Strategies for Cancer Prevention in Lynch Syndrome
Strategies for Cancer Prevention in Lynch Syndrome
In 1913, Dr Aldred Scott Warthin, a pathologist at the University of Michigan, published the first known case report of a family characterized by a distinct susceptibility to the development of endometrial and gastric cancer. The pedigree of Warthin's "Family G" has been systematically studied and provided a template for the identification of additional families with similar phenotypes. In 1966, Dr Henry Lynch described 2 large Midwestern kindreds whose members were affected with colon, gastric, and endometrial cancers and proposed that these could be attributed to an autosomal dominant "cancer family syndrome." The term Lynch syndrome was coined in 1984 and subdivided as Lynch I and Lynch II to distinguish families with a preponderance of CRC from those with additional endometrial and other noncolonic tumors. The term hereditary nonpolyposis colorectal cancer (HNPCC) subsequently emerged to distinguish these cases from those related to the classic presentation of familial adenomatous polyposis (FAP), the more commonly recognized autosomal dominant CRC syndrome associated with hundreds to thousands of colorectal adenomatous polyps.
For nearly a century after Warthin's first description of Family G, the disease was defined by its clinical manifestations. However, in 1993 genome-wide linkage analysis in several large families with autosomal dominant inheritance of CRC led to the discovery of 2 loci on chromosomes 2p and 3p. It was observed that the tumors in these cases had histopathologic features that distinguished them from other nonfamilial cases. The presence of instability at DNA microsatellites provided evidence to implicate errors in MMR in these cancers, which was a novel pathway in CRC development at the time. The association between microsatellite instability (MSI) in colorectal tumors and defects in DNA MMR was made through observations originally described in bacterial and yeast genetics, and these discoveries led to the cloning of the 4 MMR genes most commonly associated with HNPCC, beginning with MLH1 and MSH2, followed by MSH6 and PMS2.
The term HNPCC has been criticized for its narrow focus on CRC risk and has fallen out of favor, and the eponymous Lynch syndrome, along with its expanded constellation of malignancies, has been reassigned to denote families affected with germline mutations in DNA MMR genes.
Historical Perspective
In 1913, Dr Aldred Scott Warthin, a pathologist at the University of Michigan, published the first known case report of a family characterized by a distinct susceptibility to the development of endometrial and gastric cancer. The pedigree of Warthin's "Family G" has been systematically studied and provided a template for the identification of additional families with similar phenotypes. In 1966, Dr Henry Lynch described 2 large Midwestern kindreds whose members were affected with colon, gastric, and endometrial cancers and proposed that these could be attributed to an autosomal dominant "cancer family syndrome." The term Lynch syndrome was coined in 1984 and subdivided as Lynch I and Lynch II to distinguish families with a preponderance of CRC from those with additional endometrial and other noncolonic tumors. The term hereditary nonpolyposis colorectal cancer (HNPCC) subsequently emerged to distinguish these cases from those related to the classic presentation of familial adenomatous polyposis (FAP), the more commonly recognized autosomal dominant CRC syndrome associated with hundreds to thousands of colorectal adenomatous polyps.
For nearly a century after Warthin's first description of Family G, the disease was defined by its clinical manifestations. However, in 1993 genome-wide linkage analysis in several large families with autosomal dominant inheritance of CRC led to the discovery of 2 loci on chromosomes 2p and 3p. It was observed that the tumors in these cases had histopathologic features that distinguished them from other nonfamilial cases. The presence of instability at DNA microsatellites provided evidence to implicate errors in MMR in these cancers, which was a novel pathway in CRC development at the time. The association between microsatellite instability (MSI) in colorectal tumors and defects in DNA MMR was made through observations originally described in bacterial and yeast genetics, and these discoveries led to the cloning of the 4 MMR genes most commonly associated with HNPCC, beginning with MLH1 and MSH2, followed by MSH6 and PMS2.
The term HNPCC has been criticized for its narrow focus on CRC risk and has fallen out of favor, and the eponymous Lynch syndrome, along with its expanded constellation of malignancies, has been reassigned to denote families affected with germline mutations in DNA MMR genes.
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