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UBC Theses and Dissertations

Hereditary diffuse gastric cancer : cancer risk and the personal cost of preventive surgery Kaurah, Pardeep Kaur


Germline CDH1 mutation carriers are at risk for early-onset diffuse gastric cancer and female carriers have an additional risk of lobular breast cancer. Reliable estimates of cancer risk are essential for genetic counselling and clinical management of mutation carriers. Prophylactic total gastrectomy (PTG) to eliminate the gastric cancer risk is an option for mutation carriers. Current information on post-surgical outcomes and quality of life is limited. The objectives of this research were 1) To improve the evidentiary basis of genetic counselling by deriving reliable estimates of cancer risk in CDH1 mutation carriers; 2) To catalogue a comprehensive list of all novel and previously reported germline mutations to date; and 3) To provide data on post-surgical clinical outcomes and to describe the impact of the surgery on participants’ quality of life. Methods: Penetrance was derived from 67 mutation-positive families comprising 4031 individuals (350 affected with gastric cancer and 99 with breast cancer). Participants were recruited through multiple sources for clinical outcomes and quality of life study. Hospital records provided information on clinical outcomes. All participants were asked to complete validated questionnaires measuring generic and condition specific QOL (PROMIS, EORTC and SF 36v.II) at a single point. Results: By age 75 years, the cumulative incidence of gastric cancer was 70% (95% confidence interval [CI], 40%-94%) for males and 56% (95% CI, 27%-90%) for females. The risk of breast cancer for females was 42% (95% CI, 23%-68%) by 75 years. The mutational landscape of CDH1 did not reveal mutational hotspots but several shared mutations are seen in unrelated families. The 53 participants who had undergone PTG reported frequent symptoms of fatigue (59%), abdominal pain (55%), and diarrhea (45%). Cognitive, role and social function plus the symptoms anxiety, pain, taste, dyspnea and diarrhea were significant predictor variables for quality of life (p<0.05). Conclusions: Our more precise and robust penetrance figures will improve genetic counselling of unaffected carriers. Although this study reveals good overall QOL for individuals after PTG, attention should be given to managing symptoms as part of long term care to further enhance quality of life.

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