Aggregation of genome-wide common risk variants, such as polygenic risk score (PRS), can measure genetic susceptibility to cancer. A better understanding of how common germline variants associate with somatic alterations and clinical features could facilitate personalized cancer prevention and early detection. We constructed PRSs from 14 genome-wide association studies (median n = 64,905) for 12 cancer types by multiple methods and calibrated them using the UK Biobank resources (n = 335,048). Meta-analyses across cancer types in The Cancer Genome Atlas (n = 7,965) revealed that higher PRS values were associated with earlier cancer onset and lower burden of somatic alterations, including total mutations, chromosome/arm somatic copy-number alterations (SCNA), and focal SCNAs. This contrasts with rare germline pathogenic variants (e.g., BRCA1/2 variants), showing heterogeneous associations with somatic alterations. Our results suggest that common germline cancer risk variants allow early tumor development before the accumulation of many somatic alterations characteristic of later stages of carcinogenesis. Significance: Meta-analyses across cancers show that common germline risk variants affect not only cancer predisposition but the age of cancer onset and burden of somatic alterations, including total mutations and copy-number alterations.

Background: Gastric-type adenocarcinoma (GAS) of the uterine cervix is a rare malignancy with poor clinical outcomes. However, the carcinogenic processes involved remain unclear. Methods: Normal cervical glands, lobular endocervical glandular hyperplasia (LEGH), and GAS from the same patients were collected using laser microdissection for whole-exome sequencing. Single nucleotide variants (SNVs) and copy number alterations (CNAs) were analyzed. Phylogenetic trees were constructed based on the SNV and CNA profiles. Results: Analysis of seven matched samples demonstrated higher frequency of somatic mutations in the exonic regions in GAS than in LEGH. CNAs were prevalent in GAS but rare in LEGH. The phylogenetic analyses revealed various branching patterns. However, in three cases, the data suggested a sequential transition from LEGH to GAS, potentially associated with mutations in receptor-type protein tyrosine phosphatases such as PTPRF and PTPRT. STK11 and ARID1A mutations were present in LEGH, with an increased variant allele frequency observed in GAS. In contrast, SMAD4 and SMAD2 showed frequent loss-of-function–type alterations in GAS, including copy-number loss, but were not detected in LEGH. Conclusions: These findings provide insights into the genomic landscapes of LEGH and GAS and suggest potential molecular markers for this transition, which may inform future diagnostic and therapeutic research.

The Japanese government suspended its proactive recommendation for routine HPV vaccination for nine years, from June 2013 to May 2022, due to concerns about unconfirmed reports of adverse events. This study represents the fifth in our ongoing series of surveys assessing Japanese obstetricians’ and gynecologists’ attitudes toward HPV vaccination, and the first survey conducted since the recommendation was reinstated. In January 2024, we distributed a questionnaire to 632 obstetricians and gynecologists affiliated with Osaka University Hospital. The survey evaluated their attitudes toward HPV vaccination for both daughters and sons. A total of 348 specialists (55.1%) responded. After the government resumed its proactive recommendation, approximately 90% of their daughters had received or planned to receive the HPV vaccine. Among daughters eligible for catch-up vaccination, 71.4% had been vaccinated. Over 70% of respondents agreed that boys should also routinely receive HPV vaccination. Among those with sons aged 12 to 16 at the time of approval for boys, 12.5% had vaccinated them. Most respondents ensured HPV vaccination for their daughters, and some for their sons. Encouraging physicians from other specialties to do the same may help promote widespread HPV vaccine uptake in Japan.

Figures S1–S11, Tables S1–S6, Supplementary Materials and Methods, Supplementary Notes, and Supplementary References

Figures S1–S11, Tables S1–S6, Supplementary Materials and Methods, Supplementary Notes, and Supplementary References