Quiz Ref ID Gastric cancer (GC) is the third most common cause of cancer-related mortality worldwide.¹ The 2 major subtypes, diffuse GC (DGC) and intestinal-type GC, are distinguished by molecular, epidemiologic, and morphologic features.² Although GC is usually sporadic, familial aggregation occurs in approximately 10% of cases.^3,4 Quiz Ref ID Clinically defined hereditary DGC (HDGC) (OMIM #137215) is characterized by early-onset, multigenerational DGC and lobular breast cancer. Clinical criteria for this entity was established by the International Gastric Cancer Linkage Consortium (IGCLC) (Table 1).^5,6 Approximately 40% of HDGC families have germline mutations in CDH1 (E-cadherin) (Ensembl ENSG00000039068; OMIM *192090), and over 100 different pathogenic germline mutations are reported across multiple ethnicities (eTable 1 in the Supplement).

Cancer is in large part a genetic disease in the sense that acquired (somatic) mutations in tumor DNA contribute substantially to the malignant phenotype. Massively parallel (next-generation) sequencing makes it practical to define the spectrum of mutations in an individual cancer. Clinical researchers and practicing oncologists use tumor mutation profiling to guide treatment decisions and to determine patient eligibility for studies of targeted agents.¹

Objective: The purpose of this study was the clinical and pathological characterisation of a new autosomal dominant gastric polyposis syndrome, gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS). Methods: Case series were examined, documenting GAPPS in three families from Australia, the USA and Canada. The affected families were identified through referral to centralised clinical genetics centres. Results: The report identifies the clinical and pathological features of this syndrome, including the predominant dysplastic fundic gland polyp histology, the exclusive involvement of the gastric body and fundus, the apparent inverse association with current Helicobacter pylori infection and the autosomal dominant mode of inheritance. Conclusions: GAPPS is a unique gastric polyposis syndrome with a significant risk of gastric adenocarcinoma. It is characterised by the autosomal dominant transmission of fundic gland polyposis, including areas of dysplasia or intestinal-type gastric adenocarcinoma, restricted to the proximal stomach, and with no evidence of colorectal or duodenal polyposis or other heritable gastrointestinal cancer syndromes.

Purpose: Recent studies have identified mutation signatures of homologous recombination deficiency (HRD) in over 20% of breast cancers, as well as pancreatic, ovarian, and gastric cancers. There is an urgent need to understand the clinical implications of HRD signatures. Whereas BRCA1/2 mutations confer sensitivity to platinum-based chemotherapies, it is not yet clear whether mutation signatures can independently predict platinum response. Experimental Design: In this observational study, we sequenced tumor whole genomes (100× depth) and matched normals (60×) of 93 advanced-stage breast cancers (33 platinum-treated). We computed a published metric called HRDetect, independently trained to predict BRCA1/2 status, and assessed its capacity to predict outcomes on platinum-based chemotherapies. Clinical endpoints were overall survival (OS), total duration on platinum-based therapy (TDT), and radiographic evidence of clinical improvement (CI). Results: HRDetect predicted BRCA1/2 status with an area under the curve (AUC) of 0.94 and optimal threshold of 0.7. Elevated HRDetect was also significantly associated with CI on platinum-based therapy (AUC = 0.89; P = 0.006) with the same optimal threshold, even after adjusting for BRCA1/2 mutation status and treatment timing. HRDetect scores over 0.7 were associated with a 3-month extended median TDT (P = 0.0003) and 1.3-year extended median OS (P = 0.04). Conclusions: Our findings not only independently validate HRDetect, but also provide the first evidence of its association with platinum response in advanced breast cancer. We demonstrate that HRD mutation signatures may offer clinically relevant information independently of BRCA1/2 mutation status and hope this work will guide the development of clinical trials. Clin Cancer Res; 23(24); 7521–30. ©2017 AACR.