Lee, William

PURPOSE The Lynch syndrome (LS) genes, MLH1 , MSH2 , MSH6 , and PMS2 , are considered to be some of the highest-priority genes to be tested for population genomic screening, with the aim to prevent and detect cancers early in those with a higher risk for such diagnoses. The objective of this study was to determine the risk of cancer associated with pathogenic variants in MLH1 , MSH2 , MSH6 , or PMS2 in the general population to build evidence-based guidelines for population genomic screening METHODS This retrospective case-control study uses Helix Research Network data from 230,159 participants across nine US health systems. Variant interpretation was performed following the American College of Medical Genetics and Association for Molecular Pathology guidelines. Clinical diagnoses were identified from electronic health records and claims data for 11 cancer types associated with LS, including colorectal and endometrial cancers. RESULTS Individuals with pathogenic variants in MLH1 , MSH2 , and MSH6 showed substantial risk for LS-related cancers compared with those without pathogenic variants. Conversely, individuals with pathogenic variants in PMS2 had no increase in risk for all 11 LS-associated cancers with hazard ratio (HR) of 1.0 (95% CI, 0.6 to 1.8) compared with those without a pathogenic variant. There was a small increase in risk when restricting the analysis to colorectal cancer with an HR of 3.5 (1.7-7.4). This increase in colorectal cancer risk was predominantly observed after age 60 years, 10 years after US Preventive Services Task Force guidelines recommend starting colonoscopies for the average population. Up to age 60 years, 2.6% of individuals with PMS2 pathogenic variants were diagnosed with colorectal cancer, closer to the general population (0.7%) than those with MLH1 (37.3%), MSH2 (28.9%), or MSH6 (6.7%) pathogenic variants. For 100,000 individuals screened for PMS2 , 854 additional colonoscopies would be performed, which would prevent or detect early 3.2 colorectal cancers. CONCLUSION This analysis across nine health systems highlights the clinical phenotypes of PMS2 pathogenic germline variants in the entire population.

Chromophobe renal cell carcinoma (chRCC) typically shows ~7 chromosome losses (1, 2, 6, 10, 13, 17, and 21) and ~31 exonic somatic mutations, yet carries ~5%–10% metastatic incidence. Since extensive chromosomal losses can generate proteotoxic stress and compromise cellular proliferation, it is intriguing how chRCC, a tumor with extensive chromosome losses and a low number of somatic mutations, can develop lethal metastases. Genomic features distinguishing metastatic from nonmetastatic chRCC are unknown. An integrated approach, including whole-genome sequencing (WGS), targeted ultradeep cancer gene sequencing, and chromosome analyses (FACETS, OncoScan, and FISH), was performed on 79 chRCC patients including 38 metastatic (M-chRCC) cases. We demonstrate that TP53 mutations (58%), PTEN mutations (24%), and imbalanced chromosome duplication (ICD, duplication of ≥ 3 chromosomes) (25%) were enriched in M-chRCC. Reconstruction of the subclonal composition of paired primary-metastatic chRCC tumors supports the role of TP53 , PTEN , and ICD in metastatic evolution. Finally, the presence of these 3 genomic features in primary tumors of both The Cancer Genome Atlas kidney chromophobe (KICH) ( n = 64) and M-chRCC ( n = 35) cohorts was associated with worse survival. In summary, our study provides genomic insights into the metastatic progression of chRCC and identifies TP53 mutations, PTEN mutations, and ICD as high-risk features.

AbstractHomologous recombination (HR) DNA repair‐deficient (HRD) breast cancers have been shown to be sensitive to DNA repair targeted therapies. Burgeoning evidence suggests that sporadic breast cancers, lacking germline BRCA1/BRCA2 mutations, may also be HRD. We developed a functional ex vivo RAD51‐based test to identify HRD primary breast cancers. An integrated approach examining methylation, gene expression, and whole‐exome sequencing was employed to ascertain the aetiology of HRD. Functional HRD breast cancers displayed genomic features of lack of competent HR, including large‐scale state transitions and specific mutational signatures. Somatic and/or germline genetic alterations resulting in bi‐allelic loss‐of‐function of HR genes underpinned functional HRD in 89% of cases, and were observed in only one of the 15 HR‐proficient samples tested. These findings indicate the importance of a comprehensive genetic assessment of bi‐allelic alterations in the HR pathway to deliver a precision medicine‐based approach to select patients for therapies targeting tumour‐specific DNA repair defects. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

513 Background: Chromophobe renal cell carcinoma (chRCC) is the third most common histologic subtype of kidney cancer. While most of these tumors have an indolent behavior, 7% of patients with chRCC develop metastases, with no currently available standard of care. The Cancer Genome Atlas characterized chRCC, highlighting pathognomonic single copy chromosomal losses of 1, 2, 6, 10, 13 and 17, as well as a minimal mutation burden distinguishing it from all other cancer types. However, only 15% of the analyzed patients had advanced disease. We analyzed metastatic chRCC to further characterize these tumors and elucidate mechanisms leading to aggressive disease using a variety of next generation and whole genome sequencing. Methods: Our cohort of metastatic chRCC consisted of 40 patients with available clinical and pathologic data. Whole genome sequencing (WGS) was performed on 6 patients (4 primary tumors and 2 metastases), 42 additional samples from 33 patients were analyzed using targeted next-generation sequencing (MSK-IMPACT). Notably, we were able to collect and analyze matched primary and metastatic tumors from 7 patients. As control cohort 27 non-metastatic chRCC tumors were sequenced with MSK-IMPACT. Copy number patterns were computed with OncoSNP seq and FACETS. Results: The most commonly mutated genes in the aggressive chRCC tumors were TP53 and PTEN (WGS: TP53 67 %, PTEN 33%; MSK-IMPACT: TP53 61%, PTEN 27%). No other genes were mutated frequently. Primary tumor samples of chRCC did show the typical pattern of chromosomal losses in 1, 2, 6, 10, 13 and 17. Interestingly, these canonical losses could not be detected in the metastases even when accounting for tumor purity. Conclusions: TP53 and PTEN mutations are highly enriched in both primary and metastatic tumors of aggressive chRCC compared to the non-aggressive tumors and likely play a critical role in disease progression. More intriguingly, the observation of differential copy numbers in matched primary and metastatic tumors suggest whole genome or whole chromosome events in these samples. We are currently employing different bioinformatic and cytogenetic platforms to validate our novel hypothesis of chromosomal events as driver for metastatic development in chRCC.