Stephen J. Lemon

What you don't know can hurt you: adverse psychologic effects in members of BRCA1-linked and BRCA2-linked families who decline genetic testing.

PURPOSE To identify members of hereditary breast and ovarian cancer families who are at risk for adverse psychologic effects of genetic testing. PATIENTS AND METHODS A prospective cohort study with baseline (preeducation) assessments of predictor variables (ie, sociodemographic factors, cancer history, and cancer-related stress symptoms) was performed. The primary outcome variable (presence of depressive symptoms) was assessed at baseline and at 1- and 6-month follow-up evaluations. Participants were 327 adult male and female members of BRCA1- and BRCA2-linked hereditary breast and ovarian cancer families, who were identified as carriers, noncarriers, or decliners of genetic testing. RESULTS The presence of cancer-related stress symptoms at baseline was strongly predictive of the onset of depressive symptoms in family members who were invited but declined testing. Among persons who reported high baseline levels of stress, depression rates in decliners increased from 26% at baseline to 47% at 1-month follow-up; depression rates in noncarriers decreased and in carriers showed no change (odds ratio [OR] for decliners v noncarriers=8.0; 95% confidence interval [CI], 1.9 to 33.5; P=.0004). These significant differences in depression rates were still evident at the 6-month follow-up evaluation (P=.04). CONCLUSION In BRCA1/2-linked families, persons with high levels of cancer-related stress who decline genetic testing may be at risk for depression. These family members may benefit from education and counseling, even if they ultimately elect not to be tested, and should be monitored for potential adverse effects.

Colorectal carcinoma survival among hereditary nonpolyposis colorectal carcinoma family members

Patients with hereditary nonpolyposis colorectal carcinoma (HNPCC) reportedly have better prognoses than sporadic colorectal carcinoma (CRC) patients, but it has been unclear whether this could be due to differences in stage at diagnosis. The current study compared stage and survival in a retrospective cohort of HNPCC family members who developed CRC with the same factors in an unselected hospital series of patients with sporadic CRC.

Cumulative Incidence of Colorectal and Extracolonic Cancers in MLH1 and MSH2 Mutation Carriers of Hereditary Nonpolyposis Colorectal Cancer

The extracolonic tumor spectrum of hereditary nonpolyposis colorectal cancer (HNPCC) includes cancer of the endometrium, ovaries, stomach, biliary tract, and urinary tract. This study was designed to determine the penetrance of colorectal and extracolonic tumors in HNPCC mutation carriers. Forty-nine patients (22 females and 27 males) were identified with an MSH2 germline mutation, and 56 patients (28 females and 28 males) were identified with an MLH1 mutation. Cumulative incidence by age 60 (lifetime risk) and mean age of cancer diagnosis were compared. The lifetime risk of extracolonic cancers in MSH2 and MLH1 carriers was 48% and 11% respectively (P = 0.016). Extracolonic cancer risk in MSH2 females and males was 69% and 34%, respectively (P = 0.042). Mean age of extracolonic cancer diagnosis was significantly older for MSH2 males than females (55.4 vs. 39.0, P = 0.013). No difference was observed in colorectal cancer risk between MLH1 and MSH2 carriers (84% vs. 71%). Colorectal cancer risk was 96% in MSH2 males compared to 39% in MSH2 females (P = 0.034). No differences in colorectal and extracolonic cancer risks between MLH1 females and males were identified. The risk of extracolonic cancer by age 60 was greater in MSH2 mutation carriers than in MLH1 carriers. Gender differences in colorectal and extracolonic cancer risk were observed for MSH2 carriers only. These phenotypic features of HNPCC genotypes may have clinical significance in the design of genotype-specific screening, surveillance, and follow-up for affected individuals.

Colorectal and extracolonic cancer variations in MLH1/MSH2 hereditary nonpolyposis colorectal cancer kindreds and the general population

PURPOSE: This clinical case review aimed to identify phenotypic variations in colorectal and extracolonic cancer expression between hereditary nonpolyposis colorectal cancer (HNPCC) families with MLH1 and MSH2 germline mutations and the general population. METHODS: Colorectal cancer onset and site distribution were compared among 67 members of MLH1 kindreds, 45 members of MSH2 kindreds, and 1,189 patients from the general population. Synchronous and metachronous cancer rates, tumor stage, extracolonic cancer incidence, and survival were also compared. RESULTS: Mean ages of colorectal cancer onset were 44, 46, and 69 years for MLH1, MSH2, and the general population, respectively (P<0.001). More proximal and fewer distal colon cancers were noted in HNPCC than the general population (P<0.001,P=0.04). Site distribution showed disparity of rectal cancers (8 percent MLH1vs. 28 percent MSH2;P=0.01) based on genotypes. Overall, synchronous colorectal cancer rates were 7.4, 6.7, and 2.4 percent for MLH1, MSH2, and the general population, respectively (P=0.016). Annual metachronous colorectal cancer rates were 2.1, 1.7, and 0.33 percent for MLH1, MSH2, and the general population, respectively (P=0.041). Colorectal cancer stage presentation was lower in HNPCC than the general population (P=0.0028). Extracolonic cancers were noted in 33 percent of MSH2 patients, compared with 12 percent of MLH1 patients and 7.3 percent of the general population with colorectal cancers (P<0.001). Combined MLH1 and MSH2 ten-year survival was 68.7 percent compared with 47.8 percent for the general population (P=0.009 stage stratified, hazard ratio 0.57). CONCLUSION: The presence of rectal cancer should not preclude the diagnosis of HNPCC, because the incidence of rectal cancer in MSH2 was comparable with that in the general population. Phenotypic variations, including the preponderance of extracolonic cancers in MSH2 patients, did not result in survival differences between genotypic subgroups. These phenotypic features of HNPCC genotypes may have clinical significance in the design of specific screening, surveillance, and follow-up for affected individuals.

Male breast cancer in the hereditary nonpolyposis colorectal cancer syndrome

A male member of a large HNPCC kindred, affected by primary malignancies of the breast and colon, was identified. This individual was found to harbor a germline mutation of the MLH1 mismatch repair gene previously shown to segregate with disease in this kindred. The breast tumor exhibited somatic reduction to homozygosity for the MLH1 mutation, and microsatellite instability was evident in the breast tumor. We conclude that hereditary male breast cancer can occur as an integral tumor in the HNPCC syndrome.

Microsatellite Instability and Expression of MLH1 and MSH2 in Normal and Malignant Endometrial and Ovarian Epithelium in Hereditary Nonpolyposis Colorectal Cancer Family Members

Mismatch repair deficiency is a characteristic molecular finding in hereditary nonpolyposis colorectal cancer (HNPCC), and has been demonstrated in both colorectal cancers and benign adenomas. Endometrial and ovarian cancers are common extracolonic tumors in this syndrome; however, few studies have investigated whether genetic changes occur in histologically normal endometrial and ovarian epithelia from HNPCC family members. If early genetic changes exist, they might be used as molecular markers to detect susceptibility to endometrial and ovarian cancers. In this study, we analyzed microsatellite instability (MSI) and MLH1 and MSH2 immunohistochemical expression in 20 histologically normal epithelia (12 endometrial and 8 ovarian) and 8 cancers (4 endometrial and 4 ovarian) obtained from 20 individuals representing 7 unrelated HNPCC families. While MSI was observed in endometrial (75%) and ovarian (100%) cancers, no case was determined to exhibit MSI in histologically normal epithelia of the endometrium or ovary. Similarly, in immunohistochemical expressions for MLH1 and MSH2, histologically normal epithelia had no genetic changes predisposing to malignancy. In cancer cases, a correlation existed between the expression of MLH1 and MSH2, the presence of germline mutations in the hMLH1 and hMSH2 genes, and the presence of tumor MSI. These data suggest that MSI and MLH1 and MSH2 expression are not useful biomarkers for the early detection of endometrial and ovarian malignancy in cancer-unaffected HNPCC germline mutation carriers. Further studies of other genetic changes in normal and premalignant precursor lesions are needed.

Cancer risk assessment in a hereditary cancer prevention clinic and its first year's experience

Hereditary cancer accounts for 5‐10% of the estimated 1.38 million cancer cases in 1997 and requires an approach to cancer prevention that is distinct from its sporadic counterpart based on its differing natural history. The laboratory advances in the molecular biology of hereditary cancer have recently resulted in the development of specialized hereditary cancer clinics with both broad and syndrome specific hereditary cancer assessment capabilities. A key question is how well these clinics can accomplish this new mission.

Hereditary gynecologic cancer

It is estimated that approximately 1.3 million new cases of cancer will occur in the United States in 1997 (785,800 males, 596,600 females) [1]. Given a conservative estimate that 5% of these cases are hereditary, at least 65,000 patients will merit DNA testing annually. Using this same 5% estimate, then of the 181,600 cases of carcinoma of the breast and the 26,800 cases of carcinoma of the ovary that will occur in the United States during this same year, approximately 9080 patients with breast cancer and 1340 patients with ovarian carcinoma will fit a hereditary etiology. Barring new germline mutations, this means that each individual will be a member of a cancer-prone family. When viewed as annual incidence rates of hereditary cancer, it is clear that the prevalence of hereditary breast and ovarian carcinoma in the United States will truly be enormous. Similar calculations can be made for virtually all forms of cancer that will strike women.

Genetic counseling issues

Caryn Lerman, Ph.D. (Co-Chair) A June A. Peters, M.S. (Co-Chair) mong the strongest recommendations to come from this workshop was the reaffirmation that patient counseling must take place Terri Ades, R.N., M.S., O.C.N. (Rapporteur) prior to genetic testing, and that counseling should be independent Diane Fink, M.D. (Rapporteur) of testing. In other words, counseling is a prelude to the decision of Patricia Barr, J.D.* whether to be tested. Genetic test results carry immense implications Barbara Bowles Biesecker, M.S.* for patients and families, and competent clinical, psychosocial, and Sally West Brooks, R.N., M.A.* counseling support is needed for individuals who are considering Kathleen A. Calzone, R.N., B.S.N.* testing, as well as those who chose to undergo testing. Workgroup Robert T. Croyle, Ph.D.* participants identified a range of immediate needs related to infraBeth A. Fine, M.S.* structure, access to care, public and provider education, and the cultiBettye Green* vation of an emerging specialty in genetic counseling for individuals Stephen J. Lemon, M.D., M.P.H.* at risk for inherited cancer syndromes. Henry T. Lynch, M.D.* Steven A. Narod, M.D.* Recommendations Kenneth Offit, M.D., M.P.H.* 1. The American Cancer Society (ACS) can be an influential advocate Deborah Pearlman, Ph.D.* at the state and national level for the importance of quality assurSusan T. Tinley, M.S.* ance in genetic testing and patient needs. The ACS should work Claudette Varricchio, R.N., D.S.N., F.A.A.N.* with state officials to develop regulations regarding genetic testing, and should be an advocate for greater accessibility of testing and counseling, including the elimination of financial barriers. 2. The public can be informed about the scientific evidence supporting a particular test for a genetic alteration. The ACS should develop a comprehensive information data base on genetic testing in collaboration with other organizations that are supporting the development of similar data bases; organizations should not duplicate each other’s efforts. The ACS should also develop an educational brochure written at a widely accessible educational level that describes inherited cancer syndromes, the importance of family histories, and the difference between investigational and clinical research, and that identifies who should be tested and how to get tested. * Workshop participant. 3. The ACS should develop a simple and straightforward educational Presented at the American Cancer Society brochure for providers that outlines criteria for referral and testing, Workshop on Heritable Cancer Syndromes and existing levels of evidence regarding the accuracy and implication Genetic Testing, Chicago, Illinois, October 7–8, of genetic test results, and institutions to which patients can be 1996. referred for high quality counseling and testing services. Providers Address for reprints: Caryn Lerman, Ph.D., need to be educated regarding the importance of taking a detailed Georgetown University Medical Center, Cancer family history. To heighten awareness of the importance of inherGenetics, 2233 Wisconsin Avenue, Suite 535, ited susceptibility to cancer, greater attention should be given to Washington, DC 20007. the field of hereditary cancers and genetics in ACS professional journals. Received April 10, 1997; accepted April 16, 1997. The ACS should advocate a team approach to meet the needs of