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Biomedical subjects

H T Lynch

Publications and source records attributed to H T Lynch.

At least 163 records · Page 9Linked to original sources

Hereditary cancer in adults.

Primary genetic factors play a major etiologic role in approximately 5% to 10% of the total cancer burden. Since the bulk of hereditary forms of cancer lack premonitory physical stigmata of cancer risk, a well-orchestrated family history is mandatory for establishing a hereditary cancer syndrome diagnosis. Knowledge of the natural history of the particular hereditary form of cancer will aid the physician in the development and implementation of highly targeted surveillance strategies. Indeed, specific natural history features of cancer, particularly early age onset and multiple primary cancer excess, characterize the more than 200 mendelian inherited cancer syndromes. The veritable explosive developments in molecular biology now enable the identification of germline mutations so that, in certain hereditary cancers, a simple blood test will enable the physician to determine the cancer destiny of patients carrying the particular germline mutation.

Adenomatous Polyposis Coli↗

An evaluation of genetic heterogeneity in 145 breast-ovarian cancer families. Breast Cancer Linkage Consortium.

The breast-ovary cancer-family syndrome is a dominant predisposition to cancer of the breast and ovaries which has been mapped to chromosome region 17q12-q21. The majority, but not all, of breast-ovary cancer families show linkage to this susceptibility locus, designated BRCA1. We report here the results of a linkage analysis of 145 families with both breast and ovarian cancer. These families contain either a total of three or more cases of early-onset (before age 60 years) breast cancer or ovarian cancer. All families contained at least one case of ovarian cancer. Overall, an estimated 76% of the 145 families are linked to the BRCA1 locus. None of the 13 families with cases of male breast cancer appear to be linked, but it is estimated that 92% (95% confidence interval 76%-100%) of families with no male breast cancer and with two or more ovarian cancers are linked to BRCA1. These data suggest that the breast-ovarian cancer-family syndrome is genetically heterogeneous. However, the large majority of families with early-onset breast cancer and with two or more cases of ovarian cancer are likely to be due to BRCA1 mutations.

Adult↗

Clinical results using informatics to evaluate hereditary cancer risk.

A 12-year medical informatics project is described whose goal was to create a distributable computer-based service to support the identification of hereditary cancer patterns and recommend concomitant protocols of patient care surveillance. Key elements of the successful implementation strategy are described as the service has been successfully utilized at more than a dozen other cancer centers. Multi-year clinical results are presented from the implementation of this service.

Adult↗

Prophylactic oophorectomy in inherited breast/ovarian cancer families.

Prophylactic oophorectomy is chosen by some women at high risk of ovarian cancer due to inherited predisposition. Unfortunately, this surgery is not 100% effective in preventing intra-abdominal carcinomatosis that histologically resembles ovarian cancer. To determine the incidence of post-oophorectomy carcinomatosis and to quantify the effectiveness of preventive surgery, a multicenter study is ongoing between the National Cancer Institute (NCI), Creighton University, and the United Kingdom. The prospective incidence of malignancy, especially of tissues derived from coelomic epithelium (primarily ovary, fallopian tube, and peritoneum), was compared between women of similar genetic risk who have or have not undergone oophorectomy. Analysis of 12 NCI families has been completed. Prospective observation ran from the date of family ascertainment until the date of cancer incidence, death, or December 31, 1992. Approximately 1600 person-years of observation occurred among 346 first-degree relatives of a breast or ovarian cancer case patient for women who had not undergone oophorectomy. Eight ovarian cancers occurred, compared with two carcinomatosis cases during 460 person-years of observation among 44 oophorectomized women. Compared with Connecticut Tumor Registry data adjusted for age, race, and birth cohort, there was an approximately 24-fold excess of ovarian cancer among non-oophorectomized women and a 13-fold excess of "ovarian" cancer among oophorectomized women, though this difference was not statistically significant. The confidence intervals around these numbers were large, and a collaborative analysis will be required to determine whether this apparent protective effect is real.

Breast Neoplasms↗

hMSH2 mutations in hereditary nonpolyposis colorectal cancer kindreds.

It has recently been shown that hereditary nonpolyposis colorectal cancer (HNPCC) is caused by hereditable defects in DNA mismatch repair genes. However, the fraction of HNPCC due to defects in any one repair gene and the nature of these mutations are not known. We analyzed 29 HNPCC kindreds for mutations in the prototype DNA mismatch repair gene hMSH2 by a combination of linkage analysis, polymerase chain reaction-based screening, and sequencing of the coding region. The complete intron/exon structure of the gene was ascertained to facilitate this analysis. The results suggest that at least 40% of classic HNPCC kindreds are associated with germline mutations in hMSH2 and that most of these mutations produce drastic alterations in the predicted protein product.

Amino Acid Sequence↗

Psychological aspects of monitoring high risk women for breast cancer.

BACKGROUND: There is a paucity of knowledge pertaining to the attitudes, feelings, and emotions of women who are at increased familial risk for breast cancer and how these concerns will affect their surveillance behavior. A review of the literature shows an unevenness in the conclusions about these matters, with some reports indicating that anxiety aroused in the familial cancer setting may abet surveillance behavior, whereas other data indicates a negative effect. METHODS: The authors reported anecdotal accounts of such behavior in women from hereditary breast and hereditary breast-ovarian cancer prone families. RESULTS: Although these responses of fear, anxiety, and apprehension about cancer risk are not unique to this hereditary cohort, they nevertheless must have been tempered by often life-long exposure of cancer occurrences that may have decimated their families. CONCLUSIONS: All accounts agree with the need to devote more research to the special needs--psychological, social, insurance, and general public health measures--of these high risk women.

Adoption↗

Replication errors in benign and malignant tumors from hereditary nonpolyposis colorectal cancer patients.

A replication error (RER) phenotype has been documented both in sporadic colorectal tumors and in tumors from patients with hereditary nonpolyposis colorectal cancer (HNPCC). In the current study 8 of 49 (16%) sporadic colorectal cancers (CRCs) and 25 of 29 (86%) CRCs from HNPCC patients were found to be RER+. All 9 (100%) CRCs from HNPCC patients with germline mutations of the mismatch repair gene MSH2 were found to be RER+, while 16 of 20 CRCs from HNPCC kindreds unlinked or not studied for linkage to MSH2 were RER+. Corresponding analysis in colorectal adenomas revealed that only 1 of 33 (3%) sporadic tumors but 8 of 14 (57%) HNPCC tumors were RER+. Moreover, RER was found in all 6 extracolonic cancers (endometrium, 2; kidney, 1; stomach, 1; duodenum, 1; and ovary, 1) derived from members of HNPCC families. These data suggest the involvement of mismatch repair deficiency in the premalignant stage of tumorigenesis in HNPCC cases, and suggest that mismatch repair genes (MSH2 or others) are defective in the germline of nearly all these patients.

Adenoma↗

Phenotypic variation in hereditary breast cancer. Cancer control implications.

OBJECTIVE: To study hereditary breast cancer pedigrees as models for the elucidation of the natural history of the disease, including early onset; bilaterality; and tumor associations in the heterogeneous variants to aid in its diagnosis and in targeting surveillance and treatment strategies. SETTING: Oncology clinic and hereditary cancer institute. PATIENTS AND OTHER PARTICIPANTS: Physician- or self-referral probands. INTERVENTIONS: None. MAIN OUTCOME MEASURE: Greater understanding of the diagnosis, surveillance, and treatment of hereditary breast cancer. RESULTS: Eighteen pedigrees displayed the phenotypic variation of breast cancer's natural history, obligate gene carriers, and patterns of tumor combinations consonant with genetic heterogeneity. CONCLUSION: Hereditary breast cancer is an important public health problem accounting for about 9% of breast cancer cases. The recent identification of a molecular basis for the identification of a subset of hereditary breast cancer, and thereby the likelihood of the sequencing and cloning of the susceptibility gene(s), will enable targeting of surveillance and treatment measures toward patients at an inordinately high risk of developing cancer. Central to this entire process will be the identification of families with hereditary breast cancer.

Adrenal Cortex Neoplasms↗

Use of doxorubicin and dacarbazine for the management of unresectable intra-abdominal desmoid tumors in Gardner's syndrome.

PURPOSE: The aim of this study was to describe the natural history and management of surgically unresectable intra-abdominal desmoid tumors in two patients with Gardner's syndrome from two unrelated families, where each had failed on conventional therapy. METHODS: Two patients with Gardner's syndrome were placed on a chemotherapy regimen which included doxorubicin (90 mg/m2) and dacarbazine (900 mg/m2) in divided doses over four days of continuous infusion. Their progress on chemotherapy was assessed by abdominal computerized tomography and laparoscopy. RESULTS: The computerized abdominal tomography scans proved difficult to interpret because of adhesions and matted small bowel resulting from the patients original colectomies. These findings made it difficult to differentiate postoperative changes from residual desmoid tumor. Second-look laparotomy in such patients was contraindicated as this may predispose to further desmoid production. Laparoscopy disclosed a complete response to this chemotherapy. Nevertheless, we had an iatrogenic small bowel perforation in one of these patients. Each patient showed a complete response to chemotherapy. CONCLUSION: Surgical resection remains the first-line treatment of intraabdominal desmoid tumors. However, doxorubicin/dacarbazine chemotherapy on a clinical trial basis may be indicated in patients whose intra-abdominal desmoid is unresectable, or who have failed to respond to treatment with hormones (tamoxifen, Toremifene), steroids (prednisone), and nonsteroidal anti-inflammatory agents (Clinoril; Merck & Co., Inc., West Point, PA).

Adult↗

The risk of endometrial cancer in hereditary nonpolyposis colorectal cancer.

PURPOSE: Hereditary nonpolyposis colorectal cancer (HNPCC) is characterized by increased risk for cancer, especially colorectal cancer. It has been recommended that colon cancer control programs for family members be expanded to include endometrial cancer, the commonest extracolonic cancer observed in HNPCC families. We estimated the age-specific and cumulative endometrial cancer risk for women at high risk for HNPCC. PATIENTS AND METHODS: Family history data from three large HNPCC registries were combined for this study. High risk family members were identified without regard to extracolonic cancer. Life table methods were used to calculate estimates of risk. RESULTS: One thousand eighteen women from 86 families were included in the study. Cumulative incidence was 20% by age 70, compared to 3% in the general population. Risk was highest in women most likely to carry the HNPCC gene (P < 0.001). In this group, during the highest risk years (age 40 to 60), average annual risk exceeded 1%. There was no significant difference among the registries, despite different ascertainment practices regarding endometrial cancer. CONCLUSION: Interventions to reduce endometrial cancer morbidity and mortality are justified by the risk levels observed. Prophylactic total hysterectomy and bilateral salpingo-oophorectomy should be recommended to women in HNPCC families who have a syndrome cancer or offspring with a syndrome cancer. Endometrial cancer screening should be available to women at high risk. Studies of screening protocols are needed.

Colorectal Neoplasms, Hereditary Nonpolyposis↗

Deletion (5q) in a desmoid tumor of a patient with Gardner's syndrome.

Desmoid tumors are associated with as many as 20% of cases of familial adenomatous polyposis (FAP) and Gardner's syndrome. In the present study, four specimens from different regions of a massive intraabdominal desmoid tumor from a 23-year-old white male with Gardner's syndrome were analyzed cytogenetically. Two different clonal abnormalities were observed. Two of the four specimens analyzed showed a del(5)(q14q31), which involves the region q21-->22 where the familial adenomatous polyposis gene is localized. In the two other specimens, a balanced translocation involving chromosomes 3 and 4 and an inv(4) was detected. Our findings confirm previous reports about the importance of chromosome defects on 5q in development of desmoid tumors, particularly in patients with Gardner's syndrome.

Adult↗

Familial aggregation of carcinoma of the endometrium.

OBJECTIVE: Our purpose was to describe histologically verified endometrial carcinoma and other cancer types manifested through three generations in a pedigree, where these findings do not fit any classic hereditary cancer syndrome. STUDY DESIGN: Our family study protocol used detailed patient interviews whenever possible and questionnaires with permission forms that, when signed, enabled retrieval of pertinent medical-genetic and pathologic study documents. RESULTS: Endometrial carcinoma was histologically verified in five women through three consecutive generations. The triad of obesity, hypertension, and diabetes mellitus was not observed. Primary carcinomas of both the endometrium and ovary and endometrium and lymphoma were documented in two relatives in the direct genetic lineage of the pedigree. CONCLUSION: An aggregation of endometrial carcinoma in families, even when classic hereditary cancer syndrome identification is lacking, nevertheless merits surveillance and management strategies targeted to putative high-risk family members.

Endometrial Neoplasms↗

Surveillance in Lynch syndrome: how aggressive?

OBJECTIVE: To identify colorectal cancers occurring after colonoscopic screening in patients at risk for Lynch syndrome. METHODS: All cancers in Lynch syndrome families on file at the Creighton University Hereditary Cancer Institute were reviewed for history of prior colonoscopy. RESULTS: Of 225 individuals with 313 colon cancers, six patients from different families had colon cancers arising within 4 1/2 yr of colonoscopic surveillance. Another 17 patients had metachronous colon cancers within 5 yr of resection of their first colon cancer. CONCLUSION: Of 225 colorectal cancer patients from Lynch syndrome families, 10.2% of patients had colorectal cancer within 5 yr of colonoscopy or colon resection. In Lynch syndrome, the potential for interval neoplasms and the malignant potential of missed diminutive adenomas may differ from cases in the general population.

Adult↗

A common region of deletion on chromosome 17q in both sporadic and familial epithelial ovarian tumors distal to BRCA1.

Linkage analysis in familial breast and ovarian cancer and studies of allelic deletion in sporadic ovarian tumors have identified a region on chromosome 17q containing a candidate tumor-suppressor gene (referred to as BRCA1) of likely importance in ovarian carcinogenesis. We have examined normal and tumor DNA samples from 32 patients with sporadic and 8 patients with familial forms of the disease, for loss of heterozygosity (LOH) at 21 loci on chromosome 17 (7 on 17p and 14 on 17q). LOH on 17p was 55% (22/40) for informative 17p13.1 and 17p13.3 markers. When six polymorphic markers flanking the familial breast/ovarian cancer susceptibility locus on 17q12-q21 were used, LOH was 58% (23/40), with one tumor showing telomeric retention. Evaluation of a set of markers positioned telomeric to BRCA1 resulted in the highest degree of LOH, 73% (29/40), indicating that a candidate locus involved in ovarian cancer may reside distal to BRCA1. Five of the tumors demonstrating allelic loss for 17q markers were from individuals with a strong family history of breast and ovarian cancer. More important, two of these tumors (unique patient number [UPN] 57 and UPN 79) retained heterozygosity for all informative markers spanning the BRCA1 locus but showed LOH at loci distal to but not including the anonymous markers CMM86 (D17S74) and 42D6 (D17S588), respectively. Deletion mapping of seven cases (two familial and five sporadic) showing limited LOH on 17q revealed a common region of deletion, distal to GH and proximal to D17S4, that spans approximately 25 cM. These results suggest that a potential tumor-suppressor gene involved in both sporadic and familial ovarian cancer may reside on the distal portion of chromosome 17q and is distinct from the BRCA1 gene.

Base Sequence↗