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Lynch syndrome

Lynch syndrome, also called hereditary non-polyposis colorectal cancer (HNPCC), is the most common inherited colon cancer syndrome, and carries a significantly increased risk for endometrial cancer and other malignancies. Lynch syndrome has an autosomal dominant inheritance pattern involving pathogenic variants in one of the mismatch repair (MMR) genes or epithelial cell adhesion molecule (EpCAM). Diagnosis is made by genetic testing of the index patient and their family members. Management consists of an earlier screening of individuals with defective MMR genes, as well as total colectomy if colorectal neoplasia is discovered. Prophylactic hysterectomy plus salpingo-oophorectomy are recommended for women beyond reproductive age.

Last updated: 8 Jan, 2021

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Epidemiology

  • Prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency: 1 in 279 people carry defective mismatch repair (MMR) genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure.
    • The most common inherited colon Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix: Anatomy cancer syndrome 
    • Accounts for 2%–4% of colorectal cancers
    • Increased risk for endometrial cancer Endometrial Cancer Endometrial carcinoma (EC) is the most common gynecologic malignancy in the developed world, and it has several histologic types. Endometrioid carcinoma (known as type 1 EC) typically develops from atypical endometrial hyperplasia, is hormonally responsive, and carries a favorable prognosis. Endometrial Hyperplasia and Endometrial Cancer and many other cancers
  • Malignancies occur earlier than in general population (5th decade).
  • General lifetime cancer risks in Lynch syndrome (LS) (approximate midpoints of broad ranges):
    • Colorectal cancer Colorectal cancer Colorectal cancer (CRC) is the 2nd leading cause of cancer-related deaths in the United States. Colorectal cancer is a heterogeneous disease that arises from genetic and epigenetic abnormalities, with influence from environmental factors. Colorectal Cancer: 50% (right colon Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix: Anatomy > left colon Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix: Anatomy)
    • Endometrial cancer Endometrial Cancer Endometrial carcinoma (EC) is the most common gynecologic malignancy in the developed world, and it has several histologic types. Endometrioid carcinoma (known as type 1 EC) typically develops from atypical endometrial hyperplasia, is hormonally responsive, and carries a favorable prognosis. Endometrial Hyperplasia and Endometrial Cancer: 38% 
    • Ovarian cancer Ovarian cancer Ovarian cancer is a malignant tumor arising from the ovarian tissue and is classified according to the type of tissue from which it originates. The 3 major types of ovarian cancer are epithelial ovarian carcinomas (EOCs), ovarian germ cell tumors (OGCTs), and sex cord-stromal tumors (SCSTs). Ovarian Cancer: 19% 
    • Stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach: Anatomy cancer: 7% 
  • Sex Sex The totality of characteristics of reproductive structure, functions, phenotype, and genotype, differentiating the male from the female organism. Gender Dysphoria ratio: women = men
Lynch syndrome cancer risk comparison

For people with Lynch syndrome, the lifetime cancer risk is also increased to a lesser extent for other cancers, including: renal pelvis Renal pelvis Kidneys: Anatomy, ureters Ureters One of a pair of thick-walled tubes that transports urine from the kidney pelvis to the urinary bladder. Urinary Tract: Anatomy, bladder Bladder A musculomembranous sac along the urinary tract. Urine flows from the kidneys into the bladder via the ureters, and is held there until urination. Pyelonephritis and Perinephric Abscess, brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification, small bowel Small bowel The small intestine is the longest part of the GI tract, extending from the pyloric orifice of the stomach to the ileocecal junction. The small intestine is the major organ responsible for chemical digestion and absorption of nutrients. It is divided into 3 segments: the duodenum, the jejunum, and the ileum. Small Intestine: Anatomy, hepatobiliary tract, pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas: Anatomy, prostate Prostate The prostate is a gland in the male reproductive system. The gland surrounds the bladder neck and a portion of the urethra. The prostate is an exocrine gland that produces a weakly acidic secretion, which accounts for roughly 20% of the seminal fluid. , and skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions. In the figure, the upper ranges of the individual risks are given.

Image by Lecturio.

Etiology

Lynch syndrome patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship inherit one or more mutant MMR genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure and the respective normal allele Allele Variant forms of the same gene, occupying the same locus on homologous chromosomes, and governing the variants in production of the same gene product. Basic Terms of Genetics/alleles; the 2nd allele Allele Variant forms of the same gene, occupying the same locus on homologous chromosomes, and governing the variants in production of the same gene product. Basic Terms of Genetics then becomes mutated or loses function by epigenetic silencing so often that the inheritance pattern is effectively autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance.

  • MMR genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure that can become mutated: MLH1, MSH2 (an EpCAM (epithelial cell adhesion Adhesion The process whereby platelets adhere to something other than platelets, e.g., collagen; basement membrane; microfibrils; or other ‘foreign’ surfaces. Coagulation Studies molecule) gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations can also cause loss), MSH6, and PMS2 
  • Mutations then occur at rates up to 1,000 times higher than normal, mostly in regions of repetitive sequences called microsatellites. 
  • The protein products of mismatch repair (MMR) genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure are important in “spell-checking” DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure during duplication by detecting and repairing DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure defects.
  • Loss of MMR activity causes an accumulation of DNA replication DNA replication The entire DNA of a cell is replicated during the S (synthesis) phase of the cell cycle. The principle of replication is based on complementary nucleotide base pairing: adenine forms hydrogen bonds with thymine (or uracil in RNA) and guanine forms hydrogen bonds with cytosine. DNA Replication errors, particularly in repetitive sequences (“tandem repeats”).
    • Microsatellite testing that shows mutations in 30% or more microsatellites is called microsatellite instability-high (MSI-H) and is the hallmark of defective MMRs.
    • A cancer-driver mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations is eventually created by one of the uncorrected errors made during DNA replication DNA replication The entire DNA of a cell is replicated during the S (synthesis) phase of the cell cycle. The principle of replication is based on complementary nucleotide base pairing: adenine forms hydrogen bonds with thymine (or uracil in RNA) and guanine forms hydrogen bonds with cytosine. DNA Replication.
  • MMR mutations can also occur as sporadic Sporadic Selective IgA Deficiency somatic mutations.

Pathogenesis and Pathology

Pathogenis

  • Some mutated microsatellite sequences are associated with cell growth genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure, leading to a benign Benign Fibroadenoma then malignant neoplastic polyp/carcinoma.
  • The MMR pathway of colon Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix: Anatomy carcinogenesis Carcinogenesis The origin, production or development of cancer through genotypic and phenotypic changes which upset the normal balance between cell proliferation and cell death. Carcinogenesis generally requires a constellation of steps, which may occur quickly or over a period of many years. Carcinogenesis is the 2nd-most common pathway Common pathway Hemostasis of colorectal cancer Colorectal cancer Colorectal cancer (CRC) is the 2nd leading cause of cancer-related deaths in the United States. Colorectal cancer is a heterogeneous disease that arises from genetic and epigenetic abnormalities, with influence from environmental factors. Colorectal Cancer (CRC), after the adenoma-carcinoma pathway of colon Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix: Anatomy carcinogenesis Carcinogenesis The origin, production or development of cancer through genotypic and phenotypic changes which upset the normal balance between cell proliferation and cell death. Carcinogenesis generally requires a constellation of steps, which may occur quickly or over a period of many years. Carcinogenesis.

Pathology

  • Characteristics of CRCs arising via the MMR (MSI-H) pathway: tend to show more mucinous features and reactive tumor-infiltrating lymphocytes Lymphocytes Lymphocytes are heterogeneous WBCs involved in immune response. Lymphocytes develop from the bone marrow, starting from hematopoietic stem cells (HSCs) and progressing to common lymphoid progenitors (CLPs). B and T lymphocytes and natural killer (NK) cells arise from the lineage. Lymphocytes: Histology
  • Characteristics of endometrial carcinomas in LS: increased frequency of non-endometrioid carcinoma histologies
  • Slightly higher number of adenomatous polyps Adenomatous polyps Benign neoplasms derived from glandular epithelium. Colorectal Cancer than the general population, but a higher rate of progression to CRC than typical polyps.

Clinical Presentation and Diagnosis

Clinical Presentation Presentation The position or orientation of the fetus at near term or during obstetric labor, determined by its relation to the spine of the mother and the birth canal. The normal position is a vertical, cephalic presentation with the fetal vertex flexed on the neck. Normal and Abnormal Labor

  • Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship are asymptomatic until they develop malignancy Malignancy Hemothorax.
  • Colorectal adenocarcinomas:
    • LS manifests with only a low or slightly higher-than-usual number of polyps.
    • Right-side carcinomas (more common): iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements deficiency anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types due to bleeding
    • Left-sided carcinomas: changes in bowel habits or stool caliber
  • Endometrial carcinomas: abnormal endometrial bleeding

Diagnosis

  • 1 or more germline mutations in the mismatch repair (MMR) genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure or EPCAM gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics are needed for a definitive diagnosis of Lynch syndrome.
  • 2 pathways are used to establish the diagnosis: Test the tumor Tumor Inflammation first, or base testing on family history Family History Adult Health Maintenance.
  • Suspect Lynch syndrome in any patient who has:
    • CRC prior to 50 years of age, or if more than 1 CRC
    • Endometrial carcinoma < 60 years of age
    • A 1st-degree relative with known LS 
    • Fulfilled accepted criteria for LS (Amsterdam criteria or Bethesda guidelines)
  • Amsterdam II criteria (poor sensitivity Sensitivity Binary classification measures to assess test results. Sensitivity or recall rate is the proportion of true positives. Blotting Techniques, suspect LS if the following criteria are met MET Preoperative Care):
    • 3 or more relatives (at least 1 first-degree) have LS–associated cancers; familial adenomatous polyposis Familial Adenomatous Polyposis Familial adenomatous polyposis (FAP) is an autosomal dominant inherited genetic disorder that presents with numerous adenomatous polyps in the colon. Familial adenomatous polyposis is the most common of the polyposis syndromes, which is a group of inherited or acquired conditions characterized by the growth of polyps in the GI tract, associated with other extracolonic features. Familial Adenomatous Polyposis ( FAP FAP Familial adenomatous polyposis (FAP) is an autosomal dominant inherited genetic disorder that presents with numerous adenomatous polyps in the colon. Familial adenomatous polyposis is the most common of the polyposis syndromes, which is a group of inherited or acquired conditions characterized by the growth of polyps in the GI tract, associated with other extracolonic features. Familial Adenomatous Polyposis) excluded.
    • LS–associated cancers involving at least 2 generations
    • 1 or more cancers diagnosed before the age of 50 years
  • Bethesda guidelines, revised (better sensitivity Sensitivity Binary classification measures to assess test results. Sensitivity or recall rate is the proportion of true positives. Blotting Techniques and specificity Specificity Specificity is the probability of correctly determining the absence of a condition. Immunoassays than Amsterdam criteria):
    • CRC diagnosed < 50 years of age
    • 2 or more LS-associated cancers
    • CRC with MSI-H–like histology in patient < 60 years of age
    • CRC in patient with a 1st-degree relative with LS–associated cancer < 50 years
    • CRC in patient with 2 1st-degree relatives with LS–associated cancer, any age

Management

Surveillance Surveillance Developmental Milestones and Normal Growth and screening Screening Preoperative Care tests

  • For CRC: annual colonoscopy Colonoscopy Endoscopic examination, therapy or surgery of the luminal surface of the colon. Colorectal Cancer Screening starting at 20–25 years of age, or 2–5 years prior to the earliest age of CRC diagnosis in the family
  • For endometrial cancer Endometrial Cancer Endometrial carcinoma (EC) is the most common gynecologic malignancy in the developed world, and it has several histologic types. Endometrioid carcinoma (known as type 1 EC) typically develops from atypical endometrial hyperplasia, is hormonally responsive, and carries a favorable prognosis. Endometrial Hyperplasia and Endometrial Cancer: annual endometrial biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma, starting at 30 years of age
  • Annual skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions examinations to detect: sebaceous tumors ( benign Benign Fibroadenoma and malignant) and cutaneous keratoacanthomas associated with Muir-Torre syndrome (a variant of LS)
  • Reproductive counseling: LS patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship of reproductive age should be offered carrier Carrier Vaccination testing.

Surgical management

For CRC:

  • Total abdominal colectomy instead of segmental resection for CRC
  • If rectal cancer: total proctocolectomy

For endometrial cancer Endometrial Cancer Endometrial carcinoma (EC) is the most common gynecologic malignancy in the developed world, and it has several histologic types. Endometrioid carcinoma (known as type 1 EC) typically develops from atypical endometrial hyperplasia, is hormonally responsive, and carries a favorable prognosis. Endometrial Hyperplasia and Endometrial Cancer

  • Total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAHBSO) if cancer diagnosed
  • Prophylactic TAHBSO when childbearing is complete

Medical management

Chemoprevention:

  • Estrogen-progestin contraceptives reduce risk of endometrial and ovarian cancers
  • Aspirin Aspirin The prototypical analgesic used in the treatment of mild to moderate pain. It has anti-inflammatory and antipyretic properties and acts as an inhibitor of cyclooxygenase which results in the inhibition of the biosynthesis of prostaglandins. Aspirin also inhibits platelet aggregation and is used in the prevention of arterial and venous thrombosis. Nonsteroidal Antiinflammatory Drugs (NSAIDs): may reduce the risk of CRC 

Immunotherapy:

  • Pembrolizumab Pembrolizumab Squamous Cell Carcinoma (SCC) or nivolumab Nivolumab A genetically engineered, fully humanized immunoglobulin g4 monoclonal antibody that binds to the pd-1 receptor, activating an immune response to tumor cells. It is used as monotherapy or in combination with ipilimumab for the treatment of advanced malignant melanoma. It is also used in the treatment of advanced or recurring non-small cell lung cancer; renal cell carcinoma; and Hodgkin’s lymphoma. Melanoma 
  • Used in MSI-H–/MMR–deficient tumors

Differential Diagnosis

  • FAP FAP Familial adenomatous polyposis (FAP) is an autosomal dominant inherited genetic disorder that presents with numerous adenomatous polyps in the colon. Familial adenomatous polyposis is the most common of the polyposis syndromes, which is a group of inherited or acquired conditions characterized by the growth of polyps in the GI tract, associated with other extracolonic features. Familial Adenomatous Polyposis: presents with hundreds of adenomatous polyps Adenomatous polyps Benign neoplasms derived from glandular epithelium. Colorectal Cancer and typically results in CRC in the distal colon Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix: Anatomy. Lynch syndrome typically manifests with CRC in the proximal colon Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix: Anatomy and only a low number of polyps. Genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies can distinguish between the 2 conditions.
  • Familial colorectal cancer Colorectal cancer Colorectal cancer (CRC) is the 2nd leading cause of cancer-related deaths in the United States. Colorectal cancer is a heterogeneous disease that arises from genetic and epigenetic abnormalities, with influence from environmental factors. Colorectal Cancer type X (FCCTX): Amsterdam I criteria are met MET Preoperative Care but the tumors lack the MSI MSI The occurrence of highly polymorphic mono- and dinucleotide microsatellite repeats in somatic cells. It is a form of genome instability associated with defects in DNA mismatch repair. Colorectal Cancer seen in LS. No increased risk of other LS–associated cancers.

References

  1. Win, A.K. (2019). Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis. UpToDate. Retrieved November 10, 2020, from https://www.uptodate.com/contents/lynch-syndrome-hereditary-nonpolyposis-colorectal-cancer-clinical-manifestations-and-diagnosis
  2. Kumar, V., Abbas, A. K., Aster, J.C., (Eds.). (2020). Small Intestine and Colon. Robbins & Cotran Pathologic Basis of Disease. (10th ed. pp. 814-816). Elsevier, Inc.
  3. Lynch syndrome. (2020). Cancer.Net. https://www.cancer.net/cancer-types/lynch-syndrome
  4. Li, K., Luo, H., Huang, L., Luo, H., & Zhu, X. (2020). Microsatellite instability: A review of what the oncologist should know. Cancer Cell International, 20(1), 16. https://doi.org/10.1186/s12935-019-1091-8
  5. Checkpoint inhibitor immunotherapy delays colorectal cancer progression. (n.d.). News.Cancerconnect.Com. Retrieved November 11, 2020, from https://news.cancerconnect.com/colon-cancer/checkpoint-inhibitor-immunotherapy-delays-colorectal-cancer-progression-cKTur5yY-k-yUY3aHZCjEw
  6. Oiseth, S. J., & Aziz, M. S. (2017). Cancer immunotherapy: A brief review of the history, possibilities, and challenges ahead. Journal of Cancer Metastasis and Treatment, 3, 250–261. https://doi.org/10.20517/2394-4722.2017.41
  7. Mardis, E. R. (2019). Neoantigens and genome instability: Impact on immunogenomic phenotypes and immunotherapy response. Genome Medicine, 11(1), 71. https://doi.org/10.1186/s13073-019-0684-0
  8. Therkildsen, C., Ladelund, S., Smith-Hansen, L. et al. (2017). Towards gene- and gender-based risk estimates in Lynch syndrome; age-specific incidences for 13 extra-colorectal cancer types. Br J Cancer, 117, 1702–1710. https://doi.org/10.1038/bjc.2017.348 
  9. Kalady, M. F., Kravochuck, S. E., Heald, B., Burke, C. A., & Church, J. M. (2015). Defining the adenoma burden in lynch syndrome. Diseases of the colon and rectum, 58(4), 388–392. https://doi.org/10.1097/DCR.0000000000000333
  10. Burn J, Sheth H, Elliott F, et al (Eds.) (2020). Cancer prevention with aspirin in hereditary colorectal cancer (Lynch syndrome), 10-year follow-up and registry-based 20-year data in the CAPP2 study: a double-blind, randomised, placebo-controlled trial. Lancet (London, England), 395(10240), 1855–1863. https://doi.org/10.1016/S0140-6736(20)30366-4
  11. Peltomäki, P., Olkinuora, A., & Nieminen, T. T. (2020). Updates in the field of hereditary nonpolyposis colorectal cancer. Expert Review of Gastroenterology & Hepatology, 14(8), 707–720. https://doi.org/10.1080/17474124.2020.1782187
  12. Møller, P. (2020). The Prospective Lynch Syndrome Database reports enable evidence-based personal precision health care. Hereditary Cancer in Clinical Practice, 18. https://doi.org/10.1186/s13053-020-0138-0

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