Haploinsufficiency in tumor predisposition syndromes: altered genomic transcription in morphologically normal cells heterozygous for VHL or TSC mutation.

Tumor suppressor genes and their effector pathways have been identified for many dominantly heritable cancers, enabling efforts to intervene early in the course of disease. Our approach on the subject of early intervention was to investigate gene expression patterns of morphologically normal "one-hit" cells before they become hemizygous or homozygous for the inherited mutant gene which is usually required for tumor formation. Here, we studied histologically non-transformed renal epithelial cells from patients with inherited disorders that predispose to renal tumors, including von Hippel-Lindau (VHL) disease and Tuberous Sclerosis (TSC). As controls, we studied histologically normal cells from non-cancerous renal epithelium of patients with sporadic clear cell renal cell carcinoma (ccRCC). Gene expression analyses of VHLmut/wt or TSC1/2mut/wt versus wild-type (WT) cells revealed transcriptomic alterations previously implicated in the transition to precancerous renal lesions. For example, the gene expression changes in VHLmut/wt cells were consistent with activation of the hypoxia response, associated, in part, with the "Warburg effect". Knockdown of any remaining VHL mRNA using shRNA induced secondary expression changes, such as activation of NFκB and interferon pathways, that are fundamentally important in the development of RCC. We posit that this is a general pattern of hereditary cancer predisposition, wherein haploinsufficiency for VHL or TSC1/2, or potentially other tumor susceptibility genes, is sufficient to promote development of early lesions, while cancer results from inactivation of the remaining normal allele. The gene expression changes identified here are related to the metabolic basis of renal cancer and may constitute suitable targets for early intervention.

Differences in neuropsychological and behavioral parameters and brain structure in patients with familial adenomatous polyposis: a sibling-paired study.

BACKGROUND: Familial adenomatous polyposis (FAP) is an autosomal dominant hereditary colon cancer syndrome caused by mutations in adenomatous polyposis coli (APC) with both colonic and extra-colonic manifestations. Case reports have noted an association with FAP and intellectual disability and animal studies have shown that APC is implicated in neural development and function, but no studies have investigated neuropsychological, behavioral, or structural brain characteristics of patients with FAP. METHODS: We undertook a pilot, sibling-pair study comparing three patients with FAP to their sex-matched siblings without FAP. Each sibling pair underwent neuropsychological testing by a blinded examiner, high resolution brain MRI scans, and the mother of each pair rated her children's adaptive life skills and behavioral and emotional characteristics. Given the small number of study participants in this pilot study, quantitative comparisons of results were made by subtracting the score of the non-FAP sibling from the FAP patient on the various neuropsychological tests and parent rating questionnaires to calculate a difference, which was then divided by the standard deviation for each individual test to determine the difference, corrected for the standard deviation. Diffusion numbers in multiple regions of the brain as assessed by MRI were calculated for each study participant. RESULTS: We found similarity between siblings in all three pairs on a wide range of neuropsychological measures (general intelligence, executive function, and basic academic skills) as tested by the psychologist as well as in descriptions of adaptive life skills as rated by mothers. However, mothers' ratings of behavioral and emotional characteristics of two of the three pairs showed differences between the siblings, specifically that the patients with FAP were found to have more behavioral and emotional problems compared to their siblings. No differences in brain structure were identified by MRI. CONCLUSION: We report the first study exploring neuropsychological, behavioral, emotional, and structural brain characteristics of patients with FAP and found subjective differences as assessed by maternal perception in behavioral and emotional characteristics in patients with FAP compared to their siblings. Larger studies are needed to elucidate the relationship, if any, between FAP and brain function.

Selective Versus Universal Screening for Lynch Syndrome: A Six-Year Clinical Experience.

BACKGROUND: Lynch syndrome is the most common cause of hereditary colorectal cancer (CRC) and confers increased risk of other cancers. Identification of patients improves morbidity and mortality. Screening tumors for absent mismatch repair (MMR) protein expression by immunohistochemistry (IHC) is a recommended approach. Despite guidelines advocating universal screening, significant variation in clinical practice exists. AIMS/METHODS: A retrospective study of two different IHC-based Lynch syndrome screening protocols at an urban, university hospital was performed. Outcomes from a "selective" screening strategy utilized from August 2007-July 2010 on CRC tumors from patients with high-risk features were compared with a "universal" strategy of screening all CRC tumors from July 2010-August 2013. Positively screened patients were referred for genetic counseling and offered germline testing. RESULTS: A total of 392 patients with CRC were screened: 107 selectively and 285 universally. The prevalence of Lynch syndrome was 3.1 %, with no difference by strategy. There was a trend (p = 0.06) toward fewer universally screened patients agreeing to genetic counseling compared with those selectively screened. Selective criteria failed to identify one of eight cases of Lynch syndrome from the universal group, though the universal strategy screened 166 additional tumors to find this additional patient. CONCLUSIONS: Selective screening for Lynch syndrome has similar outcomes as universal screening in terms of identifying Lynch syndrome, despite screening far fewer patients. In addition, fewer eligible patients in our study agreed to undergo genetic counseling and germline testing than in prior studies. These lower rates may better reflect uptake of these services in clinical practice.

Prospective multicenter randomized intermediate biomarker study of oral contraceptive versus depo-provera for prevention of endometrial cancer in women with Lynch syndrome.

Women with Lynch syndrome have a 40% to 60% lifetime risk for developing endometrial cancer, a cancer associated with estrogen imbalance. The molecular basis for endometrial-specific tumorigenesis is unclear. Progestins inhibit estrogen-driven proliferation, and epidemiologic studies have shown that progestin-containing oral contraceptives (OCP) reduce the risk of endometrial cancer by 50% in women at general population risk. It is unknown whether they are effective in women with Lynch syndrome. Asymptomatic women ages 25 to 50 with Lynch syndrome were randomized to receive the progestin compounds Depo-Provera (depo-MPA) or OCP for three months. An endometrial biopsy and transvaginal ultrasound were conducted before and after treatment. Endometrial proliferation was evaluated as the primary endpoint. Histology and a panel of surrogate endpoint biomarkers were evaluated for each endometrial biopsy as secondary endpoints. A total of 51 women were enrolled, and 46 completed treatment. Two of the 51 women had complex hyperplasia with atypia at the baseline endometrial biopsy and were excluded from the study. Overall, both depo-MPA and OCP induced a dramatic decrease in endometrial epithelial proliferation and microscopic changes in the endometrium characteristic of progestin action. Transvaginal ultrasound measurement of endometrial stripe was not a useful measure of endometrial response or baseline hyperplasia. These results show that women with Lynch syndrome do show an endometrial response to short-term exogenous progestins, suggesting that OCP and depo-MPA may be reasonable chemopreventive agents in this high-risk patient population.

Preferences for outcomes associated with decisions to undergo or forgo genetic testing for Lynch syndrome.

BACKGROUND: Current guidelines recommend offering genetic testing for Lynch syndrome to individuals whose tumors suggest this condition and to relatives of affected individuals. Little is known, however, regarding how patients view the prospect of such testing. In addition, data on preferences (utilities) for the potential outcomes of testing decisions for use in cost-effectiveness analyses are lacking. METHODS: Time tradeoff utilities were elicited for 10 potential outcomes of Lynch syndrome testing decisions and 3 associated cancers from 70 participants, representing a range of knowledge about and experiences with Lynch syndrome. RESULTS: Highest mean utilities were assigned to scenarios in which only the assessor's sibling had Lynch-associated colorectal cancer (ranging from 0.669 ± 0.231 to 0.760 ± 0.220). Utilities assigned to scenarios in which the assessor had Lynch-associated colorectal cancer ranged from 0.605 ± 0.252 to 0.682 ± 0.246, whereas the lowest mean utilities were assigned to 2 of the general cancer states (0.601 ± 0.238 and 0.593 ± 0.272 for colorectal and ovarian cancer respectively). Only 43% of the sample assigned higher values to undergoing Lynch testing and receiving negative results versus forgoing Lynch testing, whereas 50% assigned higher values to undergoing rather than forgoing surgery to prevent a subsequent cancer. CONCLUSIONS: Genetic testing for Lynch syndrome, regardless of results, can have profound effects on quality of life; the utilities we collected can be used to incorporate these effects into cost-effectiveness analyses. Importantly, preferences for the potential outcomes of testing vary substantially, calling into question the extent to which patients would avail themselves of such testing if it were offered to them.

Impact of genetic testing on endometrial cancer risk-reducing practices in women at risk for Lynch syndrome.

OBJECTIVE: Due to the increased lifetime risk of endometrial cancer (EC), guidelines recommend that women with Lynch syndrome (LS) age ≥ 35 undergo annual EC surveillance or prophylactic hysterectomy (PH). The aim of this study was to examine the uptake of these risk-reducing strategies. METHODS: The study population included women meeting clinical criteria for genetic evaluation for LS. Data on cancer risk-reducing behaviors were collected from subjects enrolled in two distinct studies: (1) a multicenter cross-sectional study involving completion of a one-time questionnaire, or (2) a single-center longitudinal study in which subjects completed questionnaires before and after undergoing genetic testing. The main outcome was uptake of EC risk-reducing practices. RESULTS: In the cross-sectional cohort, 58/77 (75%) women at risk for LS-associated EC reported engaging in EC risk-reduction. Personal history of genetic testing was associated with uptake of EC surveillance or PH (OR 17.1; 95% CI 4.1-70.9). Prior to genetic testing for LS, 26/40 (65%) women in the longitudinal cohort reported engaging in EC risk-reduction. At one-year follow-up, 16/16 (100%) mismatch repair (MMR) gene mutation carriers were adherent to guidelines for EC risk-reduction, 9 (56%) of whom had undergone PH. By three-year follow-up, 11/16 (69%) MMR mutation carriers had undergone PH. Among women with negative or uninformative genetic test results, none underwent PH after testing. CONCLUSIONS: Genetic testing for LS is strongly associated with uptake of EC risk-reducing practices. Women found to have LS in this study underwent prophylactic gynecologic surgery at rates comparable to those published for BRCA1/2 mutation carriers.

Performance of Lynch syndrome predictive models in a multi-center US referral population.

OBJECTIVES: Lynch syndrome is the most common cause of inherited colorectal cancer (CRC) and is due to germline mutations in mismatch repair (MMR) genes. Early Lynch syndrome diagnosis and appropriate CRC surveillance improves mortality. Traditional qualitative clinical criteria including Amsterdam and Bethesda guidelines may miss mutation carriers. Recently, quantitative predictive models including MMRPredict, PREMM(1,2,6), and MMRPro were developed to facilitate diagnosis. However, these models remain to be externally validated in the United States. Therefore, we evaluated the test characteristics of Lynch syndrome predictive models in a tertiary referral group at two US academic centers. METHODS: We retrospectively collected data on 230 consecutive individuals who underwent genetic testing for MMR gene mutations at the University of Chicago and University of California at San Francisco's Cancer Risk Clinics. Each individual's risk of mutation was examined using MMRPredict, PREMM(1,2,6), and MMRPro. Amsterdam and Bethesda criteria were also determined. Testing characteristics were calculated for each of the models. RESULTS: We included 230 individuals in the combined cohort. In all, 113 (49%) probands were MMR mutation carriers. Areas under the receiver operator characteristic curves were 0.76, 0.78, and 0.82 for MMRPredict, PREMM(1,2,6), and MMRPro, respectively. While similar in overall performance, our study highlights unique test characteristics of these three quantitative models including comparisons of sensitivity and specificity. Moreover, we identify characteristics of mutation carriers who were missed by each model. CONCLUSIONS: Overall, all three Lynch syndrome predictive models performed comparably in our multi-center US referral population. These results suggest that Lynch syndrome predictive models can be used to screen for MMR mutation carriers and can provide improved test characteristics compared with traditional clinical criteria. Identification of MMR mutation carriers is paramount as appropriate screening can prevent CRC mortality in this high-risk group.

APC +/- alters colonic fibroblast proteome in FAP.

Here we compared the proteomes of primary fibroblast cultures derived from morphologically normal colonic mucosa of familial adenomatous polyposis (FAP) patients with those obtained from unaffected controls. The expression signature of about 19% of total fibroblast proteins separates FAP mutation carriers from unaffected controls (P < 0.01). More than 4,000 protein spots were quantified by 2D PAGE analysis, identifying 368 non-redundant proteins and 400 of their isoforms. Specifically, all three classes of cytoskeletal filaments and their regulatory proteins were altered as were oxidative stress response proteins. Given that FAP fibroblasts showed heightened sensitivity to transformation by KiMSV and SV40 including elevated levels of the p53 protein, events controlled in large measure by the Ras suppressor protein-1 (RSU-1) and oncogenic DJ-1, here we show decreased RSU1 and augmented DJ-1 expression in both fibroblasts and crypt-derived epithelial cells from morphologically normal colonic mucosa of FAP gene-carriers. The results indicate that heterozygosity for a mutant APC tumor suppressor gene alters the proteomes of both colon-derived normal fibroblasts in a gene-specific manner, consistent with a "one-hit" effect.

Prevalence and predictors of appropriate colorectal cancer surveillance in Lynch syndrome.

OBJECTIVES: Lynch syndrome (LS) is a hereditary cancer syndrome that conveys a high risk of colorectal cancer (CRC). Guidelines recommend colonoscopy every 1 to 2 years. There is limited information about screening compliance in this high-risk group. METHODS: Data about cancer screening behaviors were obtained from subjects recruited through four US cancer genetics clinics. The main outcome was prevalence of appropriate CRC surveillance for LS. RESULTS: A total of 181 individuals had a family history that met the Amsterdam criteria for LS (n=154) and/or had an identified mutation in a mismatch repair (MMR) gene (n=105). Of these 181 individuals, 131 (73%) had appropriate LS surveillance with colonoscopies at least every 2 years for their age >25 years. Of those with inadequate surveillance, 26/49 (53%) had colonoscopies at 3- to 5-year intervals. There were no significant differences in health-care setting, perceived risk of CRC, or compliance with screening for other cancers. Rates of appropriate surveillance were higher among individuals who had been referred for genetic evaluation for LS compared with those who had not (109/136 (80%) vs. 23/45 (51%), respectively, P=0.0004). In multivariate analysis, personal history of CRC (odds ratio (OR) 2.81), having a first-degree relative with CRC at age <50 years (OR 2.61), and having undergone a genetic evaluation (OR 4.62) were associated with appropriate CRC surveillance for LS. CONCLUSIONS: The time between colonoscopic exams in patients with LS is often longer than recommended by current guidelines and may place them at risk for interval cancers. Recognizing clinical features of LS and providing genetic counseling, evaluation, and intensive surveillance may improve cancer prevention for those at the highest risk for CRC.

Colorectal cancer risk perception on the basis of genetic test results in individuals at risk for Lynch syndrome.

PURPOSE: Lynch syndrome is associated with inherited germline mutations in mismatch repair (MMR) genes. Genetic testing in high-risk individuals may yield indeterminate results if no mutation is found or if a mutation of unclear pathogenic significance is observed. There are limited data regarding how well patients with Lynch syndrome understand the clinical implications of genetic test results. This study examines colorectal cancer (CRC) risk perception in individuals tested for MMR mutations and identifies the factors associated with an appropriate interpretation of their cancer risk. PATIENTS AND METHODS: A total of 159 individuals who met the Revised Bethesda Guidelines and had previously undergone genetic testing completed a questionnaire eliciting demographic data, cancer history, genetic test results, and an estimate of their CRC risk. Associations between clinical factors, genetic test results, and CRC risk perception were explored using multivariable analyses. RESULTS: Of the 100 individuals with a pathogenic mutation (true positive), 90 (90%) correctly estimated their CRC risk as "high" or "very high" compared with other individuals their age. However, only 23 (62%) of 37 individuals with an indeterminate genetic test result correctly estimated their risk. Individuals with a history of Lynch syndrome-associated cancer (odds ratio [OR], 0.1; 95% CI, 0.1 to 0.6) or indeterminate genetic test results (OR, 0.2; 95% CI, 0.1 to 0.6) were significantly less likely to estimate their CRC risk as increased. CONCLUSION: Patients at risk for Lynch syndrome with an indeterminate genetic test result may be falsely reassured. It is important that health care providers continue to discuss the implications of uninformative results on lifetime cancer risk.

One-hit effects in cancer: altered proteome of morphologically normal colon crypts in familial adenomatous polyposis.

We studied patients with Familial Adenomatous Polyposis (FAP) because they are virtually certain to develop colon cancer, and because much is known about the causative APC gene. We hypothesized that the inherited heterozygous mutation itself leads to changes in the proteome of morphologically normal crypts and the proteins that changed may represent targets for preventive and therapeutic agents. We determined the differential protein expression of morphologically normal colon crypts of FAP patients versus those of individuals without the mutation, using two-dimensional gel electrophoresis, mass spectrometry, and validation by two-dimensional gel Western blotting. Approximately 13% of 1,695 identified proteins were abnormally expressed in the morphologically normal crypts of APC mutation carriers, indicating that a colon crypt cell under the one-hit state is already abnormal. Many of the expression changes affect pathways consistent with the function of the APC protein, including apoptosis, cell adhesion, cell motility, cytoskeletal organization and biogenesis, mitosis, transcription, and oxidative stress response. Thus, heterozygosity for a mutant APC tumor suppressor gene alters the proteome of normal-appearing crypt cells in a gene-specific manner, consistent with a detectable one-hit event. These changes may represent the earliest biomarkers of colorectal cancer development, potentially leading to the identification of molecular targets for cancer prevention.

Sharing genetic test results in Lynch syndrome: communication with close and distant relatives.

BACKGROUND & AIMS: Clinical genetic testing can help direct cancer screening for members of Lynch syndrome families; however, there is limited information about family communication of genetic test results. METHODS: A total of 174 probands who had genetic testing for Lynch syndrome were enrolled through 4 US cancer genetics clinics. Subjects were asked whether they had disclosed their genetic test results to first-, second-, and third-degree relatives. Univariate and multivariate analyses were used to identify clinical and demographic factors associated with informing immediate and extended family of genetic test results. RESULTS: One hundred seventy-one of 174 probands (98%; 95% confidence interval, 95%-100%) reported that they had disclosed their genetic test result to a first-degree relative. Communication of test results to other relatives occurred significantly less often, with only 109 of 162 (67%; 95% confidence interval, 59%-74%) subjects with second- or third-degree relatives sharing their results. Individuals with a pathogenic mutation were significantly more likely to inform distant relatives than were subjects with a negative or indeterminate test result (odds ratio, 2.49; 95% confidence interval, 1.14-5.40). Probands' age, sex, and cancer status did not influence communication of genetic test results. Lack of closeness and concerns that relatives would worry or not understand the implications of test results were the primary reasons for not sharing genetic test results. CONCLUSIONS: Most individuals who undergo genetic testing for Lynch syndrome share their test results with first-degree family members; however, these results reach more distant relatives significantly less often. Interventions to improve communication of genetic test results to members of the extended family are necessary to provide optimal cancer prevention care to at-risk families.

Tumor histology helps to identify Lynch syndrome among colorectal cancer patients.

OBJECTIVE: To determine the value of histology in identifying Lynch syndrome among those patients with early onset of colorectal cancer (CRC). METHODS: Demographic, clinical and cancer history data from patients diagnosed with CRC before 60 years of age, and treated at our institution between 1997 and 2005, were collected from medical records and direct interview. Their tumors were assessed to identify histological features suggestive of high frequency microsatellite instability (MSI-H): tumor infiltrating lymphocytes, Crohn's like inflammatory reaction, mucinous, signet ring cells, medullary growth pattern and then, tested for microsatellite instability (MSI) and MLH1/ MSH2 protein expression. RESULTS: Sixty-five patients were included in the study. The mean age at diagnosis was 48 +/- 9.9 years. Overall, 28 (43%) patients, including 13 of 35 diagnosed between ages 50 and 60, had tumor demonstrating one or more histological features suggestive of MSI-H. These patients were younger (45 vs. 50 years, P = 0.02) and more commonly had family history of Lynch syndrome-related cancers (36 vs. 19%), though the latter feature did not reach statistical significance (P = 0.07). Eleven of 25 tumors with MSI-H histology, but only 1 of 29 tumors without special histological features were found to be MSI-H (P < 0.0001). Histology had a positive predictive value of 44% and a negative predictive value of 97% for identifying MSI-H tumors. CONCLUSIONS: Limiting MSI analysis only to those tumors with suggestive histology would have reduced the need for testing by nearly 60% of all tumors from patients that met the revised Bethesda guidelines.

Searchable high-resolution 2D gel proteome of the human colon crypt.

We seek alterations in protein patterns at the earliest possible step on the path to cancer, namely, in cells of the target tissue from normal persons versus the corresponding normally appearing cells from persons who are heterozygous for mutation in a tumor suppressor gene that predisposes strongly to carcinoma in that tissue. To begin a systematic comparison of the proteomes of cells from normal and from neoplastic colons, we have undertaken the isolation of human colon crypts that are derived from the normal-appearing mucosa of left (descending) colon of patients with sporadic colorectal cancer. Two-dimensional (2D) gel electrophoresis is a proteomic approach that excels in the resolution of protein isoforms. Here, we document the practicality of this approach with human samples using gels of three overlapping pH ranges. For the first time, about 800 nonredundant proteins and 900 isoforms from purified human colonic crypts were identified, permitting an assessment of the contributions of protein isoforms. These interactive, searchable, hyperlink-enabled proteome maps and gene ontology analyses will facilitate future studies to discover the earliest markers and intervention targets during progression to colon cancer.

Awareness of gynecologic surveillance in women from hereditary non-polyposis colorectal cancer families.

OBJECTIVE: To determine knowledge of gynecologic cancer risk and screening in women with HNPCC. STUDY DESIGN: Forty-three women with HNPCC were counseled through a gastrointestinal cancer risk program, and later sent a questionnaire regarding their screening practices for gynecologic neoplasms. RESULTS: Twenty-seven (63%) of 43 responded. Fifteen (55%) of 27 had previously been diagnosed with cancer. Among 16 women with a uterus, 11 (69%) reported surveillance by ultrasound or endometrial sampling. Among 21 respondents with ovaries, 13 (62%) reported screening by ultrasound or CA125. Twenty-two (81%) of 27 had seen a gynecologist after receiving their HNPCC diagnosis, but only 12% recalled hearing about risks from their gynecologist, and 8% from their gynecologic oncologist. Genetic counselors were cited as the most common source (48%) of gynecologic cancer risk information. CONCLUSIONS: While the effectiveness of surveillance remains in question, gynecologists can be a source of information regarding gynecologic cancer risk for women from HNPCC families.

Germ line mutations of mismatch repair genes in hereditary nonpolyposis colorectal cancer patients with small bowel cancer: International Society for Gastrointestinal Hereditary Tumours Collaborative Study.

PURPOSE: The aim of study was to determine the clinical characteristics and mutational profiles of the mismatch repair genes in hereditary nonpolyposis colorectal cancer (HNPCC) patients with small bowel cancer (SBC). EXPERIMENTAL DESIGN: A questionnaire was mailed to 55 members of the International Society for Gastrointestinal Hereditary Tumours, requesting information regarding patients with HNPCC-associated SBC and germ line mismatch repair gene mutations. RESULTS: The study population consisted of 85 HNPCC patients with identified mismatch repair gene mutations and SBCs. SBC was the first HNPCC-associated malignancy in 14 of 41 (34.1%) patients for whom a personal history of HNPCC-associated cancers was available. The study population harbored 69 different germ line mismatch repair gene mutations, including 31 mutations in MLH1, 34 in MSH2, 3 in MSH6, and 1 in PMS2. We compared the distribution of the mismatch repair mutations in our study population with that in a control group, including all pathogenic mismatch repair mutations of the International Society for Gastrointestinal Hereditary Tumours database (excluding those in our study population). In patients with MSH2 mutations, patients with HNPCC-associated SBCs had fewer mutations in the MutL homologue interaction domain (2.9% versus 19.9%, P = 0.019) but an increased frequency of mutations in codons 626 to 733, a domain that has not previously been associated with a known function, versus the control group (26.5% versus 2.8%, P < 0.001). CONCLUSIONS: In HNPCC patients, SBC can be the first and only cancer and may develop as soon as the early teens. The distribution of MSH2 mutations found in patients with HNPCC-associated SBCs significantly differed from that found in the control group (P < 0.001).

Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch syndrome.

BACKGROUND: Women with the Lynch syndrome (hereditary nonpolyposis colorectal cancer) have a 40 to 60 percent lifetime risk of endometrial cancer and a 10 to 12 percent lifetime risk of ovarian cancer. The benefit of prophylactic gynecologic surgery for women with this syndrome has been uncertain. We designed this study to determine the reduction in the risk of gynecologic cancers associated with prophylactic hysterectomy and bilateral salpingo-oophorectomy in women with the Lynch syndrome. METHODS: Three hundred fifteen women with documented germ-line mutations associated with the Lynch syndrome were identified. Women who had undergone prophylactic hysterectomy (61 women) and women who had undergone prophylactic bilateral salpingo-oophorectomy (47 women) were matched with mutation-positive women who had not undergone the procedure in question (210 women for the analysis of endometrial cancer and 223 for the analysis of ovarian cancer). Women who had undergone prophylactic surgery and their matched controls were followed from the date of the surgery until the occurrence of cancer or until the data were censored at the time of the last follow-up visit. RESULTS: There were no occurrences of endometrial, ovarian, or primary peritoneal cancer among the women who had undergone prophylactic surgery. Endometrial cancer was diagnosed in 69 women in the control group (33 percent), for an incidence density of 0.045 per woman-year, yielding a prevented fraction (the proportion of potential new cancers prevented) of 100 percent (95 percent confidence interval, 90 to 100 percent). Ovarian cancer was diagnosed in 12 women in the control group (5 percent), for an incidence density of 0.005 per woman-year, yielding a prevented fraction of 100 percent (95 percent confidence interval, -62 to 100 percent). CONCLUSIONS: These findings suggest that prophylactic hysterectomy with bilateral salpingo-oophorectomy is an effective strategy for preventing endometrial and ovarian cancer in women with the Lynch syndrome.

Pathologic features of endometrial carcinoma associated with HNPCC: a comparison with sporadic endometrial carcinoma.

BACKGROUND: Endometrial carcinoma is a common malignancy in hereditary nonpolyposis colorectal carcinoma (HNPCC). Like colon carcinoma, endometrial carcinoma is diagnosed at an earlier age in women with HNPCC. In contrast to colon carcinoma, the pathologic features of endometrial carcinoma in HNPCC have not been studied in detail. It was the purpose of this study to pathologically characterize a series of HNPCC associated endometrial carcinomas. METHODS: Fifty women with HNPCC and endometrial carcinoma were analyzed from four different hereditary cancer registries. H&E stained slides and pathology reports were reviewed for clinically important pathologic features of endometrial carcinoma. These results were compared with those for two different groups of sporadic endometrial carcinoma--women younger than age 50 years (n = 42) and women of all ages with tumors demonstrating microsatellite instability (MSI-high) secondary to methylation of MLH1 (n = 26). RESULTS: Nearly one-fourth of HNPCC patients in this study had endometrial tumors with pathologic features that would require adjuvant therapy after hysterectomy. There was a trend toward the HNPCC patients having more nonendometrioid tumors; all of these patients were carriers of MSH2 mutations. Such nonendometrioid tumors were extremely rare in the MLH1 methylated group. A subset of MLH1 methylated sporadic tumors demonstrated a unique, 'undifferentiated' histology that was not observed in HNPCC or the young group. CONCLUSION: Data suggest a genotype-phenotype relation in which microsatellite instability resulting from MLH1 methylation is almost exclusively associated with classical or 'undifferentiated' endometrioid tumors, whereas microsatellite instability secondary to MSH2 mutation can result in a more variable histologic spectrum of endometrial carcinoma.

A comparison of the phenotype and genotype in adenomatous polyposis patients with and without a family history.

OBJECTIVES: Adenomatous polyposis of the colon is often secondary to an inherited mutation in adenomatous polyposis coli (APC) gene, however, approximately one third of patients have no family history of the disease. We studied the phenotype and genotype of adenomatous polyposis in patients without a family history. METHODS: A cohort of 57 unrelated adenomatous polyposis patients were evaluated. Seventeen patients with no family history were compared with 40 patients who had a positive family history of the disease. Family history and medical records were collected and analyzed. Germline APC and Mut Y homologue (MYH) testing was undertaken. RESULTS: Patients without a family history were diagnosed with polyposis at an older age (41 years vs. 32 years) and presenting more frequently with symptoms (76 vs 20, P < 0.05). The number of colonic polyps and frequency of extracolonic manifestation associated with adenomatous polyposis did not differ between the two groups. APC mutations were detected less frequently among patients without a family history of the disease (4 out of 17 vs 25 out of 40, P=0.007), even among those with greater than 100 colorectal adenomas (4 out of 12 versus 21 out of 29, P=0.03). One homozygous MYH mutation carrier (G382D) was detected among the six patients without a family history and without a germline APC mutation who were tested. CONCLUSIONS: Adenomatous polyposis patients without a family history are usually diagnosed with symptoms, and at a later age. Phenotypically, they are similar to those with a family history. However, germline APC mutations are detected far less frequently in patients without a family history. A small percentage of these cases may be secondary to biallelic germline MYH mutations.

Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X.

CONTEXT: Approximately 60% of families that meet the Amsterdam-I criteria (AC-I) for hereditary nonpolyposis colorectal cancer (HNPCC) have a hereditary abnormality in a DNA mismatch repair (MMR) gene. Cancer incidence in AC-I families with MMR gene mutations is reported to be very high, but cancer incidence for individuals in AC-I families with no evidence of an MMR defect is unknown. OBJECTIVE: To determine if cancer risks in AC-I families with no apparent deficiency in DNA MMR are different from cancer risks in AC-I families with DNA MMR abnormalities. DESIGN, SETTING, AND PARTICIPANTS: Identification (1997-2001) of 161 AC-I pedigrees from multiple population- and clinic-based sources in North America and Germany, with families grouped into those with (group A) or without (group B) MMR deficiency by tumor testing. A total of 3422 relatives were included in the analyses. MAIN OUTCOME MEASURES: Cancer incidence in groups A and B (excluding the 3 affected members used to define each pedigree as AC-I) and computed age- and sex-adjusted standardized incidence ratios (SIRs) using Surveillance, Epidemiology, and End Results data. RESULTS: Group A families from both population- and clinic-based series showed increased incidence of the HNPCC-related cancers. Group B families showed increased incidence only for colorectal cancer (SIR, 2.3; 95% confidence interval, 1.7-3.0) and to a lesser extent than group A (SIR, 6.1; 95% confidence interval, 5.2-7.2) (P<.001). CONCLUSIONS: Families who fulfill AC-I criteria but who have no evidence of a DNA MMR defect do not share the same cancer incidence as families with HNPCC-Lynch syndrome (ie, hereditary MMR deficiency). Relatives in such families have a lower incidence of colorectal cancer than those in families with HNPCC-Lynch syndrome, and incidence may not be increased for other cancers. These families should not be described or counseled as having HNPCC-Lynch syndrome. To facilitate distinguishing these entities, the designation of "familial colorectal cancer type X" is suggested to describe this type of familial aggregation of colorectal cancer.