] The mean age of colorectal cancer diagnosis is 44 for members of families that meet the Amsterdam criteria.[ medical citation needed ] The average age of diagnosis of endometrial cancer is about 46 years.[ medical citation needed ] 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. [5] The most common symptom of endometrial cancer is abnormal vaginal bleeding. [6] In HNPCC, the mean age of diagnosis of gastric cancer 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.[ medical citation needed ]
Significant variation in the rate of cancer has been found depending on the mutation involved. [7] [8] Up to the age of 75 years the risks of different cancers by the mutations are in the table below.
Gene | colorectal cancer risk | endometrial cancer risk | ovarian cancer risk | upper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancer risk | urinary tract cancers risk | prostate cancer risk | brain tumor risk |
---|---|---|---|---|---|---|---|
MLH1 | 46% | 43% | 10% | 21% | 8% | 17% | 1% |
MSH2 | 57% | 17% | 10% | 25% | 32% | 5% | n.a. |
MSH6 | 15% | 46% | 13% | 7% | 11% | 18% | 1% |
Gene | Ovarian cancer risk | Endometrial cancer risk |
---|---|---|
MLH1 | 4-24% | 25-60% |
MSH2 / EPCAM | 4-24% | 25-60% |
MSH6 | 1-11% | 16-26% |
PMS2 | 6% (combined risk) | 15% |
Lynch syndrome is inherited in an autosomal dominant fashion. [10] The hallmark of Lynch syndrome is defective DNA mismatch repair, 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 specimens in the pathology laboratory. [11] Most cases result in changes in the lengths of dinucleotide repeats of the nucleobases cytosine and adenine (sequence: CACACACACA...). [12]
The 4 main genes involved in Lynch syndrome normally encode for proteins that form dimers to function:
The impairment of either gene for the protein dimer impairs the protein function. [17] 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 Lynch syndrome. [18] Lynch syndrome is known to be associated with other mutations in genes involved in the DNA mismatch repair pathway:
OMIM name | Genes implicated in HNPCC | Frequency of mutations in HNPCC families | Locus | First publication |
---|---|---|---|---|
HNPCC1 ( 120435) | MSH2 / EPCAM | approximately 60% | 2p22 | Fishel 1993 [16] |
HNPCC2 ( 609310) | MLH1 | approximately 30% | 3p21 | Papadopoulos 1994 [19] |
HNPCC5 | MSH6 | 7-10% | 2p16 | Miyaki 1997 [20] |
HNPCC4 | PMS2 | relatively infrequent | 7p22 [21] | Nicolaides 1994 |
HNPCC3 | PMS1 | case report [21] | 2q31-q33 | Nicolaides 1994 |
HNPCC6 | TGFBR2 | case report [22] | 3p22 | |
HNPCC7 | MLH3 | disputed [23] | 14q24.3 | |
People with MSH6 mutations are more likely to be Amsterdam criteria II-negative. [24] The presentation with MSH6 is slightly different from with MLH1 and MSH2, and the term "MSH6 syndrome" has been used to describe this condition. [25] In one study, the Bethesda guidelines were more sensitive than the Amsterdam Criteria in detecting it. [26]
Up to 39% of families with mutations in a Lynch syndrome gene do not meet the Amsterdam criteria.[ citation needed ] Therefore, families found to have a deleterious mutation in a Lynch syndrome gene should be considered to have Lynch syndrome 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 Lynch syndrome 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 Lynch syndrome 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. [27]
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 gene, identified by genetic testing. [28] 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. [28] 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. [29] Genetic testing is commercially available and consists of a blood test.[ citation needed ]
Immunohistochemistry (IHC) is a method that can be used to detect abnormal mismatch repair (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. [30] Two methods of implementation of IHC testing includes age-based testing and universal testing for all people. [31] Currently, there is no widespread agreement regarding which screening method should be used. [31] 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. [31] 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. [29]
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). [32] 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. [33] MSI is identified through DNA extraction from both a tumor tissue sample and a normal tissue sample followed by PCR analysis of microsatellite regions. [32] MSI analysis can be used to identify people who may have Lynch syndrome and direct them for further testing. [32] 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. [34]
Three major groups of MSI-H (microsatellite instability – MSI) cancers can be recognized by histopathological criteria:[ citation needed ]
The histopathological criteria are not sensitive enough to detect MSI from histology but researchers are trying to use artificial intelligence to predict MSI from histology. [29]
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). [35]
Genetic counseling and genetic testing are recommended for families that meet the Amsterdam criteria, preferably before the onset of colon cancer.
Colon cancer
Colonoscopies 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. [36] Colonoscopic surveillance should then be performed at a 1-2 year interval for Lynch Syndrome patients. [36]
Endometrial/ovarian cancer
A transvaginal ultrasound with or without endometrial biopsy is recommended annually for ovarian and endometrial cancer screening. [37] 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. [38]
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. [39] [40] These options include:
The following are the Amsterdam criteria in identifying high-risk candidates for molecular genetic testing: [41]
Amsterdam I Criteria (all bullet points must be fulfilled): The Amsterdam I criteria were published in 1990; however, were felt to be insufficiently sensitive. [42]
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. [43]
Amsterdam Criteria II (all bullet points must be fulfilled): [43]
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. [42] [43]
Revised Bethesda Guidelines
If a person meets any 1 of 5 criteria the tumour(s) from the person should be tested for MSI: [42]
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. [42]
Prophylactic hysterectomy and salpingo-oophorectomy (removal of the uterus, fallopian tubes, and ovaries to prevent cancer from developing) can be performed before ovarian or endometrial cancer develops. [37]
Surgery remains the front-line therapy for Lynch syndrome. Patients with Lynch syndrome who develop colorectal cancer may be treated with either a partial colectomy 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 Lynch syndrome, especially in younger patients. [44]
There is an ongoing controversy over the benefit of 5-fluorouracil-based adjuvant therapies for Lynch syndrome-related colorectal tumours, particularly those in stages I and II. [45]
Checkpoint blockade with anti-PD-1 therapy is now preferred first line therapy for advanced Microsatellite-Instability–High colorectal cancer. [47]
In 2024 development for a vaccine called LynchVax that would reduce the risk of cancer from the disease has been started by scientist from the University of Oxford with a grant from Cancer Research UK but clinical trials are far from being conducted yet. [48] [49]
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%. [50] [51] 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. [50] [51] Lynch syndrome-causing mutations are found in approximately 3% of all diagnosed colorectal cancers, and 1.8% of all diagnosed endometrial cancers. [50] [51] 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. [52]
Henry T. Lynch, Professor of Medicine at Creighton University Medical Center, characterized the syndrome in 1966. [53] 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. [54]
Other sources reserve the term "Lynch syndrome" when there is a known DNA mismatch repair 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. [55] 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. [56] About 35% of people who meet Amsterdam criteria do not have a DNA-mismatch-repair gene mutation. [57]
Complicating matters is the presence of an alternative set of criteria, known as the "Bethesda Guidelines." [58] [59] [60]
There are a number of non-profit organisations providing information and support, including Lynch Syndrome International, AliveAndKickn, Lynch Syndrome UK [61] and Bowel Cancer UK. [62] In the US, National Lynch Syndrome Awareness Day is March 22. [63]
Mismatch repair cancer syndrome (MMRCS) is a cancer syndrome associated with biallelic DNA mismatch repair mutations. It is also known as Turcot syndrome and by several other names.
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.
Microsatellite instability (MSI) is the condition of genetic hypermutability that results from impaired DNA mismatch repair (MMR). The presence of MSI represents phenotypic evidence that MMR is not functioning normally.
Muir–Torre syndrome is a rare hereditary, autosomal dominant cancer syndrome that is thought to be a subtype of HNPCC. Individuals are prone to develop cancers of the colon, genitourinary tract, and skin lesions, such as keratoacanthomas and sebaceous tumors. The genes affected are MLH1, MSH2, and more recently, MSH6, and are involved in DNA mismatch repair.
DNA mismatch repair protein Msh2 also known as MutS homolog 2 or MSH2 is a protein that in humans is encoded by the MSH2 gene, which is located on chromosome 2. MSH2 is a tumor suppressor gene and more specifically a caretaker gene that codes for a DNA mismatch repair (MMR) protein, MSH2, which forms a heterodimer with MSH6 to make the human MutSα mismatch repair complex. It also dimerizes with MSH3 to form the MutSβ DNA repair complex. MSH2 is involved in many different forms of DNA repair, including transcription-coupled repair, homologous recombination, and base excision repair.
DNA mismatch repair protein Mlh1 or MutL protein homolog 1 is a protein that in humans is encoded by the MLH1 gene located on chromosome 3. The gene is commonly associated with hereditary nonpolyposis colorectal cancer. Orthologs of human MLH1 have also been studied in other organisms including mouse and the budding yeast Saccharomyces cerevisiae.
MSH6 or mutS homolog 6 is a gene that codes for DNA mismatch repair protein Msh6 in the budding yeast Saccharomyces cerevisiae. It is the homologue of the human "G/T binding protein," (GTBP) also called p160 or hMSH6. The MSH6 protein is a member of the Mutator S (MutS) family of proteins that are involved in DNA damage repair.
The Amsterdam criteria are a set of diagnostic criteria used by doctors to help identify families which are likely to have Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC).
A colorectal polyp is a polyp occurring on the lining of the colon or rectum. Untreated colorectal polyps can develop into colorectal cancer.
Mismatch repair endonuclease PMS2 is an enzyme that in humans is encoded by the PMS2 gene.
Exonuclease 1 is an enzyme that in humans is encoded by the EXO1 gene.
DNA mismatch repair protein, MutS Homolog 3 (MSH3) is a human homologue of the bacterial mismatch repair protein MutS that participates in the mismatch repair (MMR) system. MSH3 typically forms the heterodimer MutSβ with MSH2 in order to correct long insertion/deletion loops and base-base mispairs in microsatellites during DNA synthesis. Deficient capacity for MMR is found in approximately 15% of colorectal cancers, and somatic mutations in the MSH3 gene can be found in nearly 50% of MMR-deficient colorectal cancers.
DNA polymerase delta catalytic subunit(DPOD1) is an enzyme that is encoded in the human by the POLD1 gene, in the DNA polymerase delta complex. DPOD1 is responsible for synthesizing the lagging strand of DNA, and has also been implicated in some activities at the leading strand. The DPOD1 subunit encodes both DNA polymerizing and exonuclease domains, which provide the protein an important second function in proofreading to ensure replication accuracy during DNA synthesis, and in a number of types of replication-linked DNA repair following DNA damage.
Methyl-CpG-binding domain protein 4 is a protein that in humans is encoded by the MBD4 gene.
PMS1 protein homolog 1 is a protein that in humans is encoded by the PMS1 gene.
DNA mismatch repair protein Mlh3 is a protein that in humans is encoded by the MLH3 gene.
Mouse models of colorectal cancer and intestinal cancer are experimental systems in which mice are genetically manipulated, fed a modified diet, or challenged with chemicals to develop malignancies in the gastrointestinal tract. These models enable researchers to study the onset, progression of the disease, and understand in depth the molecular events that contribute to the development and spread of colorectal cancer. They also provide a valuable biological system, to simulate human physiological conditions, suitable for testing therapeutics.
A hereditary cancer syndrome is a genetic disorder in which inherited genetic mutations in one or more genes predispose the affected individuals to the development of cancer and may also cause early onset of these cancers. Hereditary cancer syndromes often show not only a high lifetime risk of developing cancer, but also the development of multiple independent primary tumors.
Albert Fredrik de la Chapelle, MD, Ph.D was a Finnish human geneticist, long-time head of Finland's first Department of Medical Genetics at the University of Helsinki, and subsequently professor of Human Cancer Genetics at Ohio State University. He was best known for his role in the elucidation of the genetics of hereditary colorectal cancer and Lynch syndrome.
Polymerase proofreading-associated polyposis (PPAP) is an autosomal dominant hereditary cancer syndrome, which is characterized by numerous polyps in the colon and an increased risk of colorectal cancer. It is caused by germline mutations in DNA polymerase ε (POLE) and δ (POLD1). Affected individuals develop numerous polyps called colorectal adenomas. Compared with other polyposis syndromes, Polymerase proofreading-associated polyposis is rare. Genetic testing can help exclude similar syndromes, such as Familial adenomatous polyposis and MUTYH-associated polyposis. Endometrial cancer, duodenal polyps and duodenal cancer may also occur.