Search

Some cases of hereditary nonpolyposis colorectal cancer (HNPCC) are due to alterations in a mutS-related mismatch repair gene. A search of a large database of expressed sequence tags derived from random complementary DNA clones revealed three additional human mismatch repair genes, all related to the bacterial mutL gene. One of these genes (hMLH1) resides on chromosome 3p21, within 1 centimorgan of markers previously linked to cancer susceptibility in HNPCC kindreds. Mutations of hMLH1 that would disrupt the gene product were identified in such kindreds, demonstrating that this gene is responsible for the disease. These results suggest that defects in any of several mismatch repair genes can cause HNPCC.

Hereditary breast cancer (HBC) shows extant clinical and genetic heterogeneity. Clinically one finds the onset of breast cancer at an early age, an excess of bilaterality, and patterns of multiple primary cancer such as combinations of breast and ovarian carcinoma in the hereditary breast-ovarian cancer (HBOC) syndrome. In addition to HBOC, one sees a variety of putative breast cancer-prone genotypes inclusive of hereditary site-specific breast cancer, and the Li-Fraumeni (SBLA) syndrome that is characterized by cancers involving all three germinal layers including sarcomas, brain tumors, leukemia, lymphoma, and adrenal cortical carcinoma in addition to often markedly early-onset breast cancer. Breast cancer is also associated with autosomal dominantly inherited Cowden's disease and autosomal recessively inherited ataxia-telangiectasia. Examples of pedigrees depicting clinical examples of these several HBC syndromes are presented in order to describe HBC's heterogeneity. The recent identification of the BRCA1 gene in early-onset hereditary site-specific breast cancer and the HBOC syndrome has led to new challenges for the genetic counselor. We review genetic counseling, which embraces surveillance and management recommendations that are responsive to the natural history of HBC and address the concept for future development of centers of expertise for HBC in the interest of improving cancer control.

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.

Patients from hereditary breast cancer-prone (HBC) families provide one of the most powerful and potentially cost effective models for cancer prevention and control. Paradoxically, this opportunity is often missed in the clinical practice setting due, in part, to inattention to the family history and/or lack of knowledge about breast cancer genetics. We describe the family study process, wherein documentation of genealogy, medical, and cancer history through pathology verification is attained, often on extended families. The findings of such studies are illustrated by description of nine breast cancer-prone families. These families illustrate several important clinical/genetic features such as age of cancer onset, bilaterality and/or multiple primary cancer occurrences, incomplete gene penetrance, and the identification of putative obligate gene carriers. Interpretation of HBC pedigrees is dependent upon the understanding of these issues, which in turn may enable the physician to more readily identify those individuals who might benefit from highly targeted breast cancer control measures.

The most important consideration in the treatment of patients with the Lynch Syndromes is recognition. Specific treatment recommendations are based on the natural history of the syndrome. The newly diagnosed colon cancer patient from a Lynch Syndrome family should undergo a subtotal colectomy with low ileorectal anastomosis because of the frequency of synchronous and metachronous colon cancers. Routine sacrifice of the rectum is not justified because of the propensity for the cancers to involve the proximal colon. Lynch Syndrome II patients must have additional recommendations made to address the integrally inherited extracolonic cancer, i. e., total abdominal history and bilateral salpingo-oophorectomy (TAHBSO). For patients who are as yet unaffected by cancer, prophylactic surgery is not felt to be justified because only 50% of first degree relatives of Lynch Syndrome patients are at risk. Finally, for a patient who has been treated for colon cancer before being recognized as a member of a Lynch Syndrome family our current recommendation is aggressive screening. Subtotal colectomy is reserved for the poorly compliant patient.

The clinical features of Hereditary Nonpolyposis Colorectal Cancer (HNPCC) are well established, but less is known about the histology of the carcinomas that occur in the syndrome. We reviewed 86 colorectal cancers from 66 patients belonging to 15 HNPCC families and compared them to a series of 40 sporadic tumors.

During a colonoscopy screening program for patients at high risk for hereditary nonpolyposis colorectal cancer (HNPCC), we observed one family which was atypical in that members showed right-sided flat adenomas. The total colonic adenoma counts exceeded those found in HNPCC, but were fewer than that characteristically observed in familial adenomatous polyposis (FAP). There was a high rate of synchronous and metachronous adenomas. These observations highlight the heterogeneity in HNPCC and stress the need for careful delineation of all facets of the colonic phenotype in the interest of etiologic classification of hereditary colorectal cancer syndromes.

Few data exist regarding nutritional assessment during pancreatic abscess. We compared nonprotein caloric requirements calculated by Harris-Benedict equation and measured by indirect calorimetry in patients with pancreatic abscess. Seven patients with pancreatitis and pancreatic abscess had determinations of resting energy expenditure via Medicor metabolic cart with 20% added for activity. Caloric requirements were also estimated using the Harris-Benedict equation with stress factors. Determinations from indirect calorimetry ranged from 22.4-46.8 (mean 36.1) kcal/kg/d. Harris-Benedict calculations with stress factor 1.7 differed from indirect calorimetry by at least 15% in seven of ten determinations. Stress factor 1.9 results overestimated indirect calorimetry by over 25% in four of ten determinations. Energy requirements via indirect calorimetry of some patients with pancreatic abscess cover a wide range and do not correlate with Harris-Benedict calculations. Harris-Benedict equation with a stress factor of 1.9 may estimate adequate nonprotein calories for hyperalimentation, but there is risk of overfeeding.

Knowledge of cancer genetics, in concert with a thorough cancer family history, has the potential for providing one of the most powerful tools for the recognition of patients at high risk for cancer of specific anatomic sites. These facts have enabled the collection of a prodigious body of descriptive data dealing with the genetics of colorectal cancer. We shall discuss one facet of this problem; namely, the historical background and characteristics of the natural history, which has led to the recognition of hereditary nonpolyposis colorectal cancer (Lynch syndromes I and II). Since premonitory clinical signs of cancer risk are lacking in this disorder(s), it is clear that priority must now be given to the search for biomolecular markers of cancer risk.

ContextIdentifying families at high risk for the Lynch syndrome (ie, hereditary nonpolyposis colorectal cancer) is critical for both genetic counseling and cancer prevention. Current clinical guidelines are effective but limited by applicability and cost.ObjectiveTo develop and validate a genetic counseling and risk prediction tool that estimates the probability of carrying a deleterious mutation in mismatch repair genes MLH1, MSH2, or MSH6 and the probability of developing colorectal or endometrial cancer.Design, Setting, and PatientsExternal validation of the MMRpro model was conducted on 279 individuals from 226 clinic-based families in the United States, Canada, and Australia (referred between 1993-2005) by comparing model predictions with results of highly sensitive germline mutation detection techniques. MMRpro models the autosomal dominant inheritance of mismatch repair mutations, with parameters based on meta-analyses of the penetrance and prevalence of mutations and of the predictive values of tumor characteristics. The model's prediction is tailored to each individual's detailed family history information on colorectal and endometrial cancer and to tumor characteristics including microsatellite instability.Main Outcome MeasureAbility of MMRpro to correctly predict mutation carrier status, as measured by operating characteristics, calibration, and overall accuracy.ResultsIn the independent validation, MMRpro provided a concordance index of 0.83 (95% confidence interval, 0.78-0.88) and a ratio of observed to predicted cases of 0.94 (95% confidence interval, 0.84-1.05). This results in higher accuracy than existing alternatives and current clinical guidelines.ConclusionsMMRpro is a broadly applicable, accurate prediction model that can contribute to current screening and genetic counseling practices in a high-risk population. It is more sensitive and more specific than existing clinical guidelines for identifying individuals who may benefit from MMR germline testing. It is applicable to individuals for whom tumor samples are not available and to individuals in whom germline testing finds no mutation.

Gene-environment interactions in hereditary nonpolyposis colorectal cancer: potentiation of colon cancer risk by tobacco use and HMLH-1 mutations

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.

Background: Linkage to chromosome 17q has been identified in hereditary breast cancer and hereditary breast/ovarian cancer syndrome. A hereditary breast/ovarian cancer syndrome kindred was identified that yielded a highly significant lod score (4.20) when 17q markers were studied, enabling us to identify those who probably carried the cancerassociated gene among the high-risk members of the family. Methods: High-risk members of the hereditary breast/ ovarian cancer syndrome kindred were offered counseling on the basis of 17q markers. Family members responding positively received one-to-one genetic counseling in a structured setting. Subjects were educated before disclosure, and the immediate impact of this information was assessed after disclosure. Results: We provided genetic counseling on the basis of linkage findings to 32 relatives (four men and 28 women). Women who were told they were linkage positive expressed an increased motivation for surveillance and prophylactic surgery. Most women who were told they were linkage negative indicated that they would not proceed with prophylactic surgery but would continue careful surveillance. To date, there has been no evidence of serious emotional disturbances resulting from this disclosure. We believe that this experience can be used by cancer geneticists and physicians in developing protocols for genetic counseling in cancer-associated hereditary disorders. Conclusions: Physicians must understand current developments in cancer genetics and linkage so that they can be applied to genetic counseling and treatment of high-risk patients. (Arch Intern Med. 1993;153:1979-1987)

Familial breast cancer has been linked to the D17S74 locus on chromosome 17q. To confirm this finding and to investigate whether ovarian cancer is also linked to this locus, five large families with a hereditary predisposition to cancer of the breast and ovary were investigated. Three families were positive for linkage. For the largest family the lod score was 2.72. These findings suggest that the chromosomal region 17q12-q23, previously shown to contain a gene for early-onset breast cancer, is also associated with a proportion of hereditary ovarian cancers.

SUMMARY HNPCC is an autosomal dominantly inherited disorder with proclivity to early onset colorectal cancer in the absence of multiple polyps of the colon. There is a predilection for proximal colonic location (70 per cent) and an excess of synchronous and metachronous colorectal cancers. HNPCC is subdivided into Lynch syndrome I, which is restricted to site-specific colon cancer susceptibility, and Lynch syndrome II, which shows all of the features of Lynch syndrome I, but in addition, patients are at inordinately increased risk for carcinoma of the endometrium, ovary, and other anatomic sites. The frequency of HNPCC is conservatively estimated to be 4 to 6 per cent of the total colorectal cancer burden. Because of the fact that the family history is underreported almost uniformly in medical practice, we believe that the true frequency of this disease may be much greater. Heterogeneity may be extant with respect to tumor association, in that in certain Lynch syndrome II kindreds, carcinoma of the pancreas, kidney, breast, and other anatomic sites may predominate. Knowledge of the natural history of HNPCC predicates surveillance and management strategies. Thus, because of the early onset of and proximal predilection for colorectal cancer, we recommend initiation of colonoscopy at age 25 and annually thereafter. We also recommend guaiac testing of the stool at least twice a year. In the case of Lynch syndrome II, in addition to colonoscopy, we recommend intensive surveillance for the endometrium, including aspiration biopsies. Other targeted organs, depending on the tumor spectrum in the family, should be given priority attention. Because of an excess of synchronous and metachronous colorectal cancer in HNPCC, subtotal colectomy with ileorectal anastomosis is the treatment of choice for initial colorectal cancer. In women presenting with initial colorectal cancer who have completed their families, consideration should be given to prophylactic hysterectomy and bilateral salpingo-oophorectomy at the time of surgery for colorectal cancer. Needed are biomarkers of acceptable sensitivity and specificity for the genotype, because HNPCC lacks premonitory physical signs. We believe that increased knowledge about colorectal cancer etiology and carcinogenesis can be attained through the study of families prone to the Lynch syndromes.

A device is described which automatically measures barpresses reinforced by short opportunities to attack male mice. Data on barpress rates indicate rapid and reliable acquisition of preferences for reinforcer bars and rapid abolition of this preference when the reinforcement contingency is subsequently eliminated. The data are less reliable for reversal learning.

The family history of colon cancer was investigated in 38,823 individuals (2,129 families) who comprised a control and an oncology patient series from Tel-Aviv and nearby areas. A significant increased risk for colon cancer was observed among first-degree relatives of colon cancer patients when compared to controls. When the patient sample was divided into two groups based on country and continent of birth--European (Ashkenazim) and other (nonAshkenazim)--the relatives of the nonAshkenazi subjects showed a greater relative risk for colon cancer (P less than 0.05). Colon cancer was found to be less frequent in nonAshkenazim than in Ashkenazim controls. These findings suggest that although the colon cancer frequency in the nonAshkenazi group is lower, the genetic component may be more important than for the Ashkenazi sample. The nonAshkenazi Jews may represent distinct subgroups that differ with respect to either primary genetic susceptibility to colorectal cancer and/or they may have been subjected to peculiar, environmental carcinogenic exposures when compared to their Ashkenazim brethren.

Hereditary nonpolyposis colorectal cancer (HNPCC) accounts for about 4% to 6% of the total colorectal cancer burden. It is subdivided into Lynch syndrome I and II. Lynch syndrome I is characterized by an autosomal dominant inheritance pattern for site-specific, early onset, adenocarcinoma of the colon, with proximal predominance and an excess of synchronous and metachronous colonic cancers. Lynch syndrome II (cancer family syndrome) shows these same colon cancer characteristics, but differs in that there is an excess proclivity of other forms of cancer, particularly of the endometrium and ovary. This article documents a family that shows features of Lynch syndrome II. Unique aspects pertain to a patient who is in the direct genetic lineage (whose five brothers manifested colonic cancer), but who developed carcinoma of the uterine cervix at age 34 and laryngeal cancer at 60. The pedigree also shows uterine cervical carcinoma among other patients at genetic risk. Her son, who is a nonsmoker and nondrinker, manifested laryngeal cancer at age 31. These observations appear to add new information about tumor heterogeneity in HNPCC.

We have studied a remarkable family with seven cases of malignant lymphoma extending through three generations wherein five sisters and their mother had histopathologically documented non-Hodgkin's lymphoma, while a granddaughter had Hodgkin's disease. An immunological study of three lymphoma survivors, nine of their first degree relatives, and four spouse controls was undertaken. Significant findings consisted of a depressed serum IgG3 level in four of the nine first-degree relatives; in two of these four, lymphocyte stimulation by both pokeweed mitogen and concanavalin A were significantly depressed. The subtle immunological abnormalities present in this kindred may be associated with the pathogenesis of the lymphomas.

HBC is common, accounting for approximately 9% of the total breast cancer burden. Given 142,000 cases of breast cancer expected to occur in 1989, this would represent 12,780 cases of HBC patients. Soberingly, each patient represents a family with a variable number of inordinately high risk patients. HBC's natural history is distinctive and enables the identification of at risk patients who can benefit from highly targeted surveillance/management strategies. High priority must be given to development of biomarkers that will one day be found to have acceptable sensitivity and specificity to genotype status. Thus, we would then be able to tell which of the first-degree relatives of affected members have inherited the deleterious gene. This would result in a significant saving of time and money that would otherwise be expended through intensive surveillance strategies. We need cost-benefit research to induce third party carriers to defray expenses for surveillance. Finally, priority attention must be given to biomolecular research for identification of markers of acceptable sensitivity and specificity to the cancer-prone genotype. Eventual cloning of the deleterious gene(s) could lead to knowledge about its chemical and physiologic products, thereby enabling anticancer pharmacologic research. The reward could then be improved control and even prevention of breast cancer, and possibly of the associated cancers in heterogenous forms of this disease.

Since full breast cancer screening is not generally recommended for young women, it is important to identify individuals who are at higher risk for early onset breast cancer. We investigated the relationship between age of onset of breast cancer in 328 probands (consecutively ascertained patients from our oncology clinic) and breast cancer incidence and age of onset in their female relatives. We found that a family history of early onset breast cancer was associated with higher risk of early onset breast cancer. A family history of early onset breast cancer occurred more frequently among young (less than 40) breast cancer probands than among older (greater than or equal to 40) breast cancer probands (p less than 0.001; OR = 23). This relationship was particularly evident when the analysis was restricted to the hereditary breast cancer probands (p less than 0.001; OR = 44). We also observed a positive family history of breast cancer (any age) more frequently in young breast cancer probands than in older breast cancer probands (p less than 0.001; OR = 2.8). These observations have important pragmatic implications for surveillance. We recommend intense surveillance for breast cancer, initiated earlier, for women with close relatives diagnosed with early onset breast cancer.

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.

Primary genetic factors are etiologic in at least 5-10% of patients with colon cancer. The polyposis syndromes (FPC) are easily identified examples because of the spectacular number of polyps. The hereditary nonpolyposis syndromes (HNPCC), although five times more common than FPC, are usually not recognized because they do not have such a distinctive clinical, premonitory genetic marker. Colorectal cancer expression was surveyed in 10 extended, thoroughly documented HNPCC kindreds. One hundred sixteen patients were found to have 183 colorectal cancers. Despite the striking family history, less than 5% were correctly treated by subtotal colectomy. This provided a unique opportunity to study the natural history. Five findings differed significantly (p less than 0.05) from patients with sporadic colon cancer: (1) mean age of initial colon cancer diagnosed was 45.6 years; (2) 69.1% of first colon cancers were located proximal to the splenic flexure of the colon; (3) 18.1% had synchronous colon cancer; (4) 24.2% had metachronous colon cancer develop with life table analysis showing the risk for a metachronous lesion at 10 years to be 40%; and (5) only 23.3% of cancers were located in the sigmoid colon or rectum. Based on this data, it is recommended that the family history of all patients with a newly diagnosed colon cancer be evaluated for evidence of this syndrome. If an autosomal dominant inheritance pattern emerges, an in-depth genetic investigation is indicated. When HNPCC is confirmed, the following recommendations apply: a subtotal abdominal colectomy is indicated at the time of the initial colon cancer because of the risk of synchronous and metachronous lesions. The rectum should be spared in favor of careful lifetime surveillance because of the proclivity for proximal colon cancer involvement. As yet unaffected members of a newly diagnosed HNPCC kindred who are in the "direct genetic line" should be cautioned that they are at 50% risk and must begin an intensive surveillance program beginning in the third decade with careful attention to the right colon. Patients from newly diagnosed HNPCC families who have had a previous conventional colectomy for colon cancer should, at the very least, enter an intensive surveillance program; a prophylactic completion subtotal colectomy should be considered for patients who are less than totally compliant.

Approximately 5 to 6 percent of the total colorectal cancer burden is accounted for by hereditary nonpolyposis colorectal cancer (HNPCC). Because clinical premonitory signs such as those seen in familial polyposis coli (FPC) are lacking, the clinician must recognize clinical findings and family history typical of HNPCC. The authors have described colorectal cancer expression from a survey of ten HNPCC kindreds. Kindred members with colorectal cancer differed significantly (P less than .05) from patients with sporadic colorectal cancer: 1) mean age of initial colon cancer diagnosis was 44.6 years; 2) 72.3 percent of first colon cancers were located in the right colon, and only 25 percent were in the sigmoid colon and rectum; 3) 18.1 percent had synchronous colon cancers; and 4) 24.2 percent developed metachronous colon cancer, with a risk for metachronous lesions in ten years of 40 percent. Affecteds and their first-degree relatives should undergo early intensive education and surveillance. In families with an early age of onset, colonoscopy should begin at age 25, and biannually thereafter, with fecal occult blood testing of the stool semiannually. Third-party carriers must become more responsive to the costly surveillance measures required for these otherwise healthy patients.

Increasing recognition of the statistical burden posed by HNPCC (5 to 6 percent of all colorectal cancer) mandates that physicians have a better understanding of the genetics, natural history, and distinction between the hereditary site-specific variant (Lynch syndrome I) and the Cancer Family Syndrome (Lynch syndrome II). The authors report detailed cancer (all sites) family histories on two prototype families with Lynch syndrome I (Family R) and Lynch syndrome II (Family N), which have been under investigation for more than two decades. Emphasis is placed on shared clinicogenetic features; namely, early age of onset of colonic cancer (approximately age 44), multiple primary colonic cancer (24 percent of cases showed metachronous colonic cancer), predominance of proximal colonic cancer location (approximately 65 percent in the proximal colon), and vertical transmission consonant with an autosomal dominantly inherited factor. An increased predilection for extracolonic cancer, particularly endometrial carcinoma, occurs in Lynch syndrome II and is the primary basis for distinction from Lynch syndrome I. Surveillance and management programs must be wholly responsive to these natural history features.

Knowledge of the family history of cancer may significantly influence diagnosis and surgical management. Hereditary breast cancer (HBC) is common and accounts for approximately 9% of the total breast cancer burden. The pattern of HBC's natural history, including age of onset, increased incidence of bilaterality, integral tumor combinations in certain kindreds, and vertical transmission consonant with an autosomal dominantly inherited factor, when observed in context with the family history, enables pattern recognition so that the diagnosis might be facilitated. We describe seven families from our Hereditary Cancer Consultation Center (HCCC) and the Creighton Oncology Clinic which are noteworthy for extraordinarily early age of onset. This appears to be an additional example of heterogeneity in HBC and may represent the first account of this remarkable subset. The manner in which age of onset can be incorporated with other aspects of natural history for expediting diagnosis is discussed.

Udgivelsesdato: Apr 8

To the Editor.— The article by Eddy et al 1 provides evidence that healthy asymptomatic women between the ages of 40 and 49 years do not show sufficient health or economic benefit from mammography to offset the costs and risks. They contend that the costs for screening this cohort are high and that relatively few lives would be saved. Their data indicate that mammography screening in that decade would carry a risk of radiation-induced cancer of the breast of about 1 in 25 000. They conclude that a more prudent approach is to initiate mammography at age 50 years. The matter of hereditary breast cancer (HBC) was totally ignored in these reports. This is surprising since HBC accounts for approximately 9% of the total breast cancer burden 2 and its average age of onset is approximately 44 years. 3,4 Indeed, we recently described a subset of HBC that is characterized