Cancer risk and genotype-phenotype correlations in <em>PTEN</em> hamartoma tumor syndrome

Patients with germline PTEN mutations are at high risk of developing benign and malignant tumours. We aimed to evaluate the cumulative risk of several types of cancer and of dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease, LDD). In addition, genotype-phenotype correlations in PTEN hamartoma tumour syndrome (PHTS) were assessed. Data on patients with PTEN mutations were collected from clinical genetic centres in Western Europe, Australia, and the USA. The cumulative risk of developing cancers of the breast, thyroid, endometrium, skin, kidneys, colorectum, and lungs, and also LDD was calculated by Kaplan-Meier methods. Associations between mutations and cancer were assessed by Chi square means. A total of 180 germline PTEN mutation carriers, 81 males (45 %), from nine countries were included. The cumulative risk of developing any cancer and/or LDD at age 60 was 56 % for males and 87 % for females (p = 0.001). Females had significant higher risks of developing breast cancer, thyroid cancer, and LDD than males. The only genotype-phenotype correlation identified was a lower frequency of thyroid cancer in patients with missense mutations (p = 0.014). In conclusion, PHTS patients, particularly females, have a substantial risk of developing one or more tumours from a broad tumour spectrum. Major genotype-phenotype associations could not be identified

Cancer Risks for PMS2-Associated Lynch Syndrome (vol 29, pg 2961, 2018)

This corrects the article "Cancer Risks for PMS2-Associated Lynch Syndrome" in volume 36 on page 2961

Cancer Risks for PMS2-Associated Lynch Syndrome

PURPOSE: Lynch syndrome due to pathogenic variants in the DNA mismatch repair genes MLH1, MSH2, and MSH6 is predominantly associated with colorectal and endometrial cancer, although extracolonic cancers have been described within the Lynch tumor spectrum. However, the age-specific cumulative risk (penetrance) of these cancers is still poorly defined for PMS2-associated Lynch syndrome. Using a large data set from a worldwide collaboration, our aim was to determine accurate penetrance measures of cancers for carriers of heterozygous pathogenic PMS2 variants. METHODS: A modified segregation analysis was conducted that incorporated both genotyped and nongenotyped relatives, with conditioning for ascertainment to estimates corrected for bias. Hazard ratios (HRs) and corresponding 95% CIs were estimated for each cancer site for mutation carriers compared with the general population, followed by estimation of penetrance. RESULTS: In total, 284 families consisting of 4,878 first- and second-degree family members were included in the analysis. PMS2 mutation carriers were at increased risk for colorectal cancer (cumulative risk to age 80 years of 13% [95% CI, 7.9% to 22%] for males and 12% [95% CI, 6.7% to 21%] for females) and endometrial cancer (13% [95% CI, 7.0%-24%]), compared with the general population (6.6%, 4.7%, and 2.4%, respectively). There was no clear evidence of an increased risk of ovarian, gastric, hepatobiliary, bladder, renal, brain, breast, prostate, or small bowel cancer. CONCLUSION: Heterozygous PMS2 mutation carriers were at small increased risk for colorectal and endometrial cancer but not for any other Lynch syndrome-associated cancer. This finding justifies that PMS2-specific screening protocols could be restricted to colonoscopies. The role of risk-reducing hysterectomy and bilateral salpingo-oophorectomy for PMS2 mutation carriers needs further discussion