Prospective enterprise-level molecular genotyping of a cohort of cancer patients.

Ongoing cancer genome characterization studies continue to elucidate the spectrum of genomic abnormalities that drive many cancers, and in the clinical arena assessment of the driver genetic alterations in patients is playing an increasingly important diagnostic and/or prognostic role for many cancer types. However, the landscape of genomic abnormalities is still unknown for less common cancers, and the influence of specific genotypes on clinical behavior is often still unclear. To address some of these deficiencies, we developed Profile, a prospective cohort study to obtain genomic information on all patients at a large tertiary care medical center for cancer-related care. We enrolled patients with any cancer diagnosis, and, for each patient (unselected for cancer site or type) we applied mass spectrometric genotyping (OncoMap) of 471 common recurrent mutations in 41 cancer-related genes. We report the results of the first 5000 patients, of which 26% exhibited potentially actionable somatic mutations. These observations indicate the utility of genotyping in advancing the field of precision oncology.

Human papillomavirus vaccination and cervical cytology in young minority women.

BACKGROUND: Continued surveillance of human papillomavirus (HPV) vaccination is necessary to identify clinical benefits, particularly given the low rate of vaccine uptake and completion and vaccination of many young women after sexual debut. We studied the effect of catch-up HPV vaccination on cervical cytology and HPV infection in sexually active, low-income and minority young women. METHODS: We conducted a cross-sectional study of 235 women aged 21 to 30 years undergoing routine cervical cytology testing. Demographic and behavioral characteristics were self-reported. HPV vaccination status was determined by self-report and verified with electronic medical records. Liquid-based cytology samples were tested for HPV genotypes. Adjusted prevalence ratios between HPV vaccination and (1) abnormal cervical cytology result and (2) HPV genotype were estimated. FINDINGS: At the time of the study, 96 women (41%) had received at least 1 HPV vaccination, 54 of whom had completed the series; 97% of women were vaccinated after sexual debut. Twenty-four (10%) women had an abnormal cervical cytology result. The prevalence of abnormal cytology was 65% lower in women who received at least 1 HPV vaccination versus unvaccinated women (adjusted prevalence ratio, 0.35; 95% confidence interval, 0.14-0.89). Among 232 women with genotype results, 46 (20%; 95% confidence interval, 15%-26%) had HPV infection detected. HPV types 16, 18, 45, 53, and 66 were most prevalent. CONCLUSIONS: The prevalence of abnormal cytology was lower in vaccinated versus unvaccinated women, despite receipt of vaccination after sexual debut. Continued assessment of HPV vaccine effectiveness before and after sexual debut on HPV infection and cervical dysplasia is needed.

Foreign fetal cells persist in the maternal circulation.

OBJECTIVE: To determine whether allogenic fetal cells resulting from donor egg pregnancies persist in maternal circulation. DESIGN: Nested polymerase chain reaction (PCR) amplification of the DYS14 sequence, a region of the Y chromosome, from DNA purified from peripheral blood cells. SETTING: Academic medical center. PATIENT(S): Healthy 18-60-year-old women who have had donor egg pregnancies resulting in a male offspring (n = 11) or, as a control, female offspring (n = 8), at least 1 year previously and without any other source for male cells in their peripheral blood or a healthy male. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Detection of DYS14 sequence by nested PCR. RESULT(S): DYS14 was detected in 5/11 (45%) of women who had donor egg pregnancies resulting in a male offspring, but in 0/8 (0) of women who had donor egg pregnancies resulting in a female offspring. The longest interval between delivery of a male offspring and detection of the DYS14 gene was 9 years. CONCLUSION(S): Unmatched, allogenic fetal cells from donor egg pregnancies are able to persist in the circulation of healthy women for at least 9 years after delivery. This implies a novel mechanism by which immunologic detection is avoided by these cells and may impact on how they may be used for regenerative and transplant medicine.

PIK3CA mutation in colorectal cancer: relationship with genetic and epigenetic alterations.

Somatic PIK3CA mutations are often present in colorectal cancer. Mutant PIK3CA activates AKT signaling, which up-regulates fatty acid synthase (FASN). Microsatellite instability (MSI) and CpG island methylator phenotype (CIMP) are important molecular classifiers in colorectal cancer. However, the relationship between PIK3CA mutation, MSI and CIMP remains uncertain. Using Pyrosequencing technology, we detected PIK3CA mutations in 91 (15%) of 590 population-based colorectal cancers. To determine CIMP status, we quantified DNA methylation in eight CIMP-specific promoters [CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1] by real-time polymerase chain reaction (MethyLight). PIK3CA mutation was significantly associated with mucinous tumors [P = .0002; odds ratio (OR) = 2.44], KRAS mutation (P < .0001; OR = 2.68), CIMP-high (P = .03; OR = 2.08), phospho-ribosomal protein S6 expression (P = .002; OR = 2.19), and FASN expression (P = .02; OR = 1.85) and inversely with p53 expression (P = .01; OR = 0.54) and beta-catenin (CTNNB1) alteration (P = .004; OR = 0.43). In addition, PIK3CA G-to-A mutations were associated with MGMT loss (P = .001; OR = 3.24) but not with MGMT promoter methylation. In conclusion, PIK3CA mutation is significantly associated with other key molecular events in colorectal cancer, and MGMT loss likely contributes to the development of PIK3CA G>A mutation. In addition, Pyrosequencing is useful in detecting PIK3CA mutation in archival paraffin tumor tissue. PIK3CA mutational data further emphasize heterogeneity of colorectal cancer at the molecular level.