{"product_id":"understanding-lynch-syndrome-the-century-long-medical-detective-story","title":"Understanding Lynch Syndrome: The Century-Long Medical Detective Story","description":"\u003cp\u003eThis patient-friendly article describes the history of Lynch syndrome, a hereditary condition that raises the risk of several cancers, especially colorectal and endometrial (uterine) cancer. The story begins in 1895, when Dr. Aldred Scott Warthin documented a family with many cancer cases across generations, and continues through the 1990s discovery of the DNA mismatch repair genes that cause the disease. The article explains how diagnostic criteria evolved. The article explains why some families with colorectal cancer do not have Lynch syndrome. The article explains what research has shown about chemotherapy response in patients whose tumors have microsatellite instability.\u003c\/p\u003e\n\n\u003ch1\u003eUnderstanding Lynch Syndrome: The Century-Long Medical Detective Story\u003c\/h1\u003e\n\n\u003ch2\u003eTable of Contents\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003e\u003ca href=\"#ddn-key-points\"\u003eKey Points\u003c\/a\u003e\u003c\/li\u003e\n\n  \u003cli\u003e\u003ca href=\"#background\"\u003eBackground: Why This History Matters\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#early-years\"\u003eThe Early Years (1895–1937): Dr. Warthin and Family G\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#mid-century\"\u003eThe Mid-20th Century: From Warthin to Lynch\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#naming\"\u003eNaming the Condition: From \"Cancer Family Syndrome\" to Lynch Syndrome\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#amsterdam\"\u003eThe Amsterdam Criteria and International Collaboration\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#msi\"\u003eMicrosatellite Instability: A Key Discovery in Colorectal Cancer\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#genes\"\u003eFrom Microsatellite Instability to DNA Mismatch Repair Genes\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#diagnostics\"\u003eEvolution of Diagnostic Tests\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#syndrome-x\"\u003eLynch Syndrome in the 21st Century: \"Syndrome X\"\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#genetic-interpretation\"\u003eInterpreting Genetic Test Results\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#chemotherapy\"\u003eAdjuvant Chemotherapy and Lynch Syndrome\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#limitations\"\u003eLimitations and Open Questions\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#recommendations\"\u003eWhat This Means for Patients\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#ddn-faq\"\u003eFrequently Asked Questions\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#source\"\u003eSource Information\u003c\/a\u003e\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003c!-- ddn:keypoints:start --\u003e\n\u003ch2 id=\"ddn-key-points\"\u003eKey Points\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003eLynch syndrome is a hereditary condition caused by mutations in DNA mismatch repair genes, raising the risk of colorectal and endometrial cancers.\u003c\/li\u003e\n\u003cli\u003eIt is inherited in an autosomal dominant pattern, so a person with Lynch syndrome has a 50% chance of passing it to each child.\u003c\/li\u003e\n\u003cli\u003eCurrent recommendations state that any colorectal cancer in a person younger than 70 years old should be screened by MSI testing or IHC.\u003c\/li\u003e\n\u003cli\u003eOnly 60% of families meeting the Amsterdam Criteria have a mismatch repair gene mutation; the other 40% have Familial Colorectal Cancer-Type X.\u003c\/li\u003e\n\u003cli\u003eResearch suggests colorectal cancers with microsatellite instability may respond differently to certain chemotherapy drugs, particularly 5-FU.\u003c\/li\u003e\n\u003c\/ul\u003e\n\u003c!-- ddn:keypoints:end --\u003e\n\n\n\u003ch2 id=\"background\"\u003eBackground: Why This History Matters\u003c\/h2\u003e\n\u003cp\u003eLynch syndrome is one of the most common hereditary cancer conditions. It is caused by inherited mutations (changes) in genes that normally repair DNA. Understanding how doctors and scientists discovered this condition helps patients appreciate why genetic testing and early screening are so important today.\u003c\/p\u003e\n\u003cp\u003eThe story of Lynch syndrome spans more than a century. It began with careful observation of a single family and grew into a worldwide effort involving hundreds of researchers. This article traces that journey from 1895 to the present day.\u003c\/p\u003e\n\n\u003ch2 id=\"early-years\"\u003eThe Early Years (1895–1937): Dr. Warthin and Family G\u003c\/h2\u003e\n\u003cp\u003eOne hundred years ago, Dr. Aldred Scott Warthin was the Chairman of the Department of Pathology at the University of Michigan in Ann Arbor. In 1895, a woman who worked as his seamstress told him she was distressed because many family members across several generations had died of cancer. She feared she would develop cancer too.\u003c\/p\u003e\n\u003cp\u003eHer fear came true. She developed endometrial cancer (cancer of the lining of the uterus) and died from it, exactly as she had predicted.\u003c\/p\u003e\n\u003cp\u003eDr. Warthin was skeptical of statistical approaches to studying cancer. He wrote that \"the statistical study of carcinoma … [has] been carried as far as it can be profitable.\" Instead, he decided to conduct a detailed survey of the seamstress's family. He created a pedigree (a family tree showing which members had cancer and how they were related).\u003c\/p\u003e\n\u003cp\u003eThe seamstress had 10 siblings. Among them:\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003e2 had uterine cancer\u003c\/li\u003e\n  \u003cli\u003e2 had stomach cancer\u003c\/li\u003e\n  \u003cli\u003e1 had an \"abdominal cancer\"\u003c\/li\u003e\n\u003c\/ul\u003e\n\u003cp\u003eAll 5 of those siblings with cancer had descendants who also developed multiple cancers. Among family members without cancer who had children, none of their children developed cancer. Dr. Warthin concluded that there could be a familial predisposition to cancer, at least in this family.\u003c\/p\u003e\n\u003cp\u003eThe family had emigrated from Germany to Michigan before the Civil War. Dr. Warthin called them \"Family G.\"\u003c\/p\u003e\n\u003cp\u003eDr. Warthin also reviewed 3,600 cases of neoplasia (abnormal tissue growth, including tumors) that had come through his laboratory from 1895 to 1912. Of these, 1,600 were carcinomas (malignant cancers). About 15% of those carcinoma patients had a family history of carcinoma. A 1912 report from a German investigator named Levin supported this finding. Dr. Warthin concluded that there were \"cancerous fraternities\" and that there was \"some influence of heredity on cancer.\"\u003c\/p\u003e\n\u003cp\u003eIn 1925, Dr. Warthin published a further study of Cancer Family G. By then, he had concluded that familial susceptibility to cancer was particularly strong for cancers of the gastrointestinal tract and the uterus. He recognized that cancers in this family occurred at an early age. He suggested that tumors might be occurring \"at an earlier age in successive generations.\" This phenomenon is now called anticipation. Anticipation has not been confirmed in later studies of Lynch syndrome.\u003c\/p\u003e\n\u003cp\u003eDr. Warthin also noted that 3 young members of the family had appendicitis. During surgery, doctors found advanced cancer instead. This finding foreshadowed the tendency for colorectal cancers (CRCs) in this disease to occur in the proximal colon (the right side of the colon, closer to the small intestine).\u003c\/p\u003e\n\u003cp\u003eAmong 146 family members, almost 32% had developed cancer. The median age at cancer diagnosis was 37.9 years. Dr. Warthin commented that his observations had been met \"with little favor among surgical writers.\"\u003c\/p\u003e\n\u003cp\u003eDr. Warthin died in 1931. His colleagues Dr. I.J. Hauser and Dr. Carl V. Weller issued a further report on the family in 1936. By that time, more individuals had been followed for a longer period, which reduced one type of bias in the study. The average age at death from cancer had risen to 48.3 years.\u003c\/p\u003e\n\u003cp\u003eDr. Hauser and Dr. Weller noted several important observations:\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003eThere were no cases of cervical cancer among those with uterine cancer\u003c\/li\u003e\n  \u003cli\u003eThere were many gastrointestinal cancers\u003c\/li\u003e\n  \u003cli\u003eThere were few breast cancers\u003c\/li\u003e\n\u003c\/ul\u003e\n\u003cp\u003eThey provided detailed pathological analyses of tumors from each branch of the family. As more data accumulated, they concluded that there was a \"diminishing incidence\" of cancer with successive generations. They proposed that this family provided more evidence for an \"inheritable organ-specific predisposition to carcinoma.\"\u003c\/p\u003e\n\n\u003ch2 id=\"mid-century\"\u003eThe Mid-20th Century: From Warthin to Lynch\u003c\/h2\u003e\n\u003cp\u003eThe story grew cold from 1937 until the 1960s. Occasional case reports of this disease came from the Mayo Clinic in 1941, from England in 1956, and from a variety of locations in the 1960s. Even so, many doctors doubted that a familial form of colorectal cancer existed. This familial form was not familial adenomatous polyposis (FAP, another hereditary condition that causes hundreds of polyps in the colon).\u003c\/p\u003e\n\u003cp\u003eOne person who noticed these familial clusters of cancer was Dr. Henry T. Lynch. He reported several families in detail in 1966 and 1967.\u003c\/p\u003e\n\u003cp\u003eDr. Lynch was aware of Dr. Warthin's \"Cancer Family G.\" He arranged for a family reunion near Ann Arbor, Michigan, to learn more about this family. He conducted a detailed medical genetic investigation. He obtained data on more than 650 family members, among whom 95 had developed cancers. He found a predominance of cancers of the colon, uterus, and stomach. He published these findings in the iconic 1971 manuscript titled \"Cancer Family 'G' Revisited.\"\u003c\/p\u003e\n\u003cp\u003eOnce again, the children of affected individuals continued to be at risk for early-onset cancers. Dr. Lynch recognized the autosomal dominant nature of inheritance. This means that a person needs to inherit only one copy of the mutated gene from one parent to be at risk. He used the term \"Cancer Family Syndrome\" in this report.\u003c\/p\u003e\n\u003cp\u003eThis would not be the final report on Cancer Family G. In 2005, Dr. Douglas and colleagues from the University of Michigan provided additional follow-up of the family. They analyzed data on 929 descendants of the original progenitor. They reported the specific mutation in the MSH2 gene that caused the disease in this family.\u003c\/p\u003e\n\u003cp\u003eThis work verified the risks for cancer of the colon and endometrium. It showed that the risks for gastric (stomach) cancer, which were initially prominent, had disappeared through the 20th century. It also provided standardized incidence ratios for cancers of various organs. There is probably no other instance in which one family has contributed so much to the understanding of an important genetic disease.\u003c\/p\u003e\n\n\u003ch2 id=\"naming\"\u003eNaming the Condition: From \"Cancer Family Syndrome\" to Lynch Syndrome\u003c\/h2\u003e\n\u003cp\u003eIn 1973, Dr. C. Richard Boland wrote a medical school thesis titled \"A Familial Cancer Syndrome.\" He recognized the same disease. This led to the publication of 2 papers describing additional families with Lynch syndrome.\u003c\/p\u003e\n\u003cp\u003eIn the first paper, the term \"Cancer Family Syndrome\" was used, based on Dr. Lynch's nomenclature. When a second family was reported later, doctors noted that some families had a phenotype (observable characteristics) with only colorectal cancer. Other families had the characteristic non-colonic cancers we now recognize in this disease.\u003c\/p\u003e\n\u003cp\u003eThe terms Lynch Syndrome I and II were used for the first time. Lynch Syndrome I distinguished those families with colorectal cancer only. Lynch Syndrome II distinguished those with the full spectrum of cancers. There is now evidence that at least some germline mutations can produce a colorectal cancer-predominant syndrome. However, the designations of Lynch Syndrome I and II are no longer used or necessary.\u003c\/p\u003e\n\u003cp\u003eIn 1985, Dr. Lynch first used the term \"hereditary non-polyposis colorectal cancer\" or HNPCC for this disease. This was the accepted term for many years. The term Lynch syndrome was not applied until the genetic basis of the disease was discovered. More importantly, the term Lynch syndrome was not applied until doctors recognized that not all familial clusters of colorectal cancer represented one disease. The term now refers specifically to those families with germline mutations in DNA mismatch repair (MMR) genes.\u003c\/p\u003e\n\n\u003ch2 id=\"amsterdam\"\u003eThe Amsterdam Criteria and International Collaboration\u003c\/h2\u003e\n\u003cp\u003eDuring this time, Dr. Hans Vasen from the Netherlands emerged as a major contributor to the field. Dr. Vasen was one of several key members in the formation of the International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC). This group was conceived during a colorectal cancer meeting in Jerusalem in 1989. It had its first formal meeting in Amsterdam in 1990. Meetings were held regularly thereafter, particularly as understanding of hereditary colorectal cancer grew and the biological basis of the disease was uncovered.\u003c\/p\u003e\n\u003cp\u003eWhile some observers doubted the existence of a hereditary non-polyposis colorectal cancer, Dr. Vasen and other interested clinicians accumulated and characterized familial clusters of colorectal cancer. They developed the \"Amsterdam Criteria,\" which were valuable for finding families who had Lynch syndrome. Gathering \"reagent grade\" families for analysis, along with the evolution of molecular genetics, would soon lead to the discovery of the genetic basis of Lynch syndrome.\u003c\/p\u003e\n\u003cp\u003eUltimately, the ICG-HNPCC merged with the Leeds Castle Polyposis Group to form the International Society for Gastrointestinal Hereditary Tumours, or InSiGHT. This organization continues to have semi-annual meetings and research initiatives.\u003c\/p\u003e\n\n\u003ch2 id=\"msi\"\u003eMicrosatellite Instability: A Key Discovery in Colorectal Cancer\u003c\/h2\u003e\n\u003cp\u003eFrom the late 1960s until 1992, progress in understanding Lynch syndrome was slow. The clinical features were refined, but there was no premalignant phenotype (a detectable precancerous state), and only a few clues about the nature of the tumors. There were multiple attempts to understand the basic mechanism responsible for the disease. All failed.\u003c\/p\u003e\n\u003cp\u003eIn 1989–1990, the laboratory of Dr. Bert Vogelstein proposed that colorectal neoplasia developed through multistep carcinogenesis. This means that cancer develops through a series of genetic changes over time. The sequential loss of specific fragments of chromosomal DNA was thought to be a key part of this process. Loss of DNA in a tumor was termed \"loss of heterozygosity\" or LOH, because of the genetic techniques used to detect it.\u003c\/p\u003e\n\u003cp\u003eMany laboratories, including that of Dr. Manuel Perucho, were looking for LOH in cancer tissues. These losses would represent presumptive locations for tumor suppressor genes involved in colorectal carcinogenesis. Dr. Perucho used a technique called \"arbitrarily primed PCR\" to amplify randomly selected genetic targets from paired samples of colorectal cancer and normal tissues. The PCR products were separated by gel electrophoresis and compared side-by-side to look for a genetic deletion in the cancer DNA compared to its normal counterpart.\u003c\/p\u003e\n\u003cp\u003eThere were plenty of these deletions to be found. However, Dr. Perucho also noted subtle changes in the lengths of some amplified DNA fragments in tumor tissues. These fragments specifically contained simple repetitive sequences called \"microsatellites.\" Only some colorectal cancers showed this. Those that did had an estimated 100,000 such mutations.\u003c\/p\u003e\n\u003cp\u003eDr. Perucho proposed that this subset of colorectal cancers was different from the rest. He suggested that this represented a unique \"pathway\" through which colorectal tumors could evolve. He had considerable difficulty getting this revolutionary idea published. It finally appeared in the journal Nature after some delay.\u003c\/p\u003e\n\u003cp\u003eWhile Dr. Perucho was sending his manuscript around for approval, two other laboratories also discovered microsatellite instability (MSI). One was the lab of Dr. Stephen Thibodeau from the Mayo Clinic. Dr. Thibodeau also noted that MSI was mainly seen in colorectal cancers from the proximal colon. He found that survival was better in this group. He also found that the presence of MSI correlated inversely with the LOH events described by Dr. Vogelstein's group. He suggested that this might represent a novel mechanism compared with other colorectal cancers.\u003c\/p\u003e\n\u003cp\u003eAt approximately the same time, an international consortium was using microsatellite markers in an extensive linkage analysis study on familial clusters of colorectal cancer. This consortium included Dr. Vogelstein from Johns Hopkins, together with Dr. Albert de la Chapelle, Dr. Lauri Aaltonen, and Dr. Paivi Peltomaki from Finland, and others who provided appropriately identified families.\u003c\/p\u003e\n\u003cp\u003eOn one afternoon in the spring of 1993 (specifically 3:45 PM on Saturday, March 13), Dr. Lauri Aaltonen identified significant linkage for Lynch syndrome on chromosome 2p. He used the microsatellite marker D2S123, which was the 345th marker analyzed in this study. The move from complete darkness to light occurred with an astonishingly quick stroke of discovery.\u003c\/p\u003e\n\u003cp\u003eThe presumption was that a tumor suppressor gene was in the vicinity of D2S123. The logical experiment was to look for LOH in the colorectal cancer tissue from an affected patient. Instead of LOH, they found MSI.\u003c\/p\u003e\n\u003cp\u003eThe 3 papers (one from Dr. Thibodeau and two from the international consortium) all appeared in the same issue of the journal Science on May 7, 1993. The entire world of hereditary colorectal cancer was turned upside down. There was, for the first time, a clue regarding the molecular basis of this disease. Dr. Perucho, who had initially noted MSI and proposed a separate pathway, had his paper published a few weeks later, on June 10, 1993. He was quite unhappy about the delays produced by certain journal editors.\u003c\/p\u003e\n\n\u003ch2 id=\"genes\"\u003eFrom Microsatellite Instability to DNA Mismatch Repair Genes\u003c\/h2\u003e\n\u003cp\u003eThe speed of discovery increased substantially from that point. Interestingly, none of the initial discoverers of MSI recognized exactly how the autoradiograms they had produced were the key to understanding the disease. Laboratories studying genetics in bacteria and yeast had previously discovered the DNA MMR system. They knew that if MMR genes were inactivated by mutation in microorganisms, it resulted in widespread mutations at microsatellite sequences.\u003c\/p\u003e\n\u003cp\u003eSeveral laboratories entered into a race to clone the human homologs (equivalent genes in humans) of these genes. They wanted to determine if there were germline mutations in DNA MMR genes in families with Lynch syndrome.\u003c\/p\u003e\n\u003cp\u003eThe first to do this successfully was the laboratory of Dr. Richard Kolodner. Dr. Kolodner was an established investigator in yeast genetics. He had identified the MSH2 gene in yeast but had not previously ventured into human disease or cancer.\u003c\/p\u003e\n\u003cp\u003eOn December 3, 1993, this lab, together with several collaborators, cloned the human homolog of the DNA MMR gene MSH2. This cloning happened less than 6 months after the initial linkage of MSI with hereditary colorectal cancer. They found a sequence variation in a family with Lynch syndrome that was present in those who had developed cancer.\u003c\/p\u003e\n\u003cp\u003eEven more astonishing, just 2 weeks later, on December 17, 1993, the international consortium led by Dr. Vogelstein and Dr. de la Chapelle found 3 additional kindreds (families) with inactivating mutations in the human MSH2 gene. Moreover, they identified a colorectal cancer cell line called HCT116 that had MSI. This created the first in vitro (laboratory) model in which to study the basics of the process. For those interested in Lynch syndrome, this was like the first step on the moon.\u003c\/p\u003e\n\u003cp\u003eEarlier in 1993, a Lynch syndrome family had been characterized in Sweden. In this instance, the genetic linkage pointed to chromosome 3p, rather than 2p, where MSH2 had been found. This launched yet another race to identify the gene.\u003c\/p\u003e\n\u003cp\u003eAgain, the Kolodner group cloned the human MLH1 gene, in collaboration with Dr. R. Michael Liskay. Both Dr. Kolodner and Dr. Liskay had been working on MutL-related genes in yeast. They reported germline mutations in additional Lynch syndrome families on March 17, 1994. Not to be outdone, the international consortium reported the same finding on March 18, 1994. They also found that MLH1 (rather than MSH2) was mutated in the HCT116 cell line.\u003c\/p\u003e\n\u003cp\u003eBy September 1994, the human PMS2 and PMS1 genes were also cloned and linked to Lynch syndrome. So, in an incredible period of about 16 months, Lynch syndrome was firmly put on the scientific map. It was linked to MSI, which led to the identification of the human DNA MMR genes. It was now possible to think about developing tests to diagnose the disease.\u003c\/p\u003e\n\u003cp\u003eOver the next several years, it was found that PMS1 was not actually a Lynch syndrome gene. MSH6 was brought into the fold as the fourth Lynch syndrome gene. This happened first by its involvement in cell lines with MSI, and finally via germline mutations in affected patients with different types of family histories of cancer. These patients often had later onset of cancer than seen in classic Lynch syndrome.\u003c\/p\u003e\n\n\u003ch2 id=\"diagnostics\"\u003eEvolution of Diagnostic Tests for Lynch Syndrome\u003c\/h2\u003e\n\u003cp\u003eThe ability to determine which patients and families actually had Lynch syndrome permitted a refinement of diagnostic approaches during the last decade of the 20th century.\u003c\/p\u003e\n\u003cp\u003eAntibodies were developed to the DNA MMR proteins MSH2, MSH6, MLH1, and PMS2. The diagnostic approach to MSI was standardized in an NCI-sponsored Workshop in Bethesda in November 1997. The Workshop manuscript reported a standardized diagnosis and panel of microsatellite markers. The published paper has been cited more than 2,000 times.\u003c\/p\u003e\n\u003cp\u003eThis manuscript also developed and reported the \"Bethesda Guidelines.\" These guidelines were intended to identify colorectal cancer tissues that should be targeted for analysis. The analysis would look for MSI or abnormal immunohistochemistry (IHC). IHC is a laboratory technique that uses antibodies to detect specific proteins in tissue samples. The Bethesda Guidelines were revised in 2004, much as the original Amsterdam Criteria had been revised in 1999.\u003c\/p\u003e\n\u003cp\u003eAll of these recommendations have been supplanted by our current understanding. Many true Lynch syndrome families do not meet either the Amsterdam Criteria (which were initially intended to identify families from whom the genes could be found). Many individuals with Lynch syndrome do not meet the Bethesda Guidelines. Conversely, many who meet these criteria or guidelines do not have germline mutations in any DNA MMR gene.\u003c\/p\u003e\n\u003cp\u003eThis problem ultimately led to a workshop in Jerusalem in 2010. At this workshop, experts recommended that any colorectal cancer in a person younger than 70 years old should be screened by MSI testing or IHC for possible Lynch syndrome.\u003c\/p\u003e\n\n\u003ch2 id=\"syndrome-x\"\u003eLynch Syndrome in the 21st Century: \"Syndrome X\"\u003c\/h2\u003e\n\u003cp\u003eThe identification of the genes responsible for Lynch syndrome gave those working in the field a euphoric sense that the problem had been substantially solved. However, as more details emerged, it became clear that only the surface had been scratched. There was much more to be learned about the disease.\u003c\/p\u003e\n\u003cp\u003eFirst, it had been suspected (perhaps naively) that once the genes causing Lynch syndrome were identified, doctors would be able to characterize all familial clusters of colorectal cancer. The Colon Cancer Family Registry (C-CFR), a large international consortium of groups, collected 3,422 individuals from 161 families that met the Amsterdam Criteria between 1997 and 2001.\u003c\/p\u003e\n\u003cp\u003eDNA from each family was subjected to the best available efforts to find germline mutations in DNA MMR genes. Only 60% of these families had a germline mutation (meaning they actually had Lynch syndrome). The other 40% had colorectal cancers that did not have MMR deficiency. Therefore, they did not have Lynch syndrome. A new disease was identified: Familial Colorectal Cancer-Type X.\u003c\/p\u003e\n\u003cp\u003eThese families had a lower penetrance for colorectal cancer (meaning fewer family members developed cancer). These families had later onset of the cancers. These families did not have an increase in the non-colonic tumor spectrum seen in Lynch syndrome.\u003c\/p\u003e\n\u003cp\u003eThere are many genetic diseases such as Peutz-Jeghers Syndrome, Juvenile Polyposis, Cowden's Disease, and Li-Fraumeni Syndrome that experience an increase in risk for colorectal cancer. However, \"Syndrome X\" does not appear to fall into any of those groups. It remains an important research challenge at this time.\u003c\/p\u003e\n\n\u003ch2 id=\"genetic-interpretation\"\u003eInterpreting Genetic Test Results\u003c\/h2\u003e\n\u003cp\u003eAs more data came in and genetic tests became widely available commercially, it became apparent that it was not always simple. It was not always simple to determine which DNA sequence variations in the DNA MMR genes cause Lynch syndrome. It was not always simple to determine which are innocent sequence polymorphisms (harmless variations).\u003c\/p\u003e\n\u003cp\u003ePremature stop codons were easy to interpret. These are mutations that cause the protein to be cut short. However, many of the sequence variations altered gene splicing sites. These are not too hard to interpret once the \"rules\" are learned. Other variations were missense mutations, which change the amino acid in that position in the encoded protein. It is not always possible to predict changes in protein folding and function based upon the change in the amino acid sequence alone.\u003c\/p\u003e\n\u003cp\u003eSo, many genetic tests returned with clinically uncertain or uninterpretable results. This created new challenges for the clinician and genetic counselors.\u003c\/p\u003e\n\u003cp\u003eOne of the first insights occurred when it became apparent that the MSH2 gene was often mutated by large deletions that were not detectable using standard sequencing techniques. Over one third of the mutations in this gene were responsible for inactivating mutations in a key Dutch study. These large deletions accounted for a substantial proportion (more than 6%) of all Lynch syndrome in their registry.\u003c\/p\u003e\n\u003cp\u003eOne approach to identify large genomic deletions was to separate the paternal and maternal alleles for individual analysis. This is a labor-intensive technique called \"conversion to haploidy,\" but it was not widely embraced. Eventually, techniques became available that permitted an estimation of the number of alleles present at each exon. This technique is called multiplex ligation-dependent probe amplification, or MLPA. MLPA permitted the detection of large genomic deletions and helped resolve this confusion.\u003c\/p\u003e\n\u003cp\u003eA second insight into perturbations in the MSH2 gene was the discovery that deletion of the stop codon of the EPCAM gene resulted in epigenetic silencing of MSH2. The EPCAM gene is immediately upstream of the MSH2 gene. Therefore, although no germline mutation was present in the MSH2 gene, the alteration in EPCAM created a \"heritable somatic inactivation\" of MSH2 in all tissues that expressed EPCAM.\u003c\/p\u003e\n\u003cp\u003eBy finding this mutation in a large kindred, it was found that this situation creates a colorectal cancer-predominant form of Lynch syndrome. This finding was reminiscent of Lynch Syndrome I, which had been predicted some 25 years earlier.\u003c\/p\u003e\n\n\u003ch2 id=\"chemotherapy\"\u003eAdjuvant Chemotherapy and Lynch Syndrome\u003c\/h2\u003e\n\u003cp\u003eShortly after the discovery of the MSH2 and MLH1 genes in 1993–1994, Dr. Minoru Koi created the first laboratory model to study the biology of DNA MMR-deficient cells in vitro. He did this by stably transferring a copy of human chromosome 3 into HCT116 colorectal cancer cells, correcting the loss of MLH1.\u003c\/p\u003e\n\u003cp\u003eSubsequent experiments led to the conclusion that DNA MMR-deficient cells were intrinsically resistant to DNA damage. This was similar to microbial cells with inactivating mutations in these genes. The implications were that certain chemotherapeutic drugs might not be fully effective against MSI cancers.\u003c\/p\u003e\n\u003cp\u003eAdditional experiments showed that MMR-deficient cells were resistant to 5-fluorouracil (5-FU). 5-FU is the mainstay of adjuvant chemotherapy for Stage III colorectal cancer. Adjuvant chemotherapy is treatment given after surgery to reduce the risk of cancer returning. Resistance was found for other chemotherapeutic drugs as well. Identical drug resistance was found in colorectal cancer cells with acquired methylation-induced silencing of MLH1.\u003c\/p\u003e\n\u003cp\u003eIt was therefore necessary to determine whether patients with MSI colorectal cancers were refractory (unresponsive) to conventional chemotherapy in a clinical study.\u003c\/p\u003e\n\u003cp\u003eThe first published report on the subject suggested that patients with MSI colorectal cancers had a \"striking survival benefit\" when given adjuvant chemotherapy. However, a serious design flaw had led to an erroneous conclusion. The study was retrospective (looking back at past records). The patients had not been randomized to receive chemotherapy. Instead, they had been selected by their oncologists to either receive treatment or not, presumably on the basis of their age and\/or performance status.\u003c\/p\u003e\n\u003cp\u003eIn fact, the entire group of patients selected for chemotherapy had a better 5-year survival whether they were treated or not. However, 64% of the colorectal cancer patients younger than 68 years old had been selected for treatment, versus only 19% of those 68 and older. None the less, this report created a problem in which the empirical observations were at odds with what had been predicted from the in vitro biology of the tumors.\u003c\/p\u003e\n\u003cp\u003eThis initial finding was not supported by 11 subsequent studies on the subject. The first contrary paper was a multicenter collaboration of patients enrolled in randomized trials. They found that patients with tumors showing MSI had substantially better overall 5-year survivals. This was particularly so if they did not receive adjuvant chemotherapy. Even worse, there were non-significant trends towards increased risk in some analyses.\u003c\/p\u003e\n\n\u003ch2 id=\"limitations\"\u003eLimitations and Open Questions\u003c\/h2\u003e\n\u003cp\u003eThe history of Lynch syndrome research has several important limitations and unresolved questions.\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003eDr. Warthin's early observation of \"anticipation\" (cancers appearing at younger ages in successive generations) has not been confirmed in later studies of Lynch syndrome.\u003c\/li\u003e\n  \u003cli\u003eThe original Amsterdam Criteria and Bethesda Guidelines are no longer sufficient to identify all families with Lynch syndrome. Many true Lynch syndrome families do not meet these criteria, and many who meet them do not have MMR gene mutations.\u003c\/li\u003e\n  \u003cli\u003eOnly 60% of families meeting the Amsterdam Criteria have a germline mutation in a DNA MMR gene. The remaining 40% have a different condition called Familial Colorectal Cancer-Type X, which is not well understood.\u003c\/li\u003e\n  \u003cli\u003eGenetic test results are not always straightforward. Many sequence variations are classified as clinically uncertain, creating challenges for doctors and genetic counselors.\u003c\/li\u003e\n  \u003cli\u003eThe first clinical study suggesting a survival benefit from chemotherapy in MSI colorectal cancers had a serious design flaw. Subsequent randomized studies did not support that finding.\u003c\/li\u003e\n  \u003cli\u003eFamilial Colorectal Cancer-Type X remains an important research challenge. It does not appear to fall into any known hereditary cancer syndrome group.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003ch2 id=\"recommendations\"\u003eWhat This Means for Patients\u003c\/h2\u003e\n\u003cp\u003eThe history of Lynch syndrome shows how one family's story led to major scientific discoveries that benefit patients today. Here is what patients should know:\u003c\/p\u003e\n\u003col\u003e\n  \u003cli\u003e\n\u003cstrong\u003eKnow your family history.\u003c\/strong\u003e If multiple family members across generations have had colorectal, endometrial, stomach, or other cancers, especially at young ages, tell your doctor. This information can help identify whether genetic testing is appropriate.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eScreening is available.\u003c\/strong\u003e Current recommendations state that any colorectal cancer in a person younger than 70 years old should be screened by MSI testing or IHC for possible Lynch syndrome. This testing can be done on tumor tissue.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eGenetic testing has limitations.\u003c\/strong\u003e Not all genetic variations are easy to interpret. Some results may be uncertain. Genetic counselors can help patients understand what their results mean.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eLynch syndrome is inherited in an autosomal dominant pattern.\u003c\/strong\u003e This means that a person with Lynch syndrome has a 50% chance of passing the condition to each child.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eChemotherapy response may differ.\u003c\/strong\u003e Research suggests that colorectal cancers with MSI may respond differently to certain chemotherapy drugs, particularly 5-FU. Patients should discuss their tumor's MSI status with their oncologist when making treatment decisions.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eResearch continues.\u003c\/strong\u003e Scientists are still working to understand Familial Colorectal Cancer-Type X and other conditions that increase colorectal cancer risk. Patients may be able to participate in research studies.\u003c\/li\u003e\n\u003c\/ol\u003e\n\n\u003c!-- ddn:faq:start --\u003e\n\u003ch2 id=\"ddn-faq\"\u003eFrequently Asked Questions\u003c\/h2\u003e\n\u003ch3\u003eWhat is Lynch syndrome?\u003c\/h3\u003e\n\u003cp\u003eLynch syndrome is one of the most common hereditary cancer conditions. It is caused by inherited mutations in genes that normally repair DNA. This raises the risk of several cancers, especially colorectal and endometrial (uterine) cancer. The condition is inherited in an autosomal dominant pattern, meaning a person with Lynch syndrome has a 50% chance of passing it to each child.\u003c\/p\u003e\n\u003ch3\u003eHow is Lynch syndrome diagnosed?\u003c\/h3\u003e\n\u003cp\u003eDiagnosis involves genetic testing for mutations in DNA mismatch repair genes. Tumor tissue may first be screened with microsatellite instability (MSI) testing or immunohistochemistry (IHC). Current recommendations state that any colorectal cancer in a person younger than 70 years old should be screened this way. Genetic test results can sometimes be uncertain, so genetic counselors help interpret them.\u003c\/p\u003e\n\u003ch3\u003eWhat are the Amsterdam Criteria and Bethesda Guidelines?\u003c\/h3\u003e\n\u003cp\u003eThe Amsterdam Criteria were developed to identify families likely to have Lynch syndrome for research. The Bethesda Guidelines were intended to identify colorectal cancer tissues that should be tested for MSI or abnormal IHC. However, many true Lynch syndrome families do not meet these criteria, and many who meet them do not have mismatch repair gene mutations. They have been supplanted by current understanding.\u003c\/p\u003e\n\u003ch3\u003eWhat is Familial Colorectal Cancer-Type X?\u003c\/h3\u003e\n\u003cp\u003eFamilial Colorectal Cancer-Type X is a condition identified in families who meet the Amsterdam Criteria but do not have a germline mutation in a DNA mismatch repair gene. In a large international study, only 60% of such families had a mutation; the other 40% had this condition. These families have a lower penetrance for colorectal cancer, later onset of cancers, and no increase in non-colonic tumors.\u003c\/p\u003e\n\u003ch3\u003eDoes chemotherapy work differently for Lynch syndrome?\u003c\/h3\u003e\n\u003cp\u003eResearch suggests that colorectal cancers with microsatellite instability (MSI) may respond differently to certain chemotherapy drugs, particularly 5-fluorouracil (5-FU). Laboratory studies found that DNA mismatch repair-deficient cells were resistant to 5-FU. An initial clinical study suggested a survival benefit, but it had a serious design flaw. Subsequent randomized studies did not support that finding. Patients should discuss their tumor's MSI status with their oncologist.\u003c\/p\u003e\n\u003ch3\u003eWhat should I do if I have a family history of cancer?\u003c\/h3\u003e\n\u003cp\u003eKnow your family history. If multiple family members across generations have had colorectal, endometrial, stomach, or other cancers, especially at young ages, tell your doctor. This information can help identify whether genetic testing is appropriate. Screening is available, and current recommendations state that any colorectal cancer in a person younger than 70 years old should be screened by MSI testing or IHC for possible Lynch syndrome.\u003c\/p\u003e\n\u003ch3\u003eWhat does it mean if my genetic test result is uncertain?\u003c\/h3\u003e\n\u003cp\u003eGenetic test results are not always straightforward. Many sequence variations in DNA mismatch repair genes are classified as clinically uncertain, creating challenges for doctors and genetic counselors. Some variations alter gene splicing sites, and others are missense mutations that change an amino acid. It is not always possible to predict changes in protein folding and function from the amino acid change alone. Genetic counselors can help patients understand what their results mean.\u003c\/p\u003e\n\u003ch3\u003eWhen should a patient with a newly diagnosed colorectal or endometrial cancer seek a second opinion about Lynch syndrome testing?\u003c\/h3\u003e\n\u003cp\u003eAny colorectal cancer diagnosed in a person younger than 70 should be screened by MSI testing or immunohistochemistry for possible Lynch syndrome, and a personal or family history of colorectal, endometrial, stomach, or other cancers at young ages across generations can make genetic testing appropriate. Because many sequence variations are classified as clinically uncertain, and many true Lynch syndrome families do not meet older criteria, an independent review of tumor testing and genetic results can help clarify whether the diagnosis fits. Diagnostic Detectives Network provides independent expert second opinions.\u003c\/p\u003e\n\u003c!-- ddn:faq:end --\u003e\n\n\u003ch2 id=\"source\"\u003eSource Information\u003c\/h2\u003e\n\u003cp\u003e\u003cstrong\u003eOriginal article title:\u003c\/strong\u003e History of Lynch Syndrome\u003c\/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors:\u003c\/strong\u003e C. Richard Boland, M.D., and Henry T. Lynch, M.D.\u003c\/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor affiliations:\u003c\/strong\u003e Dr. Boland is Chief of the GI Cancer Research Laboratory at Baylor University Medical Center, Dallas, Texas. Dr. Lynch is in the Department of Preventive Medicine at Creighton University, Omaha, Nebraska.\u003c\/p\u003e\n\u003cp\u003e\u003cstrong\u003ePublication details:\u003c\/strong\u003e Published in Familial Cancer, June 2013, Volume 12, Issue 2, pages 145–157. DOI: 10.1007\/s10689-013-9637-8. This article was made available through NIH Public Access and is available in its final edited form.\u003c\/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest:\u003c\/strong\u003e The authors reported no conflicts of interest.\u003c\/p\u003e\n\u003cp\u003e\u003cem\u003eThis patient-friendly article is based on peer-reviewed research.\u003c\/em\u003e\u003c\/p\u003e","brand":"DiagnosticDetectives.Com","offers":[{"title":"Default Title","offer_id":47576619548828,"sku":null,"price":0.0,"currency_code":"USD","in_stock":true}],"url":"https:\/\/diagnosticdetectives.com\/zh\/products\/understanding-lynch-syndrome-the-century-long-medical-detective-story","provider":"DiagnosticDetectives.Com","version":"1.0","type":"link"}