Longitudinal Analysis of Cancer Risk in Children and Adults With Germline PTEN Variants

Abstract

ImportanceIdentifying hereditary cancer predisposition facilitates high-risk organ-specific cancer surveillance and prevention. In PTEN hamartoma tumor syndrome (PHTS), longitudinal studies remain lacking, and there are insufficient data on cancers in children and young adults, as well as individuals with neurodevelopmental disorders (NDD).ObjectiveTo evaluate lifetime cancer risks, including second malignant neoplasms (SMN), among patients with PHTS.Design, Setting, and ParticipantsProspective longitudinal cohort study (September 1, 2005, through January 6, 2022). General population risks from the Surveillance, Epidemiology, and End Results database. Patients with PHTS, molecularly defined as carrying germline PTEN variants, were accrued from community and academic medical centers throughout North America, South America, Europe, Australia, and Asia. Data were analyzed from July 2022 to February 2023.ExposuresReview of physical and electronic medical records, and follow-up through clinical visits or telephone interviews.Main Outcomes and MeasuresLifetime cancer risks in PHTS relative to the general population.ResultsA total of 7302 patients were prospectively accrued, 701 of whom had germline PTEN variants (median [IQR] age at consent, 38 [12-52] years; 413 female patients [59%]). Longitudinal follow-up data could be obtained for 260 patients (37%), with a median (IQR) follow-up of 4 (2-8) years. Of the 701 patients, 341 (49%) received at least 1 cancer diagnosis, with 144 (42%) of those having SMN. The study found significantly elevated lifetime risks for breast (91%), endometrial (48%), thyroid (33%), kidney (30%), and colorectal cancers (17%), as well as melanoma (5%). Cancer diagnoses were also observed in children and young adults with PHTS (15%) and in patients with PHTS with neurodevelopmental disorders (11%). Elevated risks (P < .001) of thyroid (age-adjusted standardized incidence ratios [SIR], 32.1; 95% CI, 26.0-39.0), kidney (SIR, 26.5; 95% CI, 18.8-36.3), endometrial (SIR, 26.0; 95% CI, 19.5-34.1), breast (SIR, 20.3; 95% CI, 17.3-23.7), and colorectal (SIR, 7.9; 95% CI, 5.2-11.7) cancers, and melanoma (SIR, 6.3; 95% CI, 3.5-10.5) were observed. Of the 341 patients with PHTS with cancer, 51 (15%) had 1 or more cancers diagnosed at age 29 years or younger, and 16 (31.4%) of those developed SMN at final follow-up. Twenty-three patients with PHTS with NDD and cancer were identified, with 5 (22%) having developed SMN at final follow-up. Individuals with PHTS and NDD showed higher lifetime cancer risks compared with individuals with PHTS but without NDD (hazard ratio, 2.7; 95% CI, 1.7-4.2; P < .001).Conclusions and RelevanceThis cohort study found consistently elevated lifetime cancer risks in PHTS. Organ-specific surveillance should continue in patients with PHTS. Additional study is required to ascertain elevated cancer risks in patients with PHTS with NDD.

The benefit of a complete reference genome for cancer structural variant analysis

“…B) IGV screenshot of an SV that was labeled as FN according to the benchmark by Valle-Inclan et al Our analysis calls removed thee SVs due to lack of evidence in all samples (Supplementary Table 13)Overall, the approach of incorporating alignment to CHM13-T2T followed by liftover analysis eliminated all FP somatic SV calls for COLO829. Such a reduction in FP has important impacts suppressors ITIH5, MAGI2, PTEN, WWOX, and cell-proliferation control gene TMX3(Bellon et al 2021;Cao et al 2020;Yehia et al 2023;Husanie et al 2022;Zhang et al 2019).…”

Genomic diversity in functionally relevant genes modifies neurodevelopmental versus neoplastic risks in individuals with germline PTEN variants

“…The models of NDD only/ASD only versus cancer were not adjusted for sex considering the male predominance in PHTS-NDD/ASD and the female predominance in PHTS-cancer due to the high prevalence of patients with breast cancer in PHTS. 13 The resulting performance of NDD vs. non-NDD model presented with 72% accuracy and 72% area under the curve (AUC), while the NDD only vs. cancer model presented with 65% accuracy and 67% AUC (Fig. 7a).…”

“…2a). Individuals in the PHTS-NDD group had a younger age at consent (median [IQR], 8 [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] years old) compared to PHTS-cancer (median [IQR], 50 [43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60] years old) and PHTS-other (median [IQR], 34 [16-45] years old) (Table 1). Male sex was overrepresented in the PHTS-NDD group (69%), while the female sex was overrepresented in the PHTS-cancer group (82%).…”

“…[2][3][4][5][6] It is, therefore, not surprising that germline PTEN alterations can give rise to a wide spectrum of clinical features associated with overgrowth, most notably macrocephaly and hamartomatous lesions involving various tissues, and higher lifetime risks of developing breast, thyroid, and other cancers. [7][8][9][10][11][12][13] Intriguingly, up to 17% of individuals with autism spectrum disorder (ASD) with macrocephaly are found to carry germline PTEN variants, and recent case studies suggest that up to 50% of children with PTEN variants are diagnosed with ASD. [14][15][16][17][18] PTEN is now considered one of the most common monogenic ASD-predisposition genes.…”

Lipidomic signatures of NAFLD/NASH progression to HCC in a murine model with conditional hepatocyte-specific Pten deletion

“…PTEN, located on chromosome 10q23, is the most commonly inactivated tumor suppressor gene and an important negative regulator of PI3K oncogenic signaling pathway. The frequency of somatic PTEN gene mutation is as high as 50%-80% in sporadic endometrial cancer, glioblastoma and prostate cancer, according to the Cancer Genome Atlas (TCGA) database, in addition to the germ-line PTEN gene mutation as observed in patients with the Cowden syndrome (concomitant with increased risk of obesity and cancer) [11]. In liver cancer, about 5-10% of patients contain PTEN gene mutations, and the combined rate of gene mutations in the PTEN / PI3K / AKT signaling pathway is 25% [12].…”