Historical Aspects of Lynch Syndrome

Abstract

In 1895, Aldred Warthin, M.D., a pathologist with a keen interest in patients, and a good listener, noted that his seamstress appeared to be depressed. He pursued this in detail, and she told him it was because she believed she would die of cancer at an early age, since everyone in her family seemed to succumb to cancer of the colon or female organs. Just as she predicted, she developed endometrial cancer and died of that disease. This brief background piqued Warthin's interest and he developed her pedigree and many others. In a remarkably similar scenario, Henry Lynch, M.D., in 1962, while a first year internal medicine resident, was called to see a patient who was recovering from the delirium tremens. In a statement similar to that of Warthin's seamstress, the patient stated that he drank because he knew he would die of cancer since everyone in the family died of colorectal cancer. Lynch, assuming that he was dealing with familial adenomatous polyposis, developed the pedigree only to find that the colon cancers were occurring in the absence of mul-tiple colonic adenomas. Other cancers, particularly the endometrium and ovary, occurred throughout the extended family, showing a pattern consonant with an auto-somal dominant mode of genetic transmission. The syndrome in the family, along with a strikingly similar family, were published in the Archives of Internal Medicine in 1966. Since that report, many hundreds of hereditary cancer-prone families with the same patterns of cancer occurrences, now known as Lynch syndrome, have been identified throughout the world, and it is now the undisputed most common hereditary form of colorectal cancer. History shows that these discoveries were products of collecting detailed family histories and innovative reasoning concerning their clinical significance. This manuscript will show the historical development of our understanding about the importance of a comprehensive cancer family history involving cancer of all anatomic sites, genetic counseling, and DNA testing when indicated. The fervent hope continues that these practices will significantly reduce cancer's morbidity and mortality in the Lynch syndrome. Keywords Cancer genetics • Genetic heterogeneity • Molecular biology • Lynch syndrome • Differential diagnosis • Family history • Management • Amsterdam criteria • Bethesda Guidelines • Microsatellite instability • Immunohistochemistry • HNPCC • Mismatch repair genes • MSH2 • MLH1 • MSH6 • PMS2 2.1 Introduction When one thinks of the clinical entity referred to as a " syndrome, " the first ques-tions that might come to mind are " How did it all start? " and " What criteria were used for a syndromy designation? " The syndrome pertinent to this chapter, namely the Lynch syndrome, had its beginnings in 1895 when Aldred Warthin, M.D., began his long tenure at the University of Michigan School of Medicine in Ann Arbor. At that time, his seamstress appeared depressed, and being an extremely inquisitive and caring physician, he asked her why she was depressed. She told him it was because she was convinced that she was going to die of cancer and that it would involve her gastrointestinal tract or her female organs, since " Everyone in the family dies of these cancers. " This piqued Warthin's interest and he began compiling her pedigree, along with many others from the tumor registry at the University of Michigan; he found it to be quite alarming, since the very cancers that the seam-stress had discussed with him were present through four generations. Also, just as she had predicted, she died at an early age of metastatic endometrial carcinoma. Warthin referred to the pedigree as Family G (Fig. 2.1) [1, 2]. In 1962, Lynch, then a 2nd-year resident in internal medicine, was called to see a patient who was recovering from delirium tremens and, in a statement remarkably similar to that of Warthin's seamstress, said that he knew he was going to die of colorectal cancer (CRC), which was highly prevalent in his family; he gave this as an excuse for his heavy drinking. Just as he had predicted, he died of cancer. At that time, the only known hereditary form of CRC was a syndrome known as familial adenomatous polyposis coli (FAP). When a working pedigree was initially devel-oped in this patient's family, it was initially inferred that this most likely represented a form of FAP, given the large number of CRCs present throughout the family. However, this presumptive diagnosis changed significantly once pathology reports were secured, which uniformly showed no evidence of multiple colonic adenomas in any of the CRC affecteds. Indeed, evaluation of the pedigree showed a segregat-ing pattern of not only CRC but, most remarkably, a plethora of extracolonic can-cers, particularly carcinoma of the endometrium and the ovary, consonant with an autosomal dominant inheritance pattern. Some of the family members showed syn-chronous and/or metachronous CRCs. Some showed a striking pattern of both endometrial and colorectal carcinoma, while others manifested synchronous or metachronous endometrial and ovarian carcinoma. Meanwhile, Warthin's research on Family G had been buried in the literature, which made this new family (called Family N, designating its Nebraska origin) of enough interest that an abstract of the work was accepted by the American Society of Human Genetics for an oral