The first study of a family that represented the Lynch syndrome or Hereditary Nonpolyposis Colorectal Cancer (HNPCC) began in Ann Arbor, Michigan in 1895 when Dr. Aldred Warthin, a renowned pathologist at the University of Michigan, noted that his seamstress was upset because she was convinced based on her family history that she would die early in life from cancer of the female organs or bowels. As predicted, the seamstress died at any early age from metastatic endometrial cancer.
Warthin published a description of this family which he called ‘Family G ’ in 1913, which was at the time characterised by a distinct susceptibility to cancer of the stomach and uterus, and he noted that “my observations are important in that they show in certain families an inherited predisposition to cancer”.
In 1962, Dr. Henry Lynch, a resident in internal medicine, had a patient who was recovering from delerium tremens, the patient’s explanation for his excessive drinking was that he knew like ‘everyone’ in his family that he was going to die of cancer, most likely colon cancer, shortly afterwards he was diagnosed with adrenal cortical carcinoma. Lynch & Krush compiled his family history and contacted the patient’s relatives many of whom were farmers living in Missouri, Kansas and Nebraska. Characteristics of this American mid-western kindred named Family N for ‘Nebraska’ included a high incidence of cancer particularly colon cancer diagnosed at an early age. A significant number had multiple primary cancers, including multiple colorectal cancers, and among women; colorectal cancer was also associated with endometrial and ovarian cancer. In 1964, an abstract about Family N was submitted and accepted for presentation at the American Society of Human Genetics. During the presentation, similarities among Family N with a family from Michigan (later named family M) was noted by a Geneticist at the University of Michigan, Marjorie W. Shaw who invited Lynch to collaborate with her in studying this family which were named ‘family cancer syndromes’.
Aldred Warthin’s successor Dr. A. James French, chairman of pathology at the University of Michigan School of Medicine invited Lynch to update the study of his predecessor of ‘Family G’ which was published in 1971. This reinvestigation revealed cancer involving specific anatomic sites particularly adenocarcinoma of the colon, endometrium and stomach. Of 650 blood relatives of Family G, 95 of whom had developed cancer with 13 with diagnosed with primary cancers. No significant tendency for cancer in male or female relatives were noted which supported autosomal as opposed to sex-linked inheritance.
Despite this impressive study, no mechanistic basis of the disease was even remotely apparent at that time; the possibility of an oncogenic virus interacting with a germline mutation was suspected. It was proposed that a cancer-causing virus, possibly prevalent in the general population, would prove particularly virulent to individuals with a cancer susceptibility genotype.
From the 1970s until the 1990s, periodic studies into the underlying cause of this disease were attempted with no success. In the 1980s, 2 more names emerged for this disease, Lynch syndrome was an attempt to improve upon ‘family cancer syndrome’ which seemed to suggest that every organ was non-specifically at risk for cancer, Dr. C. Richard Boland coined the term ‘Lynch Syndrome I’ to distinguish families that appeared to have only colorectal cancers from families who had uterine and other cancers as well which were called ‘ Lynch Syndrome II’.
In 1985, Dr. Henry Lynch in his description of a Navajo Indian family with an autosomal dominant pattern of cancer distribution with an early age of diagnoses and a notable tendency for right sided (proximal) colon cancers, coined the term Hereditary Nonpolyposis Colorectal Cancer (HNPCC) to differentiate this disease from Familial Adenomatous Polyposis (FAP) which has a distinctive clinical presentation, this highlights a reason why diagnosing Lynch Syndrome is difficult; there is no identifiable premorbid presentation (with the rare exception of Muir-Torre syndrome). Multiple colonic polyps in early adulthood or adolescence are the hallmark of FAP. The mean age of presentation with polyps is 16 years with almost 100% penetrance by age 40 with cancer developing in the vast majority of untreated mutation carriers.
In 1990, the International Collaborating Group on HNPCC met in Amsterdam and the ‘Amsterdam’ clinical criteria were developed to help coordinate research into this disease. By setting a threshold of three affected family members over at least two generations , one of whom was a first-degree relative of the other two, and requiring that one of these be diagnosed less than 50 years of age with FAP having been excluded, it was envisioned that only families with a unique genetic background would be included19. It was acknowledged that the Amsterdam criteria were very stringent and would exclude many cases of the disease if the family size was too small. The goal was to identify families which were suitable for genetic studies to find the causative gene(s).
In 1999, the ICG-HNPCC recognized the importance of non-colonic malignancies and revised the Amsterdam criteria to include tumours of the small intestine, ureter and renal pelvis to the spectrum associated with the syndrome (Amsterdam criteria II).
The cornerstone of both Amsterdam I & II clinical criteria is the occurrence of a Lynch syndrome tumour in two close relatives of the proband, therefore, the smaller the family size the more unlikely the family tree will fulfil these criteria. An adopted child without knowledge of his biological family is an extreme example, false paternity, outright denial and/or the lack of co-operation of family members are other reasons why documenting family histories will not be informative. As family size is generally decreasing, the family history based definitions for Lynch Syndrome will become less clear and less relevant.
Microsatellite Instability and Lynch Syndrome
Three separate series of experiments lead to the discovery that DNA mismatch repair (MMR) plays a role in the Lynch Syndrome.
In the first, three independent groups reported a novel type of genomic instability in a subset of colorectal tumours.
In 1993, Manuel Perucho utilised a molecular technique called arbitrarily primed polymerase chain reaction (AP-PCR) from colon cancers and matched normal tissue to look for genomic amplifications of deletions in tumour DNA. In a subset of approximately 12% of colorectal cancers, he recognized that some of the DNA sequences from the tumours had experienced small insertion or deletion mutations. The mutant sequences were cloned and it was found that the insertions and deletions occurred at micosatellite sequences. Microsatellites are stretches of DNA in which a short motif (usually one to five nucleotides long) is repeated several times.
Stephen Thibodeau independently discovered this novel form of genomic instability in 28% of colorectal cancers and observed that is was particularly present in the right side of the colon and he coined the term ‘microsatellite instability’ and noted that it appeared to be a good prognostic indicator.
At the same time, a large international collaboration that included Bert Vogelstein and Albert de la Chapelle were performing genome wide linkage analysis in order to identify the location of a Lynch syndrome gene in two large families with hereditary colorectal cancer and they too noted microsatellite instability but used the term ‘replicative phenotype’.
In the second critical observation, investigators working in the area of bacteria and yeast genetics recognised that the pattern of microsatellite instability observed in the colorectal tumours was similar to patterns observed in Escherichia coli and yeast with defects in DNA mismatch repair.
In the third and final observation, Vogelstein & de la Chapelle’s group discovered a significant linkage to a locus on chromosome 2p in two families with hereditary colorectal cancer.
By December 1993, this body of work led to the cloning of the hMSH2 gene on chromosome 2 and the identification of germline mutations in the same subset of Lynch Syndrome kindreds
By March 1994, hMLH1 had been cloned and additional Lynch syndrome families were linked to this gene.
By September of 1994, 2 more genes had been linked to Lynch syndrome, hPMS2 and hPMS1.
Michael P. Farrell RGN, CNS in Cancer Genetics, M. Sc. In Molecular Medicine
Date:26th August 2015