Jane F. Lynch

Familial and Genetic Factors — New Evidence

Breast cancer is a major health problem and cause of anxiety in the United States [1] and in discussing familial breast cancer (FBC) and hereditary breast cancer (HBC), it is important that these terms be clearly defined. FBC and HBC are commonly used interchangeably by authors to describe clustering of breast cancer among the relatives of a breast cancer patient. However, it is essential to distinguish between the terms ‘familial’ and ‘hereditary’ when describing families where two or more relatives manifest breast cancer.

Monitoring High Risk Women: Psychological Aspects

Hereditary breast cancer (HBC) is receiving increasing attention in the medical and lay press, and concerned patients frequently ask their physicians to explain its genetic risk, surveillance and management implications. For this purpose, the physician must be prepared not only to provide accurate scientific facts about HBC, but also to offer counselling which takes into account the emotional burden that knowledge of genetic cancer risk might entail.

Compliance by High-Risk Women

Inherited susceptibility to breast cancer includes several distinct syndromes [1–3], each involving heritable genetic mutations [4–6]. Compliance by families in the control of hereditary breast cancer (HBC) is increased if its members are educated about the genetics and natural history of the disease. We initiate education in the mid-to-late teens but breast self-examination and semi-annual physician breast examination should begin at age 20. We begin mammography at age 25 and perform this annually.

Hereditary colon cancer syndromes: polyposis and nonpolyposis (Lynch syndromes I & II) variants

Colorectal cancer is second in incidence only to lung cancer in many of the western industrialized nations [1]. Its incidence has shown a steady increase since the turn of the century, a trend which has been attributed by some to changes in dietary patterns [2]. While environmental factors are of unquestionable significance in the etiology of colorectal cancer, the role of genetic factors, as in all forms of human diseases, must be considered. Unfortunately, in the case of colorectal cancer, with the exception of familial multiple adenomatous polyposis coli (FPC), the importance of genetics has been severely neglected. Recently, this entire subject has been extensively reviewed [3–5].

Historical Aspects of Lynch Syndrome

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 multiple colonic adenomas. Other cancers, particularly the endometrium and ovary, occurred throughout the extended family, showing a pattern consonant with an autosomal 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.

Lynch Syndromes I and II - Natural History, Diagnosis and Control Strategies

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominantly inherited disorder which often shows a distinctive natural history but which lacks any well-defined phenotypic stigmata or biomarkers of cancer susceptibility. This is in striking contrast to its familial adenomatous polyposis (FAP) counterpart, with its distinguishing phenotype of multiple colonic polyps. In addition, the recent identification and characterisation of the APC gene in this region, and demonstration that FAP is caused by mutations in this gene, will enable studies that will define this disease at the biochemical level [1–4]. This discovery adds an entirely new dimension to FAP and may harbour important pathogenetic implications to cancer in general. In comparison to FAP, an HNPCC diagnosis is wholly dependent upon the recognition of certain salient features of its natural history in concert with a detailed pedigree based upon a family history of cancer of all anatomic sites.

Hereditary ovarian cancer: Heterogeneity in age at diagnosis

An unknown fraction of the ovarian cancer burden occurs in women with a family history indicative of a putative autosomal dominantly inherited cancer susceptibility syndrome. The results from a five-generation, extended, hereditary breast-ovarian cancer kindred are described 10 years after it was initially ascertained. Significantly more cancers were observed in high-risk family members during this decade than were expected (P less than 0.001). The age of ovarian cancer diagnosis was studied in additional ovarian cancer-prone families of three types: site-specific ovarian cancer syndrome, the breast-ovarian cancer syndrome, and Lynch syndrome II. The age of onset in each of the three sets was significantly (P less than 0.001) earlier than the general population mean of 59, and there were significant differences in the age of onset (P = 0.050) among these three cohorts. Ovarian cancer histology was similar to that of patients with negative family histories. There may be clinically significant heterogeneity in the age at diagnosis of ovarian cancer among these ovarian cancer-prone syndromes. This has important implications for understanding its natural history and targeting surveillance-management strategies.