Patients with PTEN hamartoma tumor syndrome (PHTS, comprising Cowden, Bannayan‐Riley‐Ruvalcaba, and Proteus‐like syndromes) are at increased risk of developing cancer due to pathogenic PTEN germline ...variants. This review summarizes age‐, sex‐, and type‐specific malignant cancer risks for PHTS patients, which is urgently needed for clinical management. A PubMed literature search for Standardized Incidence Ratios or Cumulative Lifetime cancer risks (CLTRs) resulted in nine cohort studies comprising four independent PHTS cohorts, including mainly index cases and prevalent cancer cases. The median age at diagnosis was 36 years. Reported CLTRs for any cancer varied from 81% to 90%. The tumor spectrum included female breast cancer (CLTRs including sex‐specific estimates at age 60‐70: 67% to 85%), endometrium cancer (19% to 28%), thyroid cancer (6% to 38%), renal cancer (2% to 24%), colorectal cancer (9% to 32%), and melanoma (0% to 6%). Although these estimates provide guidance for clinical care, discrepancies between studies, sample sizes, retrospective designs, strongly ascertained cases, and lack of pediatric research emphasizes that data should be interpreted with great caution. Therefore, more accurate and more personalized age‐, sex‐, and cancer‐specific risk estimates are needed to enable counseling of all PHTS patients irrespective of ascertainment, and improvement of cancer surveillance guidelines.
This review summarizes the evidence on age‐related cancer risks for PHTS patients. Females have predominantly a strong increased risk and earlier age at onset for breast, endometrial, and thyroid cancer, and males for thyroid cancer. The risks of other PHTS‐associated cancers are uncertain. At present, cancer risks are overestimated due to ascertainment bias. For more accurate and personalized cancer risks, prospective follow‐up studies of both pediatric and adult patients are needed.
Lynch syndrome is caused by germline mutations in the mismatch repair (MMR) genes. Tumors are characterized by microsatellite instability (MSI). However, a considerable number of MSI-positive tumors ...have no known molecular mechanism of development. By using Sanger and ion semiconductor sequencing, 25 MSI-positive tumors were screened for somatic mutations and loss of heterozygosity in mutL homolog 1 (MLH1) and mutS homolog 2 (MSH2) . In 13 of 25 tumors (8 MLH1-deficient and 5 MSH2-deficient tumors), we identified 2 somatic mutations in these genes. We conclude that 2 acquired events explain the MMR-deficiency in more than 50% of the MMR-deficient tumors without causal germline mutations or promoter methylation.
Purpose To evaluate the real-life performance of a breast cancer screening program for women with different categories of increased breast cancer risk with multiple follow-up rounds in an academic ...hospital with a large screening population. Materials and Methods Screening examinations (magnetic resonance MR imaging and mammography) for women at increased breast cancer risk (January 1, 2003, to January 1, 2014) were evaluated. Risk category, age, recall for workup of screening-detected abnormalities, biopsy, and histopathologic diagnosis were recorded. Recall rate, biopsy rate, positive predictive value of recall, positive predictive value of biopsy, cancer detection rate, sensitivity, and specificity were calculated for first and follow-up rounds. Results There were 8818 MR and 6245 mammographic examinations performed in 2463 women. Documented were 170 cancers; of these, there were 129 screening-detected cancers, 16 interval cancers, and 25 cancers discovered at prophylactic mastectomy. Overall sensitivity was 75.9% including the cancers discovered at prophylactic mastectomy (95% confidence interval: 69.5%, 82.4%) and 90.0% excluding those cancers (95% confidence interval: 83.3%, 93.7%). Sensitivity was lowest for carriers of the BRCA1 mutation (66.1% and 81.3% when including and not including cancers in prophylactic mastectomy specimens, respectively). Specificity was higher at follow-up (96.5%; 95% confidence interval: 96.0%, 96.9%) than in first rounds (85.1%; 95% confidence interval: 83.4%, 86.5%) and was high for both MR imaging (97.1%; 95% confidence interval: 96.7%, 97.5%) and mammography (98.7%; 95% confidence interval: 98.3%, 99.0%). Positive predictive value of recall and positive predictive value of biopsy were lowest in women who had only a family history of breast cancer. Conclusion Screening performance was dependent on risk category. Sensitivity was lowest in carriers of the BRCA1 mutation. The specificity of high-risk breast screening improved at follow-up rounds.
RSNA, 2017 Online supplemental material is available for this article.
The clinical consequences of PMS2 germline mutations are poorly understood compared with other Lynch-associated mismatch repair gene (MMR) mutations. The aim of this European cohort study was to ...define the cancer risk faced by PMS2 mutation carriers.
Data were collected from 98 PMS2 families ascertained from family cancer clinics that included a total of 2,548 family members and 377 proven mutation carriers. To adjust for potential ascertainment bias, a modified segregation analysis model was used to calculate colorectal cancer (CRC) and endometrial cancer (EC) risks. Standardized incidence ratios (SIRs) were calculated to estimate risks for other Lynch syndrome-associated cancers.
The cumulative risk (CR) of CRC for male mutation carriers by age 70 years was 19%. The CR among female carriers was 11% for CRC and 12% for EC. The mean age of CRC development was 52 years, and there was a significant difference in mean age of CRC between the probands (mean, 47 years; range, 26 to 68 years) and other family members with a PMS2 mutation (mean, 58 years; range, 31 to 86 years; P < .001). Significant SIRs were observed for cancers of the small bowel, ovaries, breast, and renal pelvis.
CRC and EC risks were found to be markedly lower than those previously reported for the other MMR. However, these risks embody the isolated risk of carrying a PMS2 mutation, and it should be noted that we observed a substantial variation in cancer phenotype within and between families, suggesting the influence of genetic modifiers and lifestyle factors on cancer risks.
Genetic testing of cancer susceptibility genes is now widely applied in clinical practice to predict risk of developing cancer. In general, sequence-based testing of germline DNA is used to determine ...whether an individual carries a change that is clearly likely to disrupt normal gene function. Genetic testing may detect changes that are clearly pathogenic, clearly neutral, or variants of unclear clinical significance. Such variants present a considerable challenge to the diagnostic laboratory and the receiving clinician in terms of interpretation and clear presentation of the implications of the result to the patient. There does not appear to be a consistent approach to interpreting and reporting the clinical significance of variants either among genes or among laboratories. The potential for confusion among clinicians and patients is considerable and misinterpretation may lead to inappropriate clinical consequences. In this article we review the current state of sequence-based genetic testing, describe other standardized reporting systems used in oncology, and propose a standardized classification system for application to sequence-based results for cancer predisposition genes. We suggest a system of five classes of variants based on the degree of likelihood of pathogenicity. Each class is associated with specific recommendations for clinical management of at-risk relatives that will depend on the syndrome. We propose that panels of experts on each cancer predisposition syndrome facilitate the classification scheme and designate appropriate surveillance and cancer management guidelines. The international adoption of a standardized reporting system should improve the clinical utility of sequence-based genetic tests to predict cancer risk. Hum Mutat 29(11), 1282-1291, 2008.
PTEN hamartoma tumor syndrome (PHTS) is caused by inactivating germline PTEN mutations with subsequent activation of Akt-mTOR signaling, leading to an increased risk of developing thyroid carcinoma ...(TC). Activation of Akt-mTOR signaling is essential for innate immune cell activation and reprogramming of TC-induced macrophages. Here, we aim to assess the effect of PTEN mutations on innate immune cell function in PHTS patients, especially in the context of TC, using a unique ex vivo model. Monocyte-derived cytokine responses were assessed in 29 PHTS patients and 29 controls. To assess the functional profile of TC-induced-macrophages, a co-culture model with two TC cell lines was performed. Rapamycin, a lactate transport blocker and metformin were used as modulators of the Akt-mTOR pathway and cell metabolism. Monocytes from PHTS patients showed increased production of IL-6, TNF-α, IL-8 and MCP-1, and higher lactate production. After co-culture with TC cell lines, TC-induced macrophages showed significantly increased production of cytokines in both patients and controls, especially after co-culture with a PTEN-deficient TC cell line; these effects were abolished after use of rapamycin or a lactate transport blocker. Metformin blocked the production of anti-inflammatory cytokines. In conclusion, innate immune cells from PHTS patients have increased lactate production and a more proinflammatory phenotype, especially after co-culture with PTEN-deficient TC. Metformin promotes a proinflammatory phenotype by blocking anti-inflammatory cytokine response, whereas rapamycin reduces production of proinflammatory cytokines. This indicates that PHTS patients may benefit from treatment with mTOR blocking agents to limit the inflammatory response in the tumor microenvironment.
Lynch Syndrome (LS) mutation carriers are at high risk for various cancer types, particularly colorectal cancer. Adherence to lifestyle and body weight recommendations for cancer prevention may lower ...this risk. To promote adherence to these recommendations, knowledge on determinants of adherence in LS mutation carriers is needed. Therefore, this study aimed to identify determinants of adherence to lifestyle recommendations for cancer prevention in LS mutation carriers.
Five focus groups were conducted with DNA confirmed LS mutation carriers (n = 29). Transcripts were analyzed by thematic analysis, using the Health Belief Model (HBM) as a theoretical framework.
Tolerance of an unhealthy lifestyle because of the desire to enjoy life and avoidance of LS dominating their life were most frequently reported as important barriers of adherence to the recommendations. Most important facilitators of adherence to the recommendations were enhancement of wellbeing and intolerance of unhealthy foods due to colon surgery.
This study provided a comprehensive overview of determinants of adherence to recommendations for cancer prevention. These determinants, of which some are typically and unique for LS mutation carriers, can be used to design a lifestyle intervention that meets the needs of LS mutation carriers.
The colorectal cancer spectrum has changed due to population screening programs, with a shift toward adenomas and early cancers. Whether it would be a feasible option to test these adenomas for ...detection of Lynch syndrome (LS) patients is unclear. Through meta-analysis and systematic review, risk factors for DNA mismatch repair deficiency (dMMR) and microsatellite instability (MSI) in adenomas were identified in LS and unselected patient cohorts. Data were extracted for patient age and MMR variant together with adenoma type, grade, size, and location. A total of 41 studies were included, and contained more than 519 LS patients and 1698 unselected patients with 1142 and 2213 adenomas respectively. dMMR/MSI was present in 69.5% of conventional adenomas in LS patients, compared with 2.8% in unselected patients. In the LS cohort, dMMR/MSI was more frequently present in patients older than 60 years (82% versus 54%). dMMR/MSI was also more common in villous adenomas (84%), adenomas over 1 cm (81%), and adenomas with high grade dysplasia (88%). No significant differences were observed for dMMR/MSI in relation to MMR variants and location of adenomas. In the context of screening, we conclude that detection of dMMR/MSI in conventional adenomas of unselected patients is uncommon and might be considered as indication for LS testing. Within the LS cohort, 69.5% of LS patients could have been detected through dMMR/MSI screening of their conventional adenomas.
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