Aligning Germline Cancer Predisposition With Tumor-Based Next-Generation Sequencing for Modern Oncology Diagnosis, Interception, and Therapeutic Development

Abstract

In the era of precision medicine, genomic interrogation for identification of both germline and somatic genetic alterations has become increasingly important. While such germline testing was usually undertaken via a phenotype-driven single-gene approach, with the advent of next-generation sequencing (NGS) technologies, the widespread utilization of multigene panels, often agnostic of cancer phenotype, has become a commonplace in many different cancer types. At the same time, somatic tumor testing in oncology performed for the purpose of guiding therapeutic decisions for targeted therapies has also rapidly expanded, recently starting to incorporate not just patients with recurrent or metastatic cancer but even patients with early-stage disease. An integrated approach may be the best approach for the optimal management of patients with different cancers. The lack of complete congruence between germline and somatic NGS tests does not minimize the power or importance of either, but highlights the need to understand their limitations so as not to overlook an important finding or omission. NGS tests built to more uniformly and comprehensively evaluate both the germline and tumor simultaneously are urgently required and are in development. In this article, we discuss approaches to somatic and germline analyses in patients with cancer and the knowledge gained from integration of tumor-normal sequencing. We also detail strategies for the incorporation of genomic analysis into oncology care delivery models and the important emergence of poly(ADP-ribose) polymerase and other DNA Damage Response inhibitors in the clinic for patients with cancer with germline and somatic BRCA1 and BRCA2 mutations.

Case report: A germline CHEK1 c.613 + 2T>C leads to a splicing error in a family with multiple cancer patients

“…While the CHEK1 gene is included in some commercial NGS panels designed for assessing hereditary cancer risk ( 49 ), the available data regarding germline CHEK1 mutations and cancer risk are limited. In a study involving 48 women with inherited ovarian cancer lacking BRCA1 or BRCA2 mutations, a CHEK1 exon 7 c.1564-1565insA frameshift mutation was identified ( 50 ).…”

Understanding the Genetic Landscape of Pancreatic Ductal Adenocarcinoma to Support Personalized Medicine: A Systematic Review

“…In the era of precision medicine, the integration of germline and somatic genetic profiling is gaining a central role in medical oncology. Indeed, germline and somatic genetic testing may help personalize therapeutic decisions for targeted therapies according to each patient’s mutational status [ 230 ]. Moreover, germline characterization of genetic variants underlying cancer susceptibility may enable the identification of individuals at risk of developing a particular cancer and guide precision prevention strategies [ 231 ].…”

Workforce Implications of Increased Referrals to Hereditary Cancer Services in Canada: A Scenario-Based Analysis

“…In addition to the expected growth in eligibility for hereditary cancer services, it is also worth considering the implications of a potential acceleration in the move towards integrating hereditary cancer genetics into oncology clinics. On the one hand, commercial next generation sequencing (NGS)-based tumour testing panels often include numerous genes linked to hereditary cancer [ 22 ] and recent studies have found that 4.3%–16% of patients undergoing tumour testing have been found to carry pathogenic (P) or likely pathogenic (LP) germline variants [ 23 ]. Given this overlap and the growing relevance of germline variants to treatment selection, greater integration of tumour and germline testing may be advisable [ 23 ].…”

“…On the one hand, commercial next generation sequencing (NGS)-based tumour testing panels often include numerous genes linked to hereditary cancer [ 22 ] and recent studies have found that 4.3%–16% of patients undergoing tumour testing have been found to carry pathogenic (P) or likely pathogenic (LP) germline variants [ 23 ]. Given this overlap and the growing relevance of germline variants to treatment selection, greater integration of tumour and germline testing may be advisable [ 23 ]. Our workforce requirements model takes this dynamic into account through Pathway 6 ( Figure 1 ), which in the base case assumes that 11.5% of new cancer patients receive tumour testing and P/LP germline mutations are detected in 3% of those patients, which leads to Pathway 6 only accounting for about 1% of the caseload and <1% of FTE requirements.…”

“…However, while the 11.5% tumour testing rate was calculated based on comprehensive country-wide data from France [ 24 ], it reflects practice as of 2017, and the 3% germline variant estimate is from 2015 [ 25 ]. If either statistic increases by 2030 (which appears likely based on more recent studies [ 23 ]), the impact of germline P/LP variants detected through somatic testing on overall hereditary cancer clinics’ workforce requirements could increase significantly.…”